1. Epidemiology and Global Health
  2. Genetics and Genomics

Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study

  1. Amanda M Hughes  Is a corresponding author
  2. Eleanor Sanderson
  3. Tim Morris
  4. Ziada Ayorech
  5. Martin Tesli
  6. Helga Ask
  7. Ted Reichborn-Kjennerud
  8. Ole A Andreassen
  9. Per Magnus
  10. Øyvind Helgeland
  11. Stefan Johansson
  12. Pål Njølstad
  13. George Davey Smith
  14. Alexandra Havdahl
  15. Laura D Howe
  16. Neil M Davies
  1. Medical Research Council Integrative Epidemiology Unit, University of Bristol, United Kingdom
  2. Population Health Sciences, Bristol Medical School, University of Bristol, Barley House, Oakfield Grove, United Kingdom
  3. PROMENTA Research Centre, Department of Psychology, University of Oslo, Norway
  4. Nic Waals Institute, Lovisenberg Diaconal Hospital, Norway
  5. Department of Mental Disorders, Norwegian Institute of Public Health, Norway
  6. Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Norway
  7. Institute of Clinical Medicine, University of Oslo, Norway
  8. Centre for Fertility and Health, Norwegian Institute of Public Health, Norway
  9. Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway
  10. Department of Clinical Science, University of Bergen, Norway
  11. Department of Medical Genetics, Haukeland University Hospital, Norway
  12. Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Norway
  13. Children and Youth Clinic, Haukeland University Hospital, Norway
  14. K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Norway
https://doi.org/10.7554/eLife.74320
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Cite this article
  1. Amanda M Hughes
  2. Eleanor Sanderson
  3. Tim Morris
  4. Ziada Ayorech
  5. Martin Tesli
  6. Helga Ask
  7. Ted Reichborn-Kjennerud
  8. Ole A Andreassen
  9. Per Magnus
  10. Øyvind Helgeland
  11. Stefan Johansson
  12. Pål Njølstad
  13. George Davey Smith
  14. Alexandra Havdahl
  15. Laura D Howe
  16. Neil M Davies
(2022)
Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study
eLife 11:e74320.
https://doi.org/10.7554/eLife.74320
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6 figures, 17 tables and 3 additional files

Figures

Figure 1
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Bias in Mendelian randomization studies which do not account for parental genotype.

Figure 1 is reproduced from Figure 1; Morris et al., 2020. Population stratification due to ancestral differences (yellow lines), dynastic effects (red lines), and assortative mating (green line). In within-family Mendelian randomization, parental genotype is controlled for, so effect estimates for the influence of child’s genotype on child phenotypes are unbiased by these processes.

Figure 2
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BMI and child’s depressive, anxiety, and ADHD symptoms, using a polygenic score for adult BMI (N=40,949 trios).

Coefficients represent standard-deviation change in outcomes per 5 kg/m2 increase in BMI, shown with 95% confidence intervals.

Figure 3
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BMI and child’s depressive, anxiety, and ADHD symptoms, using a polygenic score for childhood body size (N=40,949 trios).

Coefficients represent standard-deviation change in outcomes per 5 kg/m2 increase in BMI, shown with 95% confidence intervals.

Appendix 1—figure 1
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Flow chart of inclusion and exclusion of MoBa participants into the study sample.
Appendix 1—figure 2
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Associations of child’s BMI polygenic scores with ancestry.

Associations of the child’s polygenic scores for BMI and the child’s principal components of ancestry, adjusted for the child’s genotyping centre and chip.

Appendix 1—figure 3
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Associations of child’s BMI polygenic scores with ancestry, adjusted for parental polygenic scores.

Associations of the child’s polygenic scores for BMI and the child’s principal components of ancestry, adjusted for the child’s genotyping centre and chip and the parents’ polygenic scores.

Tables

Table 1
Descriptive characteristics of analytic sample (N=40,949)*.
Continuous variablesmeanSD
Maternal age at child’s birth (years)30.24.4
Paternal age at birth (years)32.65.1
Maternal depressive/anxiety symptoms, Hopkins Symptoms Checklist-25 (SCL-25)†1.21.9
Paternal depressive/anxiety symptoms, Hopkins Symptoms Checklist-25 (SCL-25) ‡1.12.1
Maternal ADHD symptoms: adult ADHD self-report scale §6.73.4
Paternal ADHD symptoms: adult ADHD self-report scale 8.33.1
Maternal pre-pregnancy BMI (kg/m2)24.04.1
Paternal BMI (kg/m2)25.93.2
Child’s BMI at age 8 (kg/m2)16.32.0
Child depressive symptoms age 8: Short Mood and Feelings Questionnaire (SMFQ)**1.92.5
Child anxiety symptoms age 8: Screen for Child Anxiety Related Disorders (SCARED)††1.01.2
Child ADHD symptoms age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD) ‡ ‡8.67.2
Child ADHD symptoms (inattention) age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD) § §5.04.1
Child ADHD symptoms (hyperactivity) age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)§ §3.63.9
Categorical variablesCategory%
Child’s sexMale51.1
Female48.9
Maternal educational qualifications9 year elementary education2.0
Up to 2 years further education4.1
Further education: vocational12.2
Further education: general studies, sixth form14.9
Higher education: college/university, up to 4 years42.8
Higher education: college/university, over 4 years24.0
Paternal educational qualifications9 year elementary education3.4
Up to 2 years further education5.6
Further education: vocational25.1
Further education: general studies, sixth form12.9
Higher education: college/university, up to 4 years28.4
Higher education: college/university, over 4 years24.4
Maternal parity at child’s birth046.8
135.7
214.0
3+2.7
4+0.7
Mother’s marital status at birthMarried/registered partner97.4
single2.6
Mother’s smoking status during pregnancynever51.0
Stopped before week 1742.0
Currently, sometimes2.4
Currently, daily4.5
  1. *

    The reasons for exclusions and numbers in each case are shown in Appendix 1—figure 1. Missing data in BMI, outcomes and covariates was imputed using multiple imputation by chained equations. Descriptive statistics for the unimputed data are shown in Appendix 1.

  2. †

    Based on 5 items. Possible range: 0–15.

  3. ‡

    Based on 8 items. Possible range: 0–24.

  4. §

    Possible range: 0–24.

  5. Possible range: 0–24.

  6. **

    Possible range: 0-26.

  7. ††

    Possible range: 0–10.

  8. ‡ ‡

    Possible range: 0–54.

  9. § §

    Possible range: 0–27.

Appendix 1—table 1
Descriptive statistics of full MoBa sample (N=113,691)*.
Continuous variablesmeanSDN obs
Maternal age at birth30.14.6113,691
Paternal age at birth32.75.5113,172
Maternal depressive/anxiety symptoms, based on 5 items from the
Hopkins Symptoms Checklist-25 (SCL-25)†		1.32.0100,570
Paternal depressive/anxiety symptoms, based on 8 items from the
Hopkins Symptoms Checklist-25 (SCL-25)‡		1.22.177,018
Maternal ADHD symptoms: adult ADHD self-report scale§6.63.556,255
Paternal ADHD symptoms: adult ADHD self-report scale8.23.234,425
Maternal pre-pregnancy BMI (kg/m2)24.04.1100,060
Paternal BMI (kg/m2)25.93.379,536
Child’s BMI at age 8 (kg/m2)16.22.036,894
Child depressive symptoms age 8: Short Mood and Feelings Questionnaire (SMFQ)**1.92.443,065
Child anxiety symptoms age 8: Screen for Child Anxiety Related Disorders (SCARED)††1.01.243,298
Child ADHD symptoms age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)‡ ‡8.57.243,238
Child ADHD symptoms (inattention) age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)§ §5.04.143,194
Child ADHD symptoms (hyperactivity) age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)§ §3.63.943,177
Categorical variablesCategory%N obs
Child’s sexmale51.3113,477
female48.7
maternal educational qualifications9 year elementary education2.8101,020
Up to 2 years further education5.2
Further education: vocational12.8
Further education: general studies, sixth form15.7
Higher education: college/university, up to 4 years40.9
Higher education: college/university, over 4 years22.6
paternal educational qualifications9 year elementary education4.8100,891
Up to 2 years further education6.6
Further education: vocational26.2
Further education: general studies, sixth form13.2
Higher education: college/university, up to 4 years26.5
Higher education: college/university, over 4 years22.7
maternal parity at child’s birth044.0113,691
135.9
215.6
33.4
4+1.1
Mother’s marital status at birthMarried/registered partner95.5113,691
single4.5
Mother’s smoked during pregnancynever49.9101,373
Stopped before week 1741.7
Currently, sometimes2.8
Currently, daily5.6
  1. *

    All participants in the birth registry file who had not withdrawn consent.

  2. †

    Possible range: 0–15.

  3. ‡

    Possible range: 0–24.

  4. §

    Possible range: 0–24.

  5. Possible range: 0–24.

  6. **

    Possible range: 0-26.

  7. ††

    Possible range: 0-10.

  8. ‡ ‡

    Possible range: 0–54.

  9. § §

    Possible range: 0–27.

Appendix 1—table 2
Descriptive statistics of analytic sample (N=40,949)*, unimputed data.
Continuous variablesmeanSDN obs
Maternal age at birth30.24.440,949
Paternal age at birth32.65.140,945
Maternal depressive/anxiety symptoms, based on 5 items from the
Hopkins Symptoms Checklist-25 (SCL-25)†		1.21.939,647
Paternal depressive/anxiety symptoms, based on 8 items from the
Hopkins Symptoms Checklist-25 (SCL-25)‡		1.12.138,050
Maternal ADHD symptoms: adult ADHD self-report scale§6.53.424,192
Paternal ADHD symptoms: adult ADHD self-report scale8.23.116,348
Maternal pre-pregnancy BMI (kg/m2)24.04.139,323
Paternal BMI (kg/m2)25.93.239,405
Child’s BMI at age 8 (kg/m2)16.22.016,144
Child depressive symptoms age 8: Short Mood and Feelings Questionnaire (SMFQ)**1.82.418,747
Child anxiety symptoms age 8: Screen for Child Anxiety Related Disorders (SCARED)††1.01.218,834
Child ADHD symptoms age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)‡ ‡8.47.118,813
Child ADHD symptoms (inattention) age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)§ §4.94.018,794
Child ADHD symptoms (hyperactivity) age 8: Parent/Teacher Rating Scale for Disruptive Behaviour Disorders (RS-DBD)§ §3.53.818,787
Categorical variablesCategory%N obs
Child’s sexmale51.040,949
female48.9
maternal educational qualifications9 year elementary education2.039,569
Up to 2 years further education4.1
Further education: vocational12.1
Further education: general studies, sixth form14.9
Higher education: college/university, up to 4 years42.8
Higher education: college/university, over 4 years24.8
paternal educational qualifications9 year elementary education3.440,062
Up to 2 years further education5.6
Further education: vocational25.1
Further education: general studies, sixth form12.9
Higher education: college/university, up to 4 years28.5
Higher education: college/university, over 4 years24.4
maternal parity at child’s birth046.840,949
135.7
214.0
32.7
4+0.7
Mother’s marital status at birthMarried/registered partner97.440,949
single2.6
Mother’s smoked during pregnancynever51.140,118
Stopped before week 1742.0
Currently, sometimes2.4
Currently, daily4.5
  1. *

    The reasons for exclusions and numbers in each case are shown in Appendix 1—figure 1.

  2. †

    Possible range: 0–15.

  3. ‡

    Possible range: 0–24.

  4. §

    Possible range: 0–24.

  5. Possible range: 0–24.

  6. **

    Possible range: 0-26.

  7. ††

    Possible range: 0–10.

  8. ‡ ‡

    Possible range: 0–54.

  9. § §

    Possible range: 0–27.

Appendix 1—table 3
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, adult BMI PGS (N=40,949)*.
Non-genetic estimate†MR estimate ‡Within-families MR estimate ‡
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: standardized SMFQ§ scoreChild BMI0.050.01,0.090.020.450.26,0.64<0.0010.26–0.01,0.520.06
Mother’s BMI0.050.03,0.07<0.0010.110.02,0.190.01
Father’s BMI0.01–0.02,0.030.670.02–0.09,0.130.71
Anxiety symptoms: standardized SCARED scoreChild BMI–0.07−0.11,–0.030.001–0.06–0.25,0.120.510.01–0.25,0.260.96
Mother’s BMI0.01–0.01,0.030.47–0.03–0.11,0.050.49
Father’s BMI–0.00–0.02,0.020.89–0.02–0.13,0.090.72
ADHD symptoms: standardized RS-DBD** score, ADHD itemsChild BMI–0.07−0.11,–0.030.0010.350.17,0.53<0.0010.360.09,0.630.009
Mother’s BMI0.040.02,0.06<0.0010.00–0.08,0.090.97
Father’s BMI0.02–0.00,0.040.10–0.01–0.12,0.090.80
ADHD-inattention symptoms: standardized RS-DBD** score, inattention itemsChild BMI–0.06−0.10,–0.020.0060.320.14,0.49<0.0010.380.12,0.650.005
Mother’s BMI0.050.03,0.07<0.0010.01–0.08,0.090.86
Father’s BMI0.02–0.00,0.050.06–0.06–0.17,0.040.24
ADHD-hyperactivity symptoms: standardized RS-DBD** score, hyperactivity itemsChild BMI–0.06−0.10,–0.020.0020.310.13,0.490.0010.27–0.00,0.540.05
Mother’s BMI0.030.01,0.050.005–0.00–0.09,0.080.92
Father’s BMI0.01–0.01,0.040.320.04–0.07,0.150.47
  1. *

    Coefficients represent S.D. change in symptoms per 5 kg/m2 increase in BMI.

  2. †

    Phenotypic models adjust for the child’s sex and birth year, the mother’s parity at the child’s birth, and the mother’s and father’s: educational qualifications, depressive/anxiety and ADHD symptoms, and smoking status during pregnancy. They also adjust for the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Genetic models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  4. §

    Short Mood and Feelings Questionnaire.

  5. Screen for Child Anxiety Related Disorders.

  6. **

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 4
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, childhood body size PGS (N=40,949)*.
Non-genetic estimate†MR estimate ‡Within-families MR estimate ‡
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: standardized SMFQ§ scoreChild BMI0.050.01,0.090.020.08–0.07,0.220.290.02–0.20,0.230.88
Mother’s BMI0.050.03,0.07<0.0010.02–0.09,0.140.67
Father’s BMI0.01–0.02,0.030.670.05–0.10,0.190.51
Anxiety symptoms: standardized SCARED scoreChild BMI–0.07−0.11,–0.030.001–0.04–0.18,0.110.620.02–0.18,0.230.83
Mother’s BMI0.01–0.01,0.030.47–0.02–0.12,0.090.78
Father’s BMI–0.00–0.02,0.020.89–0.06–0.19,0.080.42
ADHD symptoms: standardized RS-DBD** score, ADHD itemsChild BMI–0.07−0.11,–0.030.001–0.07–0.21,0.070.35–0.03–0.22,0.170.80
Mother’s BMI0.040.02,0.06<0.001–0.03–0.12,0.070.62
Father’s BMI0.02–0.00,0.040.10–0.02–0.15,0.110.77
ADHD-inattention symptoms: standardized RS-DBD** score, inattention itemsChild BMI–0.06−0.10,–0.020.006–0.04–0.18,0.110.63–0.05–0.25,0.140.59
Mother’s BMI0.050.03,0.07<0.0010.03–0.07,0.130.61
Father’s BMI0.02–0.00,0.050.06–0.01–0.14,0.120.86
ADHD-hyperactivity symptoms: standardized RS-DBD** score, hyperactivity itemsChild BMI–0.06−0.10,–0.020.002–0.08–0.22,0.050.240.01–0.20,0.220.95
Mother’s BMI0.030.01,0.050.005–0.07–0.18,0.030.18
Father’s BMI0.01–0.01,0.040.32–0.02–0.16,0.110.74
  1. *

    Coefficients represent S.D. change in symptoms per 5 kg/m2 increase in BMI.

  2. †

    Phenotypic models adjust for the child’s sex and birth year, the mother’s parity at the child’s birth, and the mother’s and father’s: educational qualifications, depressive/anxiety and ADHD symptoms, and smoking status during pregnancy. They also adjust for the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Genetic models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  4. §

    Short Mood and Feelings Questionnaire.

  5. Screen for Child Anxiety Related Disorders.

  6. **

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders

Appendix 1—table 5
Associations of phenotypes and polygenic scores within parental pairs*.
Phenotypes: regression of father’s BMI, depressive symptoms, and ADHD symptoms on mother’s phenotypes
Father’s: BMIFather’s: Depressive symptomsFather’s: ADHD symptoms
Beta (95% CI), pBeