1. Genetics and Genomics
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Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994

  1. Aline Jelenkovic  Is a corresponding author
  2. Yoon-Mi Hur
  3. Reijo Sund
  4. Yoshie Yokoyama
  5. Sisira H Siribaddana
  6. Matthew Hotopf
  7. Athula Sumathipala
  8. Fruhling Rijsdijk
  9. Qihua Tan
  10. Dongfeng Zhang
  11. Zengchang Pang
  12. Sari Aaltonen
  13. Kauko Heikkilä
  14. Sevgi Y Öncel
  15. Fazil Aliev
  16. Esther Rebato
  17. Adam D Tarnoki
  18. David L Tarnoki
  19. Kaare Christensen
  20. Axel Skytthe
  21. Kirsten O Kyvik
  22. Judy L Silberg
  23. Lindon J Eaves
  24. Hermine H Maes
  25. Tessa L Cutler
  26. John L Hopper
  27. Juan R Ordoñana
  28. Juan F Sánchez-Romera
  29. Lucia Colodro-Conde
  30. Wendy Cozen
  31. Amie E Hwang
  32. Thomas M Mack
  33. Joohon Sung
  34. Yun-Mi Song
  35. Sarah Yang
  36. Kayoung Lee
  37. Carol E Franz
  38. William S Kremen
  39. Michael J Lyons
  40. Andreas Busjahn
  41. Tracy L Nelson
  42. Keith E Whitfield
  43. Christian Kandler
  44. Kerry L Jang
  45. Margaret Gatz
  46. David A Butler
  47. Maria A Stazi
  48. Corrado Fagnani
  49. Cristina D'Ippolito
  50. Glen E Duncan
  51. Dedra Buchwald
  52. Catherine A Derom
  53. Robert F Vlietinck
  54. Ruth JF Loos
  55. Nicholas G Martin
  56. Sarah E Medland
  57. Grant W Montgomery
  58. Hoe-Uk Jeong
  59. Gary E Swan
  60. Ruth Krasnow
  61. Patrik KE Magnusson
  62. Nancy L Pedersen
  63. Anna K Dahl-Aslan
  64. Tom A McAdams
  65. Thalia C Eley
  66. Alice M Gregory
  67. Per Tynelius
  68. Laura A Baker
  69. Catherine Tuvblad
  70. Gombojav Bayasgalan
  71. Danshiitsoodol Narandalai
  72. Paul Lichtenstein
  73. Timothy D Spector
  74. Massimo Mangino
  75. Genevieve Lachance
  76. Meike Bartels
  77. Toos CEM van Beijsterveldt
  78. Gonneke Willemsen
  79. S Alexandra Burt
  80. Kelly L Klump
  81. Jennifer R Harris
  82. Ingunn Brandt
  83. Thomas Sevenius Nilsen
  84. Robert F Krueger
  85. Matt McGue
  86. Shandell Pahlen
  87. Robin P Corley
  88. Jacob v B Hjelmborg
  89. Jack H Goldberg
  90. Yoshinori Iwatani
  91. Mikio Watanabe
  92. Chika Honda
  93. Fujio Inui
  94. Finn Rasmussen
  95. Brooke M Huibregtse
  96. Dorret I Boomsma
  97. Thorkild I A Sørensen
  98. Jaakko Kaprio
  99. Karri Silventoinen
  1. University of Helsinki, Finland
  2. University of the Basque Country, Spain
  3. Mokpo National University, South Korea
  4. Osaka City University, Japan
  5. Institute of Research & Development, Sri Lanka
  6. Rajarata University of Sri Lanka, Sri Lanka
  7. NIHR Mental Health Biomedical Research Centre, South London and Maudsley NHS Foundation Trust and, Institute of Psychiatry Psychology and Neuroscience, King's College London, United Kingdom
  8. Keele University, United Kingdom
  9. King's College London, United Kingdom
  10. Institute of Public Health, University of Southern Denmark, Denmark
  11. Qingdao University Medical College, China
  12. Qingdao Centers for Disease Control and Prevention, China
  13. Kirikkale University, Turkey
  14. Karabuk University, Turkey
  15. Virginia Commonwealth University, United States
  16. Semmelweis University, Hungary
  17. Hungarian Twin Registry, Hungary
  18. University of Southern Denmark, Denmark
  19. Odense University Hospital, Denmark
  20. The University of Melbourne, Australia
  21. Seoul National University, Korea
  22. University of Murcia, Spain
  23. IMIB-Arrixaca, Spain
  24. QIMR Berghofer Medical Research Institute, Australia
  25. University of Southern California, United States
  26. USC Norris Comprehensive Cancer Center, United States
  27. Seoul National University, South-Korea
  28. Sungkyunkwan University School of Medicine, South-Korea
  29. Inje University College of Medicine, Korea
  30. University of California, San Diego, United States
  31. VA San Diego Center of Excellence for Stress and Mental Health, United States
  32. Boston University, United States
  33. HealthTwiSt GmbH, Germany
  34. Colorado State University, United States
  35. Duke University, United States
  36. Bielefeld University, Germany
  37. University of British Columbia, Canada
  38. Karolinska Institutet, Sweden
  39. The National Academies of Sciences, Engineering, and Medicine, United States
  40. Istituto Superiore di Sanità - National Center for Epidemiology, Surveillance and Health Promotion, Italy
  41. Washington State University - Health Sciences Spokane, United States
  42. Washington State University, United States
  43. University Hospitals Leuven, Belgium
  44. Ghent University Hospitals, Belgium
  45. Icahn School of Medicine at Mount Sinai, United States
  46. Stanford University School of Medicine, United States
  47. SRI International, United States
  48. Jönköping University, Sweden
  49. Goldsmiths, University of London, United Kingdom
  50. Örebro University, Sweden
  51. Healthy Twin Association of Mongolia, Mongolia
  52. Hiroshima University, Japan
  53. King's College, United Kingdom
  54. VU University Amsterdam, Netherlands
  55. Michigan State University, United States
  56. Norwegian Institute of Public Health, Norway
  57. University of Minnesota, United States
  58. University of Colorado, United States
  59. University of Washington, United States
  60. Osaka University, Japan
  61. Kio University, Japan
  62. University of Copenhagen, Denmark
  63. Bispebjerg and Frederiksberg Hospitals, Denmark
  64. Institute for Molecular Medicine FIMM, Finland
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Cite this article as: eLife 2016;5:e20320 doi: 10.7554/eLife.20320

Abstract

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.

https://doi.org/10.7554/eLife.20320.001

Introduction

Height is a classic anthropometric quantitative trait in humans due to its ease of measurement, approximately normal distribution and relative stability in adulthood. Since the studies of height in the late 19th and early 20th centuries (Galton, 1886; Pearson and Lee, 1903; Fisher, 1919), twin, adoption and family studies have shown that height is one of the most heritable human quantitative phenotypes (Silventoinen, 2003). More recently, genetic linkage studies have helped to elucidate the location of genetic effects in the genome (Perola et al., 2007) and genome-wide association (GWA) studies allowed identification of loci consistently associated with height in populations of different ancestry (Cho et al., 2009; Hao et al., 2013; Lango Allen et al., 2010; N'Diaye et al., 2011; Wood et al., 2014). Besides the genetic factors, a multitude of environmental factors, such as nutrition and childhood diseases, operate during the growth period and can affect the final attained height. These and other proximate biological determinants of height are further associated with social and economic conditions, which in turn are associated with living standards (Bozzoli et al., 2009; Bogin, 2001; Eveleth and Tanner, 1990; Steckel, 2009). The secular trend of increasing height over the 20th century observed in many parts of the world, which has slowed or stopped in most northern European countries, probably reflects the continuous improvement in the standard of living (Eveleth and Tanner, 1990; Cole, 2003; Stulp and Barrett, 2016). A recent study showed that the height difference between the tallest and shortest populations a century ago (19–20 cm) has remained the same for women and increased for men (NCD Risk Factor Collaboration (NCD-RisC), 2016) .

Twin and family studies have consistently estimated that the proportion of variation in adult height explained by genetic differences between individuals, or heritability, in general populations is approximately 0.80 (Fisher, 1919Silventoinen et al., 2003Stunkard et al., 1986). There is a hypothesis that heritability is not constant and can differ in environments having different amount of environmental variation. Accordingly, it has been suggested that heritability of height is lower in populations with low living standards compared with affluent populations since poverty can lead to a lack of basic necessities important for human growth in part of the population (Steckel, 2009). However, there is little direct evidence on this issue. A study in Finnish twins born between 1900 and 1957 showed that the heritability of height increased across birth cohorts born in the first half of the century when the standard of living increased and leveled off after World War II thus supporting this hypothesis (Silventoinen et al., 2000). Because this result needs to be replicated, we conducted an individual-based analysis of 40 twin cohorts from 20 countries. We aimed to analyze (i) the genetic and environmental contribution to the variation of adult height across nine birth-year cohorts covering more than 100 years and (ii) to assess whether the pattern varies by geographic-cultural region (Europe, North America and Australia, and East Asia).

Results

In the pooled data (all twin cohorts together), mean height was greater in men than in women and increased over the birth-year cohorts in both sexes; the decrease ( > 1 cm) observed in the latest birth cohort mainly reflects differences in the distribution of different twin cohorts within each group (Table 1). Both means and variances were significantly different between twin cohorts in all birth-year and sex groups. Mean height was shorter in East Asia than in Europe and North America and Australia in all birth-year and sex groups. The increase in mean height over the birth cohorts (from 1940–1949 to 1980–1994) was substantially greater in East Asia than in the other two geographic-cultural regions. The variance of height was generally greater in men than in women, lowest in East Asia and greatest in North America and Australia, and showed a general trend to increase over the birth cohorts.

Table 1

Descriptive statistics of age and height by sex, birth year and geographic-cultural region. Names list of the participating twin cohorts in this study: two cohorts from Australia (Australian Twin Registry and Queensland Twin Register), six cohorts from East-Asia (Korean Twin-Family Register, Mongolian Twin Registry, Osaka University Aged Twin Registry, South Korea Twin Registry, Qingdao Twin Registry of Adults and West Japan Twins and Higher Order Multiple Births Registry), 18 cohorts from Europe (Adult Netherlands Twin Registry, Berlin Twin Register, Bielefeld Longitudinal Study of Adult Twins, Danish Twin Cohort, East Flanders Prospective Twin Survey, Finnish Older Twin Cohort, FinnTwin12, FinnTwin16, Genesis 12–19 Study, Hungarian Twin Registry, Italian Twin Registry, Murcia Twin Registry, Norwegian Twin Registry, Swedish Twin Cohorts, Swedish Young Male Twins Study of Adults, TCHAD-study, TwinsUK and Young Netherlands Twin Registry), two cohorts from South-Asia and Middle-East (Sri Lanka Twin Registry and Turkish Twin Study) and 12 cohorts from North-America (California Twin Program, Carolina African American Twin Study of Aging, Colorado Twin Registry, Michigan State University Twin Registry, Mid Atlantic Twin Registry, Minnesota Twin Registry, NAS-NRC Twin Registry, SRI-international, University of British Columbia Twin Project, University of Southern California Twin Study, University of Washington Twin Registry and Vietnam Era Twin Study of Aging).

https://doi.org/10.7554/eLife.20320.002

Age

Height

All cohorts

All cohorts

Europe

NA and Australia

East Asia

Birth year

Mean

SD

Range

N

Mean (F, p-value)*

SD (F, p-value)

N

Mean

SD

N

Mean

SD

N

Mean

SD

Men

1886–1909

67.0

7.5

53.5–99.2

3747

171.6 (15, < 0.001)

6.34 (2.5,0.019)

3569

171.5

6.27

178

174.6

6.88

1910–1919

52.2

16.2

20.0–95.8

9171

174.2 (23, < 0.001)

6.72 (5.0,<0.001)

4117

173.3

6.37

5052

174.9

6.91

1920–1929

51.6

16.1

20.0–90.9

23147

175.4 (62, < 0.001)

6.81 (5.7,<0.001)

6382

173.9

6.42

16714

176.0

6.82

1930–1939

57.5

10.5

33.5–83.2

12028

175.7 (413, < 0.001)

6.70 (2.9,<0.001)

9308

175.2

6.42

2658

178.1

6.78

1940–1949

49.3

10.6

23.5–73.9

22967

177.4 (72, < 0.001)

6.73 (2.5,<0.001)

16629

177.0

6.53

6235

178.4

6.95

68

164.8

6.57

1950–1959

41.4

10.0

19.5–65.0

24560

178.4 (120, < 0.001)

6.96 (6.5,<0.001)

15199

178.5

6.73

9124

178.7

7.04

161

167.1

4.79

1960–1969

35.5

7.1

19.5–54.0

13264

179.0 (99, < 0.001)

7.49 (2.3,<0.001)

6218

179.6

7.04

6574

179.2

7.22

298

168.1

6.24

1970–1979

28.7

5.4

19.5–44.0

14975

179.9 (121, < 0.001)

7.55 (5.5,<0.001)

10339

180.7

7.01

3906

179.7

7.51

456

170.1

5.68

1980–1994

23.1

3.2

19.5–34.4

9948

178.4 (70, < 0.001)

7.59 (4.9,<0.001)

5077

178.8

7.22

4066

179.4

7.49

329

173.1

6.37

Women

1886–1909

68.5

8.1

53.5–98.0

5423

160.2 (23, < 0.001)

6.14 (3.3,0.006)

5011

160.2

6.11

412

160.2

6.41

1910–1919

62.0

10.9

43.6–95.9

7169

161.1 (18, < 0.001)

5.93 (2.5,0.002)

5621

161.0

5.85

1548

161.2

6.20

1920–1929

59.7

11.4

37.5–91.7

10975

162.1 (65, < 0.001)

5.99 (3.8,<0.001)

7908

162.0

5.89

3052

162.4

6.16

1930–1939

57.9

10.0

33.5–83.0

14610

162.7 (249, < 0.001)

6.05 (5.8,<0.001)

11226

162.5

5.83

3344

163.2

6.49

1940–1949

49.9

10.2

23.5–74.0

28537

163.7 (175, < 0.001)

6.19 (10.3,<0.001)

20097

163.9

5.93

8285

163.5

6.57

100

153.6

5.33

1950–1959

41.3

9.5

19.5–64.0

31250

164.4 (146, < 0.001)

6.58 (13.6,<0.001)

18817

164.8

6.22

12080

164.1

6.78

225

155.1

5.10

1960–1969

35.8

6.9

19.5–54.3

20422

165.1 (163, < 0.001)

7.00 (8.6,<0.001)

9604

166.2

6.58

10182

164.6

6.87

438

156.8

5.17

1970–1979

29.3

5.4

19.5–44.3

19893

165.9 (180, < 0.001)

7.27 (11.5,<0.001)

11819

167.3

6.67

7034

165.0

7.22

718

158.5

5.58

1980–1994

23.4

3.3

19.5–34.3

14694

164.7 (118, < 0.001)

7.07 (6.2,<0.001)

7291

165.6

6.77

6274

164.9

6.96

633

159.8

5.74

  1. *Welch ANOVA test for equality of means

  2. Levene’s test for equality of variances; SD: standard deviation

The variance of adult height explained by additive genetic, shared environmental and unique environmental factors by birth-year cohorts is presented in Figure 1 (estimates with 95% confidence intervals (CIs) are available in Supplementary file 1A). In men, there was a trend for an increasing total variance from birth cohort 1940–1949 onwards; genetic variance also increased during this period but especially in the two latest birth-year cohorts (1970–1979 and 1980–1994). Height variance due to the environment shared by co-twins was significant from birth cohorts 1920–1929 to 1970–1979, being greatest from 1950 to 1969. The effect of environmental factors unique to each twin individual including measurement error was more similar across birth-year cohorts. Heritability estimates ranged from 0.69 to 0.84 and were greatest in the two earliest and the two latest birth-year cohorts (Table 2). In women, although the total variance also started to increase from birth cohort 1940–1949, genetic variance showed an increasing trend from the earliest birth-year cohort. Both shared and unique environmental factors explained variation in height in all analyzed birth-year cohorts; whereas the shared environmental variance was somewhat greater in the latest cohorts (1970–1979 and 1980–1994) unique environmental variance was greatest in the earliest one. Although the variance components differed between sexes in all birth-year cohorts, the relative contribution of the genetic and environmental variance components did not differ by sex from 1930–1939 to 1960–1969 (Supplementary file1B). In contrast to the results in men, heritability estimates in women (0.53 to 0.78) were lowest in the earliest and latest cohorts, particularly in 1886–1909. When we studied the effect of birth year on the genetic variance by using gene-environment interaction models, modest but statistically significant increase was found. The interaction effect was 0.050 (95% CI 0.018–0.082) in men and 0.043 (95% CI 0.019–0.071) in women for the genetic path coefficient per 10 years. This turns to 1.37 (95% CI 0.50–2.27) increase of genetic variance in men and 1.07 (95% CI 0.46–1.79) increase of genetic variance in women per 25 years, i.e. approximately one human generation.

Additive genetic (grey), shared environmental (black) and unique environmental (white) variances of height across birth-year cohorts for the pooled data and by geographic-cultural region.
https://doi.org/10.7554/eLife.20320.003
Table 2

Proportion of the height variance explained by additive genetic, shared environmental and unique environmental factors by birth year, sex and geographic-cultural region.

https://doi.org/10.7554/eLife.20320.004

Men

Women

Additive genetics

Shared environment

Unique environment

Additive genetics

Shared environment

Unique environment

Birth year

A

95% CIs

C

95% CIs

E

95% CIs

A

95% CIs

C

95% CIs

E

95% CIs

All cohorts

1886–1909

0.78

0.69

0.80

0.00

0.00

0.08

0.22

0.20

0.25

0.53

0.43

0.62

0.13

0.05

0.21

0.34

0.31

0.37

1910–1919

0.82

0.76

0.87

0.04

0.00

0.10

0.14

0.13

0.15

0.67

0.60

0.74

0.11

0.04

0.18

0.22

0.20

0.24

1920–1929

0.72

0.69

0.76

0.14

0.10

0.17

0.14

0.13

0.15

0.70

0.64

0.76

0.12

0.07

0.18

0.18

0.17

0.19

1930–1939

0.73

0.68

0.79

0.10

0.04

0.16

0.16

0.15

0.18

0.74

0.68

0.79

0.11

0.06

0.16

0.15

0.14

0.16

1940–1949

0.74

0.70

0.78

0.13

0.09

0.17

0.13

0.12

0.13

0.78

0.75

0.82

0.09

0.05

0.13

0.13

0.12

0.13

1950–1959

0.72

0.69

0.76

0.16

0.12

0.20

0.12

0.11

0.12

0.73

0.69

0.76

0.15

0.11

0.18

0.12

0.12

0.13

1960–1969

0.69

0.63

0.76

0.16

0.09

0.21

0.15

0.14

0.16

0.70

0.66

0.75

0.14

0.09

0.18

0.16

0.15

0.17

1970–1979

0.77

0.72

0.83

0.11

0.06

0.17

0.11

0.10

0.12

0.68

0.64

0.73

0.19

0.14

0.23

0.13

0.12

0.13

1980–1994

0.84

0.77

0.90

0.05

0.00

0.13

0.11

0.10

0.12

0.66

0.61

0.72

0.21

0.16

0.27

0.13

0.12

0.13

Europe

1886–1909

0.78

0.69

0.80

0.00

0.00

0.08

0.22

0.20

0.25

0.50

0.40

0.60

0.14

0.06

0.23

0.35

0.32

0.39

1910–1919

0.85

0.79

0.87

0.00

0.00

0.07

0.15

0.13

0.16

0.66

0.58

0.74

0.10

0.02

0.17

0.24

0.22

0.26

1920–1929

0.69

0.62

0.76

0.14

0.07

0.20

0.17

0.16

0.19

0.72

0.65

0.79

0.09

0.03

0.16

0.19

0.17

0.21

1930–1939

0.75

0.69

0.81

0.11

0.05

0.17

0.14

0.13

0.16

0.76

0.70

0.82

0.09

0.03

0.14

0.16

0.15

0.17

1940–1949

0.77

0.72

0.82

0.10

0.06

0.15

0.13

0.12

0.13

0.79

0.75

0.83

0.08

0.04

0.13

0.13

0.12

0.13

1950–1959

0.72

0.68

0.77

0.16

0.11

0.20

0.12

0.11

0.12

0.79

0.75

0.83

0.09

0.05

0.13

0.12

0.11

0.13

1960–1969

0.74

0.66

0.83

0.15

0.06

0.23

0.11

0.10

0.12

0.78

0.72

0.85

0.08

0.02

0.15

0.13

0.12

0.14

1970–1979

0.81

0.74

0.88

0.09

0.02

0.16

0.10

0.09

0.10

0.74

0.69

0.81

0.15

0.09

0.21

0.11

0.10

0.11

1980–1994

0.87

0.77

0.92

0.04

0.00

0.14

0.09

0.08

0.10

0.64

0.57

0.72

0.26

0.18

0.32

0.10

0.09

0.11

North America and Australia

1886–1909

0.83

0.33

0.90

0.01

0.00

0.49

0.16

0.10

0.26

0.76

0.43

0.82

0.00

0.00

0.31

0.24

0.18

0.32

1910–1919

0.78

0.70

0.87

0.09

0.00

0.17

0.13

0.12

0.15

0.60

0.44

0.78

0.24

0.06

0.39

0.16

0.14

0.19

1920–1929

0.73

0.69

0.77

0.14

0.10

0.18

0.13

0.12

0.14

0.63

0.52

0.76

0.22

0.09

0.33

0.15

0.14

0.17

1930–1939

0.81

0.66

0.83

0.00

0.00

0.14

0.19

0.17

0.22

0.70

0.59

0.82

0.17

0.04

0.28

0.13

0.12

0.15

1940–1949

0.69

0.61

0.77

0.19

0.10

0.27

0.13

0.12

0.14

0.80

0.72

0.87

0.08

0.00

0.15

0.13

0.12

0.14

1950–1959

0.75

0.68

0.82

0.14

0.07

0.21

0.11

0.10

0.12

0.67

0.61

0.73

0.21

0.15

0.26

0.13

0.12

0.13

1960–1969

0.66

0.58

0.76

0.16

0.06

0.24

0.18

0.17

0.20

0.63

0.57

0.70

0.18

0.11

0.24

0.18

0.17

0.20

1970–1979

0.68

0.57

0.81

0.18

0.05

0.29

0.14

0.13

0.16

0.60

0.53

0.67

0.25

0.18

0.32

0.15

0.14

0.16

1980–1994

0.83

0.72

0.89

0.04

0.00

0.16

0.12

0.11

0.14

0.71

0.62

0.81

0.14

0.04

0.23

0.15

0.14

0.16

East Asia

1940–1949

0.83

0.33

0.97

0.12

0.00

0.61

0.05

0.03

0.12

0.71

0.17

0.94

0.19

0.00

0.73

0.10

0.06

0.18

1950–1959

0.64

0.24

0.91

0.23

0.00

0.63

0.13

0.08

0.20

0.42

0.14

0.92

0.48

0.00

0.75

0.10

0.07

0.15

1960–1969

0.67

0.36

0.94

0.24

0.00

0.56

0.08

0.06

0.12

0.92

0.67

0.94

0.00

0.00

0.25

0.08

0.06

0.10

1970–1979

0.85

0.51

0.95

0.08

0.00

0.43

0.07

0.05

0.09

0.79

0.52

0.96

0.17

0.00

0.43

0.05

0.04

0.06

1980–1994

0.88

0.51

0.91

0.00

0.00

0.37

0.12

0.09

0.17

0.58

0.34

0.90

0.31

0.00

0.55

0.11

0.09

0.14

Univariate quantitative genetic models for height were then conducted separately in the three geographic-cultural regions (Figure 1 and Supplementary file 1A). The pattern in Europe was practically the same as that observed for the pooled data because it represents a large proportion of the total sample. In North America and Australia, the total variance of height was greater than in Europe, but the pattern of genetic and environmental variances was less consistent across birth-year cohorts. In East Asia, because of the smaller sample size, the magnitude of the variance components between the birth-year cohorts fluctuated more than in the other two geographic-cultural regions. Genetic variance was generally greater in men than in women in the three geographic-cultural regions. Variance components of height (both raw and relative proportion) showed a similar pattern across birth-year cohorts when analyses were performed for men and women together (Supplementary file 1C).

Discussion

This very large twin study showed no clear pattern in the heritability of height across birth-year cohorts and thus does not support the hypothesis that the heritability of height is lower in populations with low living standards compared with affluent populations, nor that the heritability of height will increase within a population as living standards improve. Since infant mortality rates are higher in men than in women, both in singletons (Drevenstedt et al., 2008) and twins (Pongou, 2013), the higher heritability observed for men in the earliest cohorts could be explained by selection effects since those who survived were the genetically more advantaged and thus less vulnerable to environmental conditions. The greater relative environmental effect on height variation in women than in men, although unexpected because women’s growth is considered to be more resistant to environmental influences, is in agreement with the findings in Finnish twins born prior to 1958 (Silventoinen et al., 2000). This might indicate differential access to food and medical care (Eveleth and Tanner, 1990). Women are also more likely to develop osteoporosis leading to shrinking in old age (National Institute of Arthritis and musculoskeletal and Skin Diseases, 2014), which may affect the greater influence of unique environmental factors in women born in 1886–1910. This idea is supported by results showing that although genetic factors play an important role in bone loss in early postmenopausal women, their effect weakens with age and completely disappears with advanced aging (Moayyeri et al., 2012).

Total and genetic variance of height generally increased across birth-year cohorts; gene-birth year interaction analysis showed that the genetic variance increase was only modest even when it was statistically significant in this very large twin cohort. However, part of the increase in total variance in some birth-year cohorts was also due to the increase in shared environmental variance. This suggests that both greater ethnic diversity and variation in living standards have contributed to the secular increase in height variation. The greatest total height variation in North America and Australia was due to both genetic and environmental factors and the pattern of variance components across the birth cohorts was less consistent than in Europe. A recent study across 14 European countries found that many independent loci contribute to population genetic differences in height and estimated that these differences account for 24% of the captured additive genetic variance (Robinson et al., 2015). Therefore, it may be that both allelic frequencies and the effects of genes affecting height vary between the geographic-cultural regions. It has been previously shown that even when the total variance of height was greater in Western populations than in East Asian populations, heritability estimates were largely similar in adolescence (Hur et al., 2008) and from 1 to 19 years of age (Jelenkovic et al., 2016); however, the limited statistical power in the data from East Asia does not allow for comparisons across birth cohorts.

The main strength of the present study is the very large sample size of our multinational database of twin cohorts, with adult height data from individuals born between year 1886 and 1994, allowing a more detailed investigation of the genetic and environmental contributions to individual differences in height across birth cohorts than in the previous studies. Important advantages of individual-based data are improved opportunities for statistical modeling and lack of publication bias. This type of analysis is difficult to perform by using literature-based meta-analyses because most of the published studies do not provide the needed statistics by birth-year cohorts. However, our study also has limitations. Countries and/or ethnic-cultural regions are not equally represented and the database is heavily weighted toward populations following Westernized lifestyles. In the classical twin design, parental phenotypic assortment increases dizygotic correlations and thus inflates the shared environmental component when not accounted for in the modeling. In our database, we do not have information on parental height and thus could not take into account assortative mating, which may thus explain part of the shared environmental variation. In addition, most of the height measures were self-reported (Silventoinen et al., 2015), which may bias our analyses toward higher estimates of unique environmental effects due to increased measurement error. However, these sources of bias are unlikely to explain our main result, i.e., relatively similar heritability estimates of adult height over birth cohorts. Finally, since we previously showed that there was no zygosity difference in height variance (Jelenkovic et al., 2015), variance components estimates should not be affected by changes in the proportion of MZ to DZ twins across birth-year cohorts.

In conclusion, although the genetic variance of height showed a slightly increasing trend with birth year, heritability estimates did not present any clear pattern of secular changes across birth-year cohorts from 1886 to 1994. Thus, our findings do not support the hypothesis that the heritability of height increases along with increasing living standards and diminishing rate of absolute poverty within populations.

Materials and methods

Sample

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This study is based on the data from the Collaborative project of Development of Anthropometrical measures in Twins (CODATwins), which was intended to pool data from all twin projects in the world with information on height and weight measurements for MZ and DZ twins (Silventoinen et al., 2015). For the present analyses, we selected height measurements at ages 19.5–99.5 years. After excluding four cohorts having less than 50 twin individuals in the final database, we had data from 40 cohorts in 20 countries. The participating twin cohorts are identified in Table 1 (footnote) and were previously described in detail (Silventoinen et al., 2015).

From the initial 558,672 height measurements, we excluded those <145 or>210 cm in men and <135 or >195 cm in women (<0.1% of the measurements). Since individuals in longitudinal studies have more than one measurement over time, analyses were restricted to one observation per individual resulting in 323,491 individuals. After excluding unmatched pairs (without data on their co-twins), we had 286,780 twin individuals (143,390 complete twin pairs) born between year 1886 and 1994 (40% monozygotic (MZ), 41% same- sex dizygotic (SSDZ) and 19% opposite-sex dizygotic (OSDZ) twin pairs). The smaller proportion of OSDZ compared to SSDZ twins in this study is explained by the fact that some of the twin cohorts in our database have collected, by design, only SSDZ twins and thus do not have data on OSDZ twins. These individuals were categorized into nine consecutive birth year groups described in Table 1. In order to analyze possible ethnic-cultural differences in the genetic and environmental contribution on height, cohorts were grouped in three geographical-cultural regions: Europe (18 cohorts), North America and Australia (14 cohorts) and East Asia (six cohorts) with 87,116, 53,359 and 1793 twin pairs, respectively. One cohort from the Middle-East and the one from South-Asia were not included in these sub-analyses by geographic-cultural region because the data were too sparse to study these two areas separately.

Statistical analyses

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We first tested whether the means and variances of height differed between twin cohorts within each sex and birth-year group (Table 1). Since the Levene´s test for homogeneity indicated that variances were not homogeneous, a Welch’s ANOVA was performed showing that means were significantly different between twin cohorts in all sex and birth-year groups.

To analyze genetic and environmental influences on the variation of height, we used classic twin modeling based on linear structural equations (Neale and Cardon, 1992). MZ twins share the same genomic sequence, whereas DZ twins share, on average, 50% of their genes identical-by-descent. On this basis, it is possible to divide the total variance of height into variance due to additive genetic effects (A: correlated 1.0 for MZ and 0.5 for DZ pairs), dominance genetic effects (D: 1.0 for MZ and 0.25 for DZ pairs), common (shared) environmental effects (C: by definition, correlated 1.0 for MZ and DZ pairs) and unique (non-shared) environmental effects (E: by definition, uncorrelated in MZ and DZ pairs). However, since our data included only twins reared together, we cannot simultaneously estimate shared environmental and dominance genetic effects. All genetic models were fitted by the OpenMx package (version 2.0.1) in the R statistical platform (Boker et al., 2011) using the maximum likelihood method.

Prior to conducting the modeling, height values were adjusted for the year of birth and twin cohort within each birth year and sex groups using linear regressions, and the resulting residuals were used as input phenotypes. The ACE sex-limitation model was selected as a starting point of the univariate modeling based on the following criteria: (i) MZ within-pair correlations were clearly higher than DZ correlations consistent with the influence of genetic effects, (ii) the magnitude of the difference between MZ and DZ correlations (rDZ > 1/2 rMZ) indicated the presence of common environmental effects and (iii) the lower within-pair correlations for OSDZ than for SSDZ twins observed for most birth-year groups suggested the presence of sex-specific genetic effects (results not shown). Previous findings from this international database showed that both male and female DZ twins are slightly taller than MZ twins in these age groups (Jelenkovic et al., 2015), and thus different means for MZ and DZ twins were allowed. The fit of the univariate models for height at each birth-year group is shown in Supplementary file 1B. In the present study, the equal-environment assumption was tested by comparing the ACE model to the saturated model. The fit of the models after Bonferroni correction of multiple testing did not worsen for most birth-year groups, which suggested that the assumption of equality of variances between MZ and DZ twins was not violated. When fixing A, C and E parameters to be the same in men and women, the fit of the model was poorer in all birth-year groups (p<0.0001), suggesting that these variance components differ between sexes. We additionally fitted a scale model allowing for different sizes of variance components but fixing the relative size of these components to be equal. Since this model also showed statistically significant differences (p<0.0001) in some birth-year cohorts, we decided to present the results separately for men and women. Sex-specific genetic effects were significant for some birth-year cohorts, and thus all modeling results are presented in sex-limited form for consistency. Comparative model fitting revealed that the C parameter could be not excluded from the model without a significant deterioration in fit. In order to study how birth year modifies the genetic and environmental variances of height, we additionally conducted gene-environment interaction modeling using birth year as an environmental modification factor (Purcell, 2002). This modeling offers intercept and interaction term describing the change per birth year which then need to be squared to get raw genetic and environmental variances. To make the results easier to understand, we calculated expected variance change with 95% CI per 25 years, i.e. approximately one human generation.

References

  1. Book
    1. Bogin B
    (2001)
    The Growth of Humanity
    New York: Wiley-Liss.
  2. Book
    1. Eveleth PB
    2. Tanner JM
    (1990)
    Worldwide Variation in Human Growth (2nd edn)
    Cambridge: Cambridge University Press.
    1. Jelenkovic A
    2. Yokoyama Y
    3. Sund R
    4. Honda C
    5. Bogl LH
    6. Aaltonen S
    7. Ji F
    8. Ning F
    9. Pang Z
    10. Ordoñana JR
    11. Sánchez-Romera JF
    12. Colodro-Conde L
    13. Burt SA
    14. Klump KL
    15. Medland SE
    16. Montgomery GW
    17. Kandler C
    18. McAdams TA
    19. Eley TC
    20. Gregory AM
    21. Saudino KJ
    22. Dubois L
    23. Boivin M
    24. Tarnoki AD
    25. Tarnoki DL
    26. Haworth CM
    27. Plomin R
    28. Öncel SY
    29. Aliev F
    30. Stazi MA
    31. Fagnani C
    32. D'Ippolito C
    33. Craig JM
    34. Saffery R
    35. Siribaddana SH
    36. Hotopf M
    37. Sumathipala A
    38. Rijsdijk F
    39. Spector T
    40. Mangino M
    41. Lachance G
    42. Gatz M
    43. Butler DA
    44. Bayasgalan G
    45. Narandalai D
    46. Freitas DL
    47. Maia JA
    48. Harden KP
    49. Tucker-Drob EM
    50. Kim B
    51. Chong Y
    52. Hong C
    53. Shin HJ
    54. Christensen K
    55. Skytthe A
    56. Kyvik KO
    57. Derom CA
    58. Vlietinck RF
    59. Loos RJ
    60. Cozen W
    61. Hwang AE
    62. Mack TM
    63. He M
    64. Ding X
    65. Chang B
    66. Silberg JL
    67. Eaves LJ
    68. Maes HH
    69. Cutler TL
    70. Hopper JL
    71. Aujard K
    72. Magnusson PK
    73. Pedersen NL
    74. Aslan AK
    75. Song YM
    76. Yang S
    77. Lee K
    78. Baker LA
    79. Tuvblad C
    80. Bjerregaard-Andersen M
    81. Beck-Nielsen H
    82. Sodemann M
    83. Heikkilä K
    84. Tan Q
    85. Zhang D
    86. Swan GE
    87. Krasnow R
    88. Jang KL
    89. Knafo-Noam A
    90. Mankuta D
    91. Abramson L
    92. Lichtenstein P
    93. Krueger RF
    94. McGue M
    95. Pahlen S
    96. Tynelius P
    97. Duncan GE
    98. Buchwald D
    99. Corley RP
    100. Huibregtse BM
    101. Nelson TL
    102. Whitfield KE
    103. Kremen WS
    104. Lyons MJ
    105. Ooki S
    106. Brandt I
    107. Nilsen TS
    108. Inui F
    109. Watanabe M
    110. Bartels M
    111. van Beijsterveldt TC
    112. Wardle J
    113. Llewellyn CH
    114. Fisher A
    115. Rebato E
    116. Martin NG
    117. Iwatani Y
    118. Hayakawa K
    119. Sung J
    120. Harris JR
    121. Willemsen G
    122. Busjahn A
    123. Goldberg JH
    124. Rasmussen F
    125. Hur YM
    126. Boomsma DI
    127. Sørensen TI
    128. Kaprio J
    129. Silventoinen K
    (2015) Zygosity differences in height and body mass index of twins from infancy to old age: A study of the CODATwins project
    Twin Research and Human Genetics 18:557–570.
    https://doi.org/10.1017/thg.2015.57
    1. Lango Allen H
    2. Estrada K
    3. Lettre G
    4. Berndt SI
    5. Weedon MN
    6. Rivadeneira F
    7. Willer CJ
    8. Jackson AU
    9. Vedantam S
    10. Raychaudhuri S
    11. Ferreira T
    12. Wood AR
    13. Weyant RJ
    14. Segrè AV
    15. Speliotes EK
    16. Wheeler E
    17. Soranzo N
    18. Park JH
    19. Yang J
    20. Gudbjartsson D
    21. Heard-Costa NL
    22. Randall JC
    23. Qi L
    24. Vernon Smith A
    25. Mägi R
    26. Pastinen T
    27. Liang L
    28. Heid IM
    29. Luan J
    30. Thorleifsson G
    31. Winkler TW
    32. Goddard ME
    33. Sin Lo K
    34. Palmer C
    35. Workalemahu T
    36. Aulchenko YS
    37. Johansson A
    38. Zillikens MC
    39. Feitosa MF
    40. Esko T
    41. Johnson T
    42. Ketkar S
    43. Kraft P
    44. Mangino M
    45. Prokopenko I
    46. Absher D
    47. Albrecht E
    48. Ernst F
    49. Glazer NL
    50. Hayward C
    51. Hottenga JJ
    52. Jacobs KB
    53. Knowles JW
    54. Kutalik Z
    55. Monda KL
    56. Polasek O
    57. Preuss M
    58. Rayner NW
    59. Robertson NR
    60. Steinthorsdottir V
    61. Tyrer JP
    62. Voight BF
    63. Wiklund F
    64. Xu J
    65. Zhao JH
    66. Nyholt DR
    67. Pellikka N
    68. Perola M
    69. Perry JR
    70. Surakka I
    71. Tammesoo ML
    72. Altmaier EL
    73. Amin N
    74. Aspelund T
    75. Bhangale T
    76. Boucher G
    77. Chasman DI
    78. Chen C
    79. Coin L
    80. Cooper MN
    81. Dixon AL
    82. Gibson Q
    83. Grundberg E
    84. Hao K
    85. Juhani Junttila M
    86. Kaplan LM
    87. Kettunen J
    88. König IR
    89. Kwan T
    90. Lawrence RW
    91. Levinson DF
    92. Lorentzon M
    93. McKnight B
    94. Morris AP
    95. Müller M
    96. Suh Ngwa J
    97. Purcell S
    98. Rafelt S
    99. Salem RM
    100. Salvi E
    101. Sanna S
    102. Shi J
    103. Sovio U
    104. Thompson JR
    105. Turchin MC
    106. Vandenput L
    107. Verlaan DJ
    108. Vitart V
    109. White CC
    110. Ziegler A
    111. Almgren P
    112. Balmforth AJ
    113. Campbell H
    114. Citterio L
    115. De Grandi A
    116. Dominiczak A
    117. Duan J
    118. Elliott P
    119. Elosua R
    120. Eriksson JG
    121. Freimer NB
    122. Geus EJ
    123. Glorioso N
    124. Haiqing S
    125. Hartikainen AL
    126. Havulinna AS
    127. Hicks AA
    128. Hui J
    129. Igl W
    130. Illig T
    131. Jula A
    132. Kajantie E
    133. Kilpeläinen TO
    134. Koiranen M
    135. Kolcic I
    136. Koskinen S
    137. Kovacs P
    138. Laitinen J
    139. Liu J
    140. Lokki ML
    141. Marusic A
    142. Maschio A
    143. Meitinger T
    144. Mulas A
    145. Paré G
    146. Parker AN
    147. Peden JF
    148. Petersmann A
    149. Pichler I
    150. Pietiläinen KH
    151. Pouta A
    152. Ridderstråle M
    153. Rotter JI
    154. Sambrook JG
    155. Sanders AR
    156. Schmidt CO
    157. Sinisalo J
    158. Smit JH
    159. Stringham HM
    160. Bragi Walters G
    161. Widen E
    162. Wild SH
    163. Willemsen G
    164. Zagato L
    165. Zgaga L
    166. Zitting P
    167. Alavere H
    168. Farrall M
    169. McArdle WL
    170. Nelis M
    171. Peters MJ
    172. Ripatti S
    173. van Meurs JB
    174. Aben KK
    175. Ardlie KG
    176. Beckmann JS
    177. Beilby JP
    178. Bergman RN
    179. Bergmann S
    180. Collins FS
    181. Cusi D
    182. den Heijer M
    183. Eiriksdottir G
    184. Gejman PV
    185. Hall AS
    186. Hamsten A
    187. Huikuri HV
    188. Iribarren C
    189. Kähönen M
    190. Kaprio J
    191. Kathiresan S
    192. Kiemeney L
    193. Kocher T
    194. Launer LJ
    195. Lehtimäki T
    196. Melander O
    197. Mosley TH
    198. Musk AW
    199. Nieminen MS
    200. O'Donnell CJ
    201. Ohlsson C
    202. Oostra B
    203. Palmer LJ
    204. Raitakari O
    205. Ridker PM
    206. Rioux JD
    207. Rissanen A
    208. Rivolta C
    209. Schunkert H
    210. Shuldiner AR
    211. Siscovick DS
    212. Stumvoll M
    213. Tönjes A
    214. Tuomilehto J
    215. van Ommen GJ
    216. Viikari J
    217. Heath AC
    218. Martin NG
    219. Montgomery GW
    220. Province MA
    221. Kayser M
    222. Arnold AM
    223. Atwood LD
    224. Boerwinkle E
    225. Chanock SJ
    226. Deloukas P
    227. Gieger C
    228. Grönberg H
    229. Hall P
    230. Hattersley AT
    231. Hengstenberg C
    232. Hoffman W
    233. Lathrop GM
    234. Salomaa V
    235. Schreiber S
    236. Uda M
    237. Waterworth D
    238. Wright AF
    239. Assimes TL
    240. Barroso I
    241. Hofman A
    242. Mohlke KL
    243. Boomsma DI
    244. Caulfield MJ
    245. Cupples LA
    246. Erdmann J
    247. Fox CS
    248. Gudnason V
    249. Gyllensten U
    250. Harris TB
    251. Hayes RB
    252. Jarvelin MR
    253. Mooser V
    254. Munroe PB
    255. Ouwehand WH
    256. Penninx BW
    257. Pramstaller PP
    258. Quertermous T
    259. Rudan I
    260. Samani NJ
    261. Spector TD
    262. Völzke H
    263. Watkins H
    264. Wilson JF
    265. Groop LC
    266. Haritunians T
    267. Hu FB
    268. Kaplan RC
    269. Metspalu A
    270. North KE
    271. Schlessinger D
    272. Wareham NJ
    273. Hunter DJ
    274. O'Connell JR
    275. Strachan DP
    276. Wichmann HE
    277. Borecki IB
    278. van Duijn CM
    279. Schadt EE
    280. Thorsteinsdottir U
    281. Peltonen L
    282. Uitterlinden AG
    283. Visscher PM
    284. Chatterjee N
    285. Loos RJ
    286. Boehnke M
    287. McCarthy MI
    288. Ingelsson E
    289. Lindgren CM
    290. Abecasis GR
    291. Stefansson K
    292. Frayling TM
    293. Hirschhorn JN
    (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height
    Nature 467:832–838.
    https://doi.org/10.1038/nature09410
  3. Book
    1. Neale MC
    2. Cardon LR
    (1992)
    Methodology for Genetic Studies of Twins and Families
    Dordrecht: Kluwer Academic Publishers.
    1. Silventoinen K
    2. Jelenkovic A
    3. Sund R
    4. Honda C
    5. Aaltonen S
    6. Yokoyama Y
    7. Tarnoki AD
    8. Tarnoki DL
    9. Ning F
    10. Ji F
    11. Pang Z
    12. Ordoñana JR
    13. Sánchez-Romera JF
    14. Colodro-Conde L
    15. Burt SA
    16. Klump KL
    17. Medland SE
    18. Montgomery GW
    19. Kandler C
    20. McAdams TA
    21. Eley TC
    22. Gregory AM
    23. Saudino KJ
    24. Dubois L
    25. Boivin M
    26. Haworth CM
    27. Plomin R
    28. Öncel SY
    29. Aliev F
    30. Stazi MA
    31. Fagnani C
    32. D'Ippolito C
    33. Craig JM
    34. Saffery R
    35. Siribaddana SH
    36. Hotopf M
    37. Sumathipala A
    38. Spector T
    39. Mangino M
    40. Lachance G
    41. Gatz M
    42. Butler DA
    43. Bayasgalan G
    44. Narandalai D
    45. Freitas DL
    46. Maia JA
    47. Harden KP
    48. Tucker-Drob EM
    49. Christensen K
    50. Skytthe A
    51. Kyvik KO
    52. Hong C
    53. Chong Y
    54. Derom CA
    55. Vlietinck RF
    56. Loos RJ
    57. Cozen W
    58. Hwang AE
    59. Mack TM
    60. He M
    61. Ding X
    62. Chang B
    63. Silberg JL
    64. Eaves LJ
    65. Maes HH
    66. Cutler TL
    67. Hopper JL
    68. Aujard K
    69. Magnusson PK
    70. Pedersen NL
    71. Aslan AK
    72. Song YM
    73. Yang S
    74. Lee K
    75. Baker LA
    76. Tuvblad C
    77. Bjerregaard-Andersen M
    78. Beck-Nielsen H
    79. Sodemann M
    80. Heikkilä K
    81. Tan Q
    82. Zhang D
    83. Swan GE
    84. Krasnow R
    85. Jang KL
    86. Knafo-Noam A
    87. Mankuta D
    88. Abramson L
    89. Lichtenstein P
    90. Krueger RF
    91. McGue M
    92. Pahlen S
    93. Tynelius P
    94. Duncan GE
    95. Buchwald D
    96. Corley RP
    97. Huibregtse BM
    98. Nelson TL
    99. Whitfield KE
    100. Franz CE
    101. Kremen WS
    102. Lyons MJ
    103. Ooki S
    104. Brandt I
    105. Nilsen TS
    106. Inui F
    107. Watanabe M
    108. Bartels M
    109. van Beijsterveldt TC
    110. Wardle J
    111. Llewellyn CH
    112. Fisher A
    113. Rebato E
    114. Martin NG
    115. Iwatani Y
    116. Hayakawa K
    117. Rasmussen F
    118. Sung J
    119. Harris JR
    120. Willemsen G
    121. Busjahn A
    122. Goldberg JH
    123. Boomsma DI
    124. Hur YM
    125. Sørensen TI
    126. Kaprio J
    (2015) The CODATwins project: The cohort description of collaborative project of development of Anthropometrical measures in twins to study Macro-environmental variation in genetic and environmental effects on Anthropometric traits
    Twin Research and Human Genetics 18:348–360.
    https://doi.org/10.1017/thg.2015.29
    1. Wood AR
    2. Esko T
    3. Yang J
    4. Vedantam S
    5. Pers TH
    6. Gustafsson S
    7. Chu AY
    8. Estrada K
    9. Luan J
    10. Kutalik Z
    11. Amin N
    12. Buchkovich ML
    13. Croteau-Chonka DC
    14. Day FR
    15. Duan Y
    16. Fall T
    17. Fehrmann R
    18. Ferreira T
    19. Jackson AU
    20. Karjalainen J
    21. Lo KS
    22. Locke AE
    23. Mägi R
    24. Mihailov E
    25. Porcu E
    26. Randall JC
    27. Scherag A
    28. Vinkhuyzen AA
    29. Westra HJ
    30. Winkler TW
    31. Workalemahu T
    32. Zhao JH
    33. Absher D
    34. Albrecht E
    35. Anderson D
    36. Baron J
    37. Beekman M
    38. Demirkan A
    39. Ehret GB
    40. Feenstra B
    41. Feitosa MF
    42. Fischer K
    43. Fraser RM
    44. Goel A
    45. Gong J
    46. Justice AE
    47. Kanoni S
    48. Kleber ME
    49. Kristiansson K
    50. Lim U
    51. Lotay V
    52. Lui JC
    53. Mangino M
    54. Mateo Leach I
    55. Medina-Gomez C
    56. Nalls MA
    57. Nyholt DR
    58. Palmer CD
    59. Pasko D
    60. Pechlivanis S
    61. Prokopenko I
    62. Ried JS
    63. Ripke S
    64. Shungin D
    65. Stancáková A
    66. Strawbridge RJ
    67. Sung YJ
    68. Tanaka T
    69. Teumer A
    70. Trompet S
    71. van der Laan SW
    72. van Setten J
    73. Van Vliet-Ostaptchouk JV
    74. Wang Z
    75. Yengo L
    76. Zhang W
    77. Afzal U
    78. Arnlöv J
    79. Arscott GM
    80. Bandinelli S
    81. Barrett A
    82. Bellis C
    83. Bennett AJ
    84. Berne C
    85. Blüher M
    86. Bolton JL
    87. Böttcher Y
    88. Boyd HA
    89. Bruinenberg M
    90. Buckley BM
    91. Buyske S
    92. Caspersen IH
    93. Chines PS
    94. Clarke R
    95. Claudi-Boehm S
    96. Cooper M
    97. Daw EW
    98. De Jong PA
    99. Deelen J
    100. Delgado G
    101. Denny JC
    102. Dhonukshe-Rutten R
    103. Dimitriou M
    104. Doney AS
    105. Dörr M
    106. Eklund N
    107. Eury E
    108. Folkersen L
    109. Garcia ME
    110. Geller F
    111. Giedraitis V
    112. Go AS
    113. Grallert H
    114. Grammer TB
    115. Gräßler J
    116. Grönberg H
    117. de Groot LC
    118. Groves CJ
    119. Haessler J
    120. Hall P
    121. Haller T
    122. Hallmans G
    123. Hannemann A
    124. Hartman CA
    125. Hassinen M
    126. Hayward C
    127. Heard-Costa NL
    128. Helmer Q
    129. Hemani G
    130. Henders AK
    131. Hillege HL
    132. Hlatky MA
    133. Hoffmann W
    134. Hoffmann P
    135. Holmen O
    136. Houwing-Duistermaat JJ
    137. Illig T
    138. Isaacs A
    139. James AL
    140. Jeff J
    141. Johansen B
    142. Johansson Å
    143. Jolley J
    144. Juliusdottir T
    145. Junttila J
    146. Kho AN
    147. Kinnunen L
    148. Klopp N
    149. Kocher T
    150. Kratzer W
    151. Lichtner P
    152. Lind L
    153. Lindström J
    154. Lobbens S
    155. Lorentzon M
    156. Lu Y
    157. Lyssenko V
    158. Magnusson PK
    159. Mahajan A
    160. Maillard M
    161. McArdle WL
    162. McKenzie CA
    163. McLachlan S
    164. McLaren PJ
    165. Menni C
    166. Merger S
    167. Milani L
    168. Moayyeri A
    169. Monda KL
    170. Morken MA
    171. Müller G
    172. Müller-Nurasyid M
    173. Musk AW
    174. Narisu N
    175. Nauck M
    176. Nolte IM
    177. Nöthen MM
    178. Oozageer L
    179. Pilz S
    180. Rayner NW
    181. Renstrom F
    182. Robertson NR
    183. Rose LM
    184. Roussel R
    185. Sanna S
    186. Scharnagl H
    187. Scholtens S
    188. Schumacher FR
    189. Schunkert H
    190. Scott RA
    191. Sehmi J
    192. Seufferlein T
    193. Shi J
    194. Silventoinen K
    195. Smit JH
    196. Smith AV
    197. Smolonska J
    198. Stanton AV
    199. Stirrups K
    200. Stott DJ
    201. Stringham HM
    202. Sundström J
    203. Swertz MA
    204. Syvänen AC
    205. Tayo BO
    206. Thorleifsson G
    207. Tyrer JP
    208. van Dijk S
    209. van Schoor NM
    210. van der Velde N
    211. van Heemst D
    212. van Oort FV
    213. Vermeulen SH
    214. Verweij N
    215. Vonk JM
    216. Waite LL
    217. Waldenberger M
    218. Wennauer R
    219. Wilkens LR
    220. Willenborg C
    221. Wilsgaard T
    222. Wojczynski MK
    223. Wong A
    224. Wright AF
    225. Zhang Q
    226. Arveiler D
    227. Bakker SJ
    228. Beilby J
    229. Bergman RN
    230. Bergmann S
    231. Biffar R
    232. Blangero J
    233. Boomsma DI
    234. Bornstein SR
    235. Bovet P
    236. Brambilla P
    237. Brown MJ
    238. Campbell H
    239. Caulfield MJ
    240. Chakravarti A
    241. Collins R
    242. Collins FS
    243. Crawford DC
    244. Cupples LA
    245. Danesh J
    246. de Faire U
    247. den Ruijter HM
    248. Erbel R
    249. Erdmann J
    250. Eriksson JG
    251. Farrall M
    252. Ferrannini E
    253. Ferrières J
    254. Ford I
    255. Forouhi NG
    256. Forrester T
    257. Gansevoort RT
    258. Gejman PV
    259. Gieger C
    260. Golay A
    261. Gottesman O
    262. Gudnason V
    263. Gyllensten U
    264. Haas DW
    265. Hall AS
    266. Harris TB
    267. Hattersley AT
    268. Heath AC
    269. Hengstenberg C
    270. Hicks AA
    271. Hindorff LA
    272. Hingorani AD
    273. Hofman A
    274. Hovingh GK
    275. Humphries SE
    276. Hunt SC
    277. Hypponen E
    278. Jacobs KB
    279. Jarvelin MR
    280. Jousilahti P
    281. Jula AM
    282. Kaprio J
    283. Kastelein JJ
    284. Kayser M
    285. Kee F
    286. Keinanen-Kiukaanniemi SM
    287. Kiemeney LA
    288. Kooner JS
    289. Kooperberg C
    290. Koskinen S
    291. Kovacs P
    292. Kraja AT
    293. Kumari M
    294. Kuusisto J
    295. Lakka TA
    296. Langenberg C
    297. Le Marchand L
    298. Lehtimäki T
    299. Lupoli S
    300. Madden PA
    301. Männistö S
    302. Manunta P
    303. Marette A
    304. Matise TC
    305. McKnight B
    306. Meitinger T
    307. Moll FL
    308. Montgomery GW
    309. Morris AD
    310. Morris AP
    311. Murray JC
    312. Nelis M
    313. Ohlsson C
    314. Oldehinkel AJ
    315. Ong KK
    316. Ouwehand WH
    317. Pasterkamp G
    318. Peters A
    319. Pramstaller PP
    320. Price JF
    321. Qi L
    322. Raitakari OT
    323. Rankinen T
    324. Rao DC
    325. Rice TK
    326. Ritchie M
    327. Rudan I
    328. Salomaa V
    329. Samani NJ
    330. Saramies J
    331. Sarzynski MA
    332. Schwarz PE
    333. Sebert S
    334. Sever P
    335. Shuldiner AR
    336. Sinisalo J
    337. Steinthorsdottir V
    338. Stolk RP
    339. Tardif JC
    340. Tönjes A
    341. Tremblay A
    342. Tremoli E
    343. Virtamo J
    344. Vohl MC
    345. Amouyel P
    346. Asselbergs FW
    347. Assimes TL
    348. Bochud M
    349. Boehm BO
    350. Boerwinkle E
    351. Bottinger EP
    352. Bouchard C
    353. Cauchi S
    354. Chambers JC
    355. Chanock SJ
    356. Cooper RS
    357. de Bakker PI
    358. Dedoussis G
    359. Ferrucci L
    360. Franks PW
    361. Froguel P
    362. Groop LC
    363. Haiman CA
    364. Hamsten A
    365. Hayes MG
    366. Hui J
    367. Hunter DJ
    368. Hveem K
    369. Jukema JW
    370. Kaplan RC
    371. Kivimaki M
    372. Kuh D
    373. Laakso M
    374. Liu Y
    375. Martin NG
    376. März W
    377. Melbye M
    378. Moebus S
    379. Munroe PB
    380. Njølstad I
    381. Oostra BA
    382. Palmer CN
    383. Pedersen NL
    384. Perola M
    385. Pérusse L
    386. Peters U
    387. Powell JE
    388. Power C
    389. Quertermous T
    390. Rauramaa R
    391. Reinmaa E
    392. Ridker PM
    393. Rivadeneira F
    394. Rotter JI
    395. Saaristo TE
    396. Saleheen D
    397. Schlessinger D
    398. Slagboom PE
    399. Snieder H
    400. Spector TD
    401. Strauch K
    402. Stumvoll M
    403. Tuomilehto J
    404. Uusitupa M
    405. van der Harst P
    406. Völzke H
    407. Walker M
    408. Wareham NJ
    409. Watkins H
    410. Wichmann HE
    411. Wilson JF
    412. Zanen P
    413. Deloukas P
    414. Heid IM
    415. Lindgren CM
    416. Mohlke KL
    417. Speliotes EK
    418. Thorsteinsdottir U
    419. Barroso I
    420. Fox CS
    421. North KE
    422. Strachan DP
    423. Beckmann JS
    424. Berndt SI
    425. Boehnke M
    426. Borecki IB
    427. McCarthy MI
    428. Metspalu A
    429. Stefansson K
    430. Uitterlinden AG
    431. van Duijn CM
    432. Franke L
    433. Willer CJ
    434. Price AL
    435. Lettre G
    436. Loos RJ
    437. Weedon MN
    438. Ingelsson E
    439. O'Connell JR
    440. Abecasis GR
    441. Chasman DI
    442. Goddard ME
    443. Visscher PM
    444. Hirschhorn JN
    445. Frayling TM
    446. Electronic Medical Records and Genomics (eMEMERGEGE) Consortium
    447. MIGen Consortium
    448. PAGEGE Consortium
    449. LifeLines Cohort Study
    (2014) Defining the role of common variation in the genomic and biological architecture of adult human height
    Nature Genetics 46:1173–1186.
    https://doi.org/10.1038/ng.3097

Decision letter

  1. Eduardo Franco
    Reviewing Editor; McGill University, Canada

In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.

Thank you for submitting your article "Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994" for consideration by eLife. Your article has been favorably evaluated by Prabhat Jha (Senior Editor) and four reviewers, one of whom, Eduardo Franco, is a member of our Board of Reviewing Editors. The following individual involved in review of your submission has agreed to reveal their identity: Timothy Frayling.

The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.

Summary:

This study tested the plausible hypothesis – grounded on economic theory – that the genetic influences on adult height may have increased over the last several decades as living standards improved, which would have decreased the environmental constraints from socioeconomic deprivation on attained height. The investigators could only test this hypothesis because of the opportunity to pool together via a massive consortium many twin cohorts across multiple continents. They concluded that the hypothesis could not be confirmed, as the heritability of height did not follow any clear secular trends, irrespective of population. This study addresses an interesting question using the power of almost all, if not all, the twin studies in the world – how has the genetic and environmental component to height altered over the last 100 years? Given all the studies included this can be regarded as as close to the definitive study as one can get.

Essential revisions:

The following are specific points summarized from the reviewers' critiques. They require your attention for us to consider a revised version of your paper.

1) Could the relative proportion of MZ to DZ twins have changed over time and this affected the conclusions of this study? The entire set included 40% MZ, 41% same-sex DZ, and 19% opposite-sex DZ. Greater than average height and weight increases the likelihood of a pregnancy resulting in DZ twins. Age over 40 and prior history does the same. Average age at first pregnancy and numbers thereof are likely to have changed over time and represent variables that could be sensitive to era effects related to war and other determinants of deprivation. On the other hand, there are no known genetic correlates of MZ pregnancies and the rate is constant across populations. Another potential confounder related to the above is the improvements in obstetric care over time, which would have increased the survivability of MZ twins.

2) As a sidebar to the above question: Shouldn't the proportion of opposite-sex DZ be higher than what the study found?

3) I am intrigued by the apparent secular decreases in the proportion of variation due to the unique environment component. This happened for both men and women and were more noticeable for the European cohorts. It seems to me that this suggests that the original declining-deprivation hypothesis has some merit. The authors focused on the additive genetic component but did not discuss much what happened to the other components.

4) It is worth considering presenting the results of both sexes together as well as split by sex. Whilst I can think of reasons why changes in the heritability of height may differ by sex, it is not clear why the authors have stratified their primary analysis by sex. If the main hypothesis is that secular changes will change the heritability of height, one would expect these to operate in the childhood growth of boys and girls. Perhaps girls will be less susceptible because they grow for a shorter period of their lives. But why reduce the power of the study by half? (Especially when there are wider confidence intervals around estimates from before 1940s.)

5) Are the differences between men and women in the earliest time points significant? It is not clear. The authors speculate that there may have been stronger survival effects in men, but this will be unnecessary speculation if there is no evidence of a difference between sexes.

6) It is not possible to prove the negative. Instead can the authors place some bounds on their conclusions? E.g., "we could exclude an increase of x% genetic variance per generation (25 years) with 95% confidence"? On a related note, there are no p values or effect sizes anywhere in the main text. This makes the reader take the results on faith (e.g. It is not clear whether "trend" means a statistically robust trend or just a hint). I realise these appear in the supplementary information, but I think it would help the reader to see the genetic variances across time with 95% CIs at least (and combined sexes would be most powerful).

7) Can the authors comment more on the overall increase in variance observed? It is worth noting that the genetic variance appears to go up in line with the overall variance. The reasons for this are not testable I imagine, but presumably could be due to increased ethnic diversity, and greater variation in living standards, as the average increases. It is clear in Figure 1 but not in the text.

8) Supplementary file 1: Tables 1 and 2 should be part of the main article. It would help the reader to see some stats in the main section of the paper.

https://doi.org/10.7554/eLife.20320.006

Author response

[…]

Essential revisions:

The following are specific points summarized from the reviewers' critiques. They require your attention for us to consider a revised version of your paper.

1) Could the relative proportion of MZ to DZ twins have changed over time and this affected the conclusions of this study? The entire set included 40% MZ, 41% same-sex DZ, and 19% opposite-sex DZ. Greater than average height and weight increases the likelihood of a pregnancy resulting in DZ twins. Age over 40 and prior history does the same. Average age at first pregnancy and numbers thereof are likely to have changed over time and represent variables that could be sensitive to era effects related to war and other determinants of deprivation. On the other hand, there are no known genetic correlates of MZ pregnancies and the rate is constant across populations. Another potential confounder related to the above is the improvements in obstetric care over time, which would have increased the survivability of MZ twins.

As mentioned by the reviewer, changes in twinning rates are largely attributable to dizygotic (DZ) twinning. Monozygotic (MZ) twinning is considered an essentially random event with fairly constant rates worldwide, but a significant increase from 1960 has been reported for some countries (Imaizumi et al., 2003). This increasing MZ twinning rate could be explained by the improvements in obstetric care over time increasing the survivability of MZ twins but it has also been associated with increasing use of oral contraceptives (Imaizumi et al., 2003). in vitro fertilization (IVF) also causes MZ twinning occasionally (Aston et al., 2008). Changes in DZ twinning rates are influenced by maternal age, ethnicity, family history, and height and weight. The higher DZ twinning rate since the 1980s have been attributed to the widespread use of IVF and other fertility treatments in most industrialized countries (Imaizumi et al., 2003; Blickstein et al., 2005). Therefore, after the introduction of fertility drugs and IVF, variations in the DZ twinning were not only due to biological factors, but also depended on the popularity of fertility drugs and IVF in each country.

In this sample, the proportion of MZ to DZ twins across the studied birth-year cohorts (from 1886-1909 to 1980-1994) is as follows: 37%, 39%, 41%, 35%, 33%, 38%, 43%, 48%, 50%. This shows that the proportion of MZ to DZ twins is quite similar from 1886-1909 to 1950-1959 (33-41%) and starts to increase from 1960, which does not reflect the rise in DZ twins seen in developed countries during the past three decades. In a previous study on this database, we showed that there was no zygosity difference in height variance, neither in childhood nor in adulthood (Jelenkovic et al., 2015). Therefore, there is no reason to think that changes in the proportion of MZ to DZ twins would affect variance components estimates. This has now been discussed in limitations.

2) As a sidebar to the above question: Shouldn't the proportion of opposite-sex DZ be higher than what the study found?

The reviewer is right in that the proportion of same sex (SSDZ) and opposite sex (OSDZ) dizygotic twins should be the same. The considerably smaller proportion of OSDZ compared to SSDZ twins in this study is explained by the fact that some of the twin cohorts in our database have collected, by design, only SSDZ twins and thus do not have data on OSDZ twins. This has now been mentioned in the manuscript.

3) I am intrigued by the apparent secular decreases in the proportion of variation due to the unique environment component. This happened for both men and women and were more noticeable for the European cohorts. It seems to me that this suggests that the original declining-deprivation hypothesis has some merit. The authors focused on the additive genetic component but did not discuss much what happened to the other components.

A decreasing trend in the proportion of variation due to unique environmental factors (E) across birth-year cohorts was observed only for the four earliest birth cohorts, and was more noticeable in Europe and in women. That is, this trend was not observed in East Asia or North America and Australia (except for the slightly greater relative E variance in 1886-1909 for women in North America and Australia), nor in Europe from 1940 onwards. Moreover, in men, the decrease in relative E variance was not associated with a parallel increase in relative A variance (because relative C variance increased), which does not support the declining-deprivation hypothesis. That is, since height is influenced by environmental factors during the whole growth period (particularly in infancy and puberty), we expect that some of these environmental factors are shared by co-twins; therefore, and according to the hypothesis, this should have been seen as a decrease in C variance, which was not observed. In fact, in several cases a decrease in relative E variance was associated with an increase in relative C variance. If we look at the raw variances, the decreasing trend in E variance in the earliest birth cohorts is noticeable for women but not clear for men.

In summary, the parallel decrease in relative E variance and increase in relative A variance was observed only in European women for the four earliest birth-year cohorts; in fact, the heritability estimate decreased again in the two latest birth cohorts. Therefore, we alternatively speculated that the greater influence of unique environmental factors in the earliest birth cohorts in womenmight be explained byshrinkage in old age. Finally, since shared environmental factors did not show any pattern across birth-years cohorts, we described the results but not discussed them in the Discussion.

4) It is worth considering presenting the results of both sexes together as well as split by sex. Whilst I can think of reasons why changes in the heritability of height may differ by sex, it is not clear why the authors have stratified their primary analysis by sex. If the main hypothesis is that secular changes will change the heritability of height, one would expect these to operate in the childhood growth of boys and girls. Perhaps girls will be less susceptible because they grow for a shorter period of their lives. But why reduce the power of the study by half? (Especially when there are wider confidence intervals around estimates from before 1940s.)

We presented the results separately in men and women because the model fit statistics showed that the variance components differed between sexes in all birth-year cohorts, and the relative contribution of the genetic and environmental variance components differ in the three earliest and two latest birth-year cohorts (Table 2 in Supplementary file 1).

As suggested by the reviewer, we have now estimated both raw and relative genetic and environmental variances for men and women together. However, we decided to present these combined results as a supplementary table (Table 3 in Supplementary file 1) because 1) they did not provide any additional information on the trend across birth-year cohorts compared to the results for men and women separately and 2) since variance components differed between sexes, we think it is more appropriate to estimate them separately in men and women. This has now been mentioned in the text.

5) Are the differences between men and women in the earliest time points significant? It is not clear. The authors speculate that there may have been stronger survival effects in men, but this will be unnecessary speculation if there is no evidence of a difference between sexes.

The variance components differed between sexes in all birth-year cohorts, and the relative contribution of the genetic and environmental variance components differed in the three earliest and two latest birth-year cohorts (Table 2 in Supplementary file 1). We have now mentioned in Methods section that these differences were statistically significant at p<0.0001. Based on these results, we think that it is worth to speculate that there may have been stronger survival effects in men.

6) It is not possible to prove the negative. Instead can the authors place some bounds on their conclusions? E.g., "we could exclude an increase of x% genetic variance per generation (25 years) with 95% confidence"? On a related note, there are no p values or effect sizes anywhere in the main text. This makes the reader take the results on faith (e.g. It is not clear whether "trend" means a statistically robust trend or just a hint). I realise these appear in the supplementary information, but I think it would help the reader to see the genetic variances across time with 95% CIs at least (and combined sexes would be most powerful).

As suggested by the reviewer, we have quantified the increase in genetic variance per generation by using G-E interaction analyses. The results showed that genetic variance increased 1.37 (95% CI 0.50-2.27) and 1.07 (95% CI 0.46-1.79) per 25 years in men and women, respectively, which information is now given in the main text. The 95% CIs thus shows that the increase of genetic variance is statistically significant but the increasing effect in variance is still quite modest. As suggested by the reviewer, we have now also included in the main text the table showing the proportion of height variance explained by A, C and E factors. As previously explained in comment 4, we finally decided to present in the main text the results separately in men and women (and combined results in supplementary table) because variance components differed between sexes and thus we think that, even if less powerful, results are more correct.

7) Can the authors comment more on the overall increase in variance observed? It is worth noting that the genetic variance appears to go up in line with the overall variance. The reasons for this are not testable I imagine, but presumably could be due to increased ethnic diversity, and greater variation in living standards, as the average increases. It is clear in Figure 1 but not in the text.

Although there is a general trend to increasing total and genetic variance across birth cohorts, genetic variance does not always go up with total variance. For example, in men, the greatest increase in total variance was observed from birth cohort 1940-1949 to 1960-1969 and although genetic variance also increased during this period it increased especially in the two latest birth-year cohorts (1970-1979 and 1980-1994). In women, although total variance also started to increase from birth cohort 1940-1949, genetic variance showed the greatest increase from 1886-1900 to 1940-1949. As can be seen in Figure 1, part of the increase in total variance is due to the increase in shared environmental variance. Therefore, and as suggested by the reviewer, the increase in total height variation could be due to both increased ethnic diversity and greater variation in living standards. This has now been discussed in the text.

8) Supplementary file 1: Tables 1 and 2 should be part of the main article. It would help the reader to see some stats in the main section of the paper.

Supplementary Table 2 is now part the main text as Table 2: however, we have not included Supplementary Table 1 because the results are already provided in Figure 1 (without CIs) and we think it would provide repeated information.

https://doi.org/10.7554/eLife.20320.007

Article and author information

Author details

  1. Aline Jelenkovic

    1. Department of Social Research, University of Helsinki, Helsinki, Finland
    2. Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain
    Contribution
    AJ, In charge of data management, Conducted the analyses, Wrote the first draft of the manuscript and has primary responsibility of the final content
    For correspondence
    aline.jelenkovic@helsinki.fi
    Competing interests
    The authors declare that no competing interests exist.
  2. Yoon-Mi Hur

    Department of Education, Mokpo National University, Jeonnam, South Korea
    Contribution
    Y-MH, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  3. Reijo Sund

    Department of Social Research, University of Helsinki, Helsinki, Finland
    Contribution
    RS, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  4. Yoshie Yokoyama

    Department of Public Health Nursing, Osaka City University, Osaka, Japan
    Contribution
    YY, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  5. Sisira H Siribaddana

    1. Institute of Research & Development, Battaramulla, Sri Lanka
    2. Faculty of Medicine & Allied Sciences, Rajarata University of Sri Lanka, Saliyapura, Sri Lanka
    Contribution
    SHS, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  6. Matthew Hotopf

    NIHR Mental Health Biomedical Research Centre, South London and Maudsley NHS Foundation Trust and, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, United Kingdom
    Contribution
    MH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  7. Athula Sumathipala

    1. Institute of Research & Development, Battaramulla, Sri Lanka
    2. Research Institute for Primary Care and Health Sciences, School for Primary Care Research, Faculty of Health, Keele University, Staffordshire, United Kingdom
    Contribution
    ASu, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  8. Fruhling Rijsdijk

    MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
    Contribution
    FRi, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  9. Qihua Tan

    Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, Odense, Denmark
    Contribution
    QT, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  10. Dongfeng Zhang

    Department of Public Health, Qingdao University Medical College, Qingdao, China
    Contribution
    DZ, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  11. Zengchang Pang

    Department of Noncommunicable Diseases Prevention, Qingdao Centers for Disease Control and Prevention, Qingdao, China
    Contribution
    ZP, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  12. Sari Aaltonen

    1. Department of Social Research, University of Helsinki, Helsinki, Finland
    2. Department of Public Health, University of Helsinki, Helsinki, Finland
    Contribution
    SA, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  13. Kauko Heikkilä

    Department of Public Health, University of Helsinki, Helsinki, Finland
    Contribution
    KH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  14. Sevgi Y Öncel

    Department of Statistics, Faculty of Arts and Sciences, Kirikkale University, Kirikkale, Turkey
    Contribution
    SYÖ, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  15. Fazil Aliev

    1. Faculty of Business, Karabuk University, Karabuk, Turkey
    2. Department of Psychology, Virginia Commonwealth University, Richmond, United States
    3. Department of African American Studies, Virginia Commonwealth University, Richmond, United States
    Contribution
    FA, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  16. Esther Rebato

    Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain
    Contribution
    ER, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  17. Adam D Tarnoki

    1. Department of Radiology and Oncotherapy, Semmelweis University, Budapest, Hungary
    2. Hungarian Twin Registry, Budapest, Hungary
    Contribution
    ADT, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  18. David L Tarnoki

    1. Department of Radiology and Oncotherapy, Semmelweis University, Budapest, Hungary
    2. Hungarian Twin Registry, Budapest, Hungary
    Contribution
    DLT, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  19. Kaare Christensen

    1. The Danish Twin Registry, University of Southern Denmark, Odense, Denmark
    2. Department of Public Health, Epidemiology, Biostatistics & Biodemography, University of Southern Denmark, Odense, Denmark
    3. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
    4. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
    Contribution
    KC, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  20. Axel Skytthe

    1. The Danish Twin Registry, University of Southern Denmark, Odense, Denmark
    2. Department of Public Health, Epidemiology, Biostatistics & Biodemography, University of Southern Denmark, Odense, Denmark
    Contribution
    ASk, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  21. Kirsten O Kyvik

    1. Department of Clinical Research, University of Southern Denmark, Odense, Denmark
    2. Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark
    Contribution
    KOK, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  22. Judy L Silberg

    Department of Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States
    Contribution
    JLS, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  23. Lindon J Eaves

    Department of Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States
    Contribution
    LJE, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  24. Hermine H Maes

    Department of Human and Molecular Genetics, Psychiatry & Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States
    Contribution
    HHM, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  25. Tessa L Cutler

    The Australian Twin Registry, Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia
    Contribution
    TLC, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  26. John L Hopper

    1. The Australian Twin Registry, Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Australia
    2. Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea
    Contribution
    JLH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  27. Juan R Ordoñana

    1. Department of Human Anatomy and Psychobiology, University of Murcia, Murcia, Spain
    2. IMIB-Arrixaca, Murcia, Spain
    Contribution
    JRO, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  28. Juan F Sánchez-Romera

    1. IMIB-Arrixaca, Murcia, Spain
    2. Department of Developmental and Educational Psychology, University of Murcia, Murcia, Spain
    Contribution
    JFS-R, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  29. Lucia Colodro-Conde

    1. Department of Human Anatomy and Psychobiology, University of Murcia, Murcia, Spain
    2. QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Contribution
    LC-C, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  30. Wendy Cozen

    1. Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, United States
    2. USC Norris Comprehensive Cancer Center, Los Angeles, United States
    Contribution
    WC, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  31. Amie E Hwang

    Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, United States
    Contribution
    AEH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  32. Thomas M Mack

    1. Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, United States
    2. USC Norris Comprehensive Cancer Center, Los Angeles, United States
    Contribution
    TMM, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  33. Joohon Sung

    1. Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea
    2. Institute of Health and Environment, Seoul National University, Seoul, South-Korea
    Contribution
    JS, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  34. Yun-Mi Song

    Department of Family Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South-Korea
    Contribution
    Y-MS, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  35. Sarah Yang

    1. Department of Epidemiology, School of Public Health, Seoul National University, Seoul, Korea
    2. Institute of Health and Environment, Seoul National University, Seoul, South-Korea
    Contribution
    SY, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  36. Kayoung Lee

    Department of Family Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
    Contribution
    KL, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  37. Carol E Franz

    Department of Psychiatry, University of California, San Diego, San Diego, United States
    Contribution
    CEF, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  38. William S Kremen

    1. Department of Psychiatry, University of California, San Diego, San Diego, United States
    2. VA San Diego Center of Excellence for Stress and Mental Health, La Jolla, CA, United States
    Contribution
    WSK, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  39. Michael J Lyons

    Department of Psychology, Boston University, Boston, United States
    Contribution
    MJL, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  40. Andreas Busjahn

    HealthTwiSt GmbH, Berlin, Germany
    Contribution
    AB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  41. Tracy L Nelson

    Department of Health and Exercise Sciences and Colorado School of Public Health, Colorado State University, Colorado, United States
    Contribution
    TLN, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  42. Keith E Whitfield

    Psychology and Neuroscience, Duke University, Durham, United States
    Contribution
    KEW, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  43. Christian Kandler

    Department of Psychology, Bielefeld University, Bielefeld, Germany
    Contribution
    CK, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  44. Kerry L Jang

    Department of Psychiatry, University of British Columbia, Vancouver, Canada
    Contribution
    KLJ, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  45. Margaret Gatz

    1. Department of Psychology, University of Southern California, Los Angeles, United States
    2. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Contribution
    MG, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  46. David A Butler

    Health and Medicine Division, The National Academies of Sciences, Engineering, and Medicine, Washington, United States
    Contribution
    DAB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  47. Maria A Stazi

    Istituto Superiore di Sanità - National Center for Epidemiology, Surveillance and Health Promotion, Rome, Italy
    Contribution
    MAS, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  48. Corrado Fagnani

    Istituto Superiore di Sanità - National Center for Epidemiology, Surveillance and Health Promotion, Rome, Italy
    Contribution
    CF, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  49. Cristina D'Ippolito

    Istituto Superiore di Sanità - National Center for Epidemiology, Surveillance and Health Promotion, Rome, Italy
    Contribution
    CD, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  50. Glen E Duncan

    Washington State Twin Registry, Washington State University - Health Sciences Spokane, Spokane, United States
    Contribution
    GED, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  51. Dedra Buchwald

    Washington State Twin Registry, Washington State University, Seattle, United States
    Contribution
    DB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  52. Catherine A Derom

    1. Centre of Human Genetics, University Hospitals Leuven, Leuven, Belgium
    2. Department of Obstetrics and Gynaecology, Ghent University Hospitals, Ghent, Belgium
    Contribution
    CAD, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  53. Robert F Vlietinck

    Centre of Human Genetics, University Hospitals Leuven, Leuven, Belgium
    Contribution
    RFV, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  54. Ruth JF Loos

    1. The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
    2. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Contribution
    RJFL, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  55. Nicholas G Martin

    Genetic Epidemiology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Contribution
    NGM, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  56. Sarah E Medland

    Genetic Epidemiology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Contribution
    SEM, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  57. Grant W Montgomery

    Molecular Epidemiology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
    Contribution
    GWM, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  58. Hoe-Uk Jeong

    Department of Education, Mokpo National University, Jeonnam, South Korea
    Contribution
    H-UJ, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  59. Gary E Swan

    Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, United States
    Contribution
    GES, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  60. Ruth Krasnow

    Center for Health Sciences, SRI International, Menlo Park, United States
    Contribution
    RK, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  61. Patrik KE Magnusson

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Contribution
    PKEM, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  62. Nancy L Pedersen

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Contribution
    NLP, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  63. Anna K Dahl-Aslan

    1. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    2. Institute of Gerontology and Aging Research Network – Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Jönköping, Sweden
    Contribution
    AKD-A, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  64. Tom A McAdams

    MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
    Contribution
    TAM, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  65. Thalia C Eley

    MRC Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom
    Contribution
    TCE, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  66. Alice M Gregory

    Department of Psychology, Goldsmiths, University of London, London, United Kingdom
    Contribution
    AMG, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  67. Per Tynelius

    Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden
    Contribution
    PT, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  68. Laura A Baker

    Department of Psychology, University of Southern California, Los Angeles, United States
    Contribution
    LAB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  69. Catherine Tuvblad

    1. Department of Psychology, University of Southern California, Los Angeles, United States
    2. School of Law, Psychology and Social Work, Örebro University, Örebro, Sweden
    Contribution
    CT, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  70. Gombojav Bayasgalan

    Healthy Twin Association of Mongolia, Ulaanbaatar, Mongolia
    Contribution
    GB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  71. Danshiitsoodol Narandalai

    1. Healthy Twin Association of Mongolia, Ulaanbaatar, Mongolia
    2. Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
    Contribution
    DN, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  72. Paul Lichtenstein

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    Contribution
    PL, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  73. Timothy D Spector

    Department of Twin Research and Genetic Epidemiology, King's College, London, United Kingdom
    Contribution
    TDS, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  74. Massimo Mangino

    Department of Twin Research and Genetic Epidemiology, King's College, London, United Kingdom
    Contribution
    MMa, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  75. Genevieve Lachance

    Department of Twin Research and Genetic Epidemiology, King's College, London, United Kingdom
    Contribution
    GL, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  76. Meike Bartels

    Department of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands
    Contribution
    MB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  77. Toos CEM van Beijsterveldt

    Department of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands
    Contribution
    TCEMvB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  78. Gonneke Willemsen

    Department of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands
    Contribution
    GW, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  79. S Alexandra Burt

    Michigan State University, East Lansing, Michigan, United States
    Contribution
    SAB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  80. Kelly L Klump

    Michigan State University, East Lansing, Michigan, United States
    Contribution
    KLK, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  81. Jennifer R Harris

    Norwegian Institute of Public Health, Oslo, Norway
    Contribution
    JRH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  82. Ingunn Brandt

    Norwegian Institute of Public Health, Oslo, Norway
    Contribution
    IB, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  83. Thomas Sevenius Nilsen

    Norwegian Institute of Public Health, Oslo, Norway
    Contribution
    TSN, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  84. Robert F Krueger

    Department of Psychology, University of Minnesota, Minneapolis, United States
    Contribution
    RFK, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  85. Matt McGue

    Department of Psychology, University of Minnesota, Minneapolis, United States
    Contribution
    MMcGu, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  86. Shandell Pahlen

    Department of Psychology, University of Minnesota, Minneapolis, United States
    Contribution
    SP, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  87. Robin P Corley

    Institute for Behavioral Genetics, University of Colorado, Boulder, United States
    Contribution
    RPC, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  88. Jacob v B Hjelmborg

    1. The Danish Twin Registry, University of Southern Denmark, Odense, Denmark
    2. Department of Public Health, Epidemiology, Biostatistics & Biodemography, University of Southern Denmark, Odense, Denmark
    Contribution
    JvBH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  89. Jack H Goldberg

    Department of Epidemiology, School of Public Health, University of Washington, Seattle, United States
    Contribution
    JHG, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  90. Yoshinori Iwatani

    Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
    Contribution
    YI, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  91. Mikio Watanabe

    Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
    Contribution
    MW, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  92. Chika Honda

    Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
    Contribution
    CH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  93. Fujio Inui

    1. Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
    2. Faculty of Health Science, Kio University, Nara, Japan
    Contribution
    FI, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  94. Finn Rasmussen

    Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden
    Contribution
    FRa, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  95. Brooke M Huibregtse

    Institute for Behavioral Genetics, University of Colorado, Boulder, United States
    Contribution
    BMH, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  96. Dorret I Boomsma

    Department of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands
    Contribution
    DIB, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  97. Thorkild I A Sørensen

    1. Novo Nordisk Foundation Centre for Basic Metabolic Research (Section on Metabolic Genetics), University of Copenhagen, Copenhagen, Denmark
    2. Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    3. Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
    Contribution
    TIAS, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  98. Jaakko Kaprio

    1. Department of Public Health, University of Helsinki, Helsinki, Finland
    2. Institute for Molecular Medicine FIMM, Helsinki, Finland
    Contribution
    JK, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.
  99. Karri Silventoinen

    1. Department of Social Research, University of Helsinki, Helsinki, Finland
    2. Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
    Contribution
    KS, Planned the study design of the CODATwins project, Collected the data used in this study, Commented the manuscript, Read and approved the final version of the manuscript
    Competing interests
    The authors declare that no competing interests exist.

Funding

Suomen Akatemia (266592)

  • Karri Silventoinen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Acknowledgements

Support for collaborating projects: The Australian Twin Registry is supported by a Centre of Research Excellence (grant ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01). The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. Colorado Twin Registry is funded by NIDA funded center grant DA011015, and Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637-11. Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US National Institute of Health (P01 AG08761). Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE – European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J Kaprio). K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. Waves 1–3 of Genesis 12–19 were funded by the W T Grant Foundation, the University of London Central Research fund and a Medical Research Council Training Fellowship (G81/343) and Career Development Award (G120/635) to Thalia C. Eley. Wave four was supported by grants from the Economic and Social Research Council (RES-000-22–2206) and the Institute of Social Psychiatry (06/07–11) to Alice M. Gregory who was also supported at that time by a Leverhulme Research Fellowship (RF/2/RFG/2008/0145). Wave five was supported by funding to Alice M. Gregory from Goldsmiths, University of London. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011–220-E00006). The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health. The Murcia Twin Registry is supported by Fundación Séneca, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08, 15302/PHCS/10 and 19479/PI/14) and Ministry of Science and Innovation, Spain (PSI2009-11560 and PSI2014-56680-R). Data collection and research stemming from the Norwegian Twin Registry is supported, in part, from the European Union’s Seventh Framework Programmes ENGAGE Consortium (grant agreement HEALTH-F4-2007–201413, and BioSHaRE EU (grant agreement HEALTH-F4-2010–261433). The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61–090, 985-10–002, 912-10–020, 904-61–193,480-04–004, 463-06–001, 451-04–034, 400-05–717, Addiction-31160008, Middelgroot-911-09–032, Spinozapremie 56-464–14192; VU University’s Institute for Health and Care Research (EMGO+); the European Research Council (ERC - 230374), the Avera Institute, Sioux Falls, South Dakota (USA). South Korea Twin Registry is supported by the National Research Foundation of Korea (NRF-371-2011–1 B00047). S.Y. Öncel and F. Aliev are supported by Kırıkkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. TwinsUK was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007–2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). Washington State Twin Registry (formerly the University of Washington Twin Registry) was supported in part by grant NIH RC2 HL103416 (D. Buchwald, PI). Vietnam Era Twin Study of Aging was supported by the National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research and Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science.

Ethics

Human subjects: All participants were volunteers and gave their informed consent when participating in their original study. Only a limited set of observational variables and anonymized data were delivered to the data management center at University of Helsinki. The pooled analysis was approved by the ethical committee of Department of Public Health, University of Helsinki.

Reviewing Editor

  1. Eduardo Franco, McGill University, Canada

Publication history

  1. Received: August 4, 2016
  2. Accepted: November 21, 2016
  3. Version of Record published: December 14, 2016 (version 1)

Copyright

© 2016, Jelenkovic et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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    Circular RNAs (circRNAs) are found across eukaryotes and can function in post-transcriptional gene regulation. Their biogenesis through a circle-forming backsplicing reaction is facilitated by reverse-complementary repetitive sequences promoting pre-mRNA folding. Orthologous genes from which circRNAs arise, overall contain more strongly conserved splice sites and exons than other genes, yet it remains unclear to what extent this conservation reflects purifying selection acting on the circRNAs themselves. Our analyses of circRNA repertoires from five species representing three mammalian lineages (marsupials, eutherians: rodents, primates) reveal that surprisingly few circRNAs arise from orthologous exonic loci across all species. Even the circRNAs from orthologous loci are associated with young, recently active and species-specific transposable elements, rather than with common, ancient transposon integration events. These observations suggest that many circRNAs emerged convergently during evolution – as a byproduct of splicing in orthologs prone to transposon insertion. Overall, our findings argue against widespread functional circRNA conservation.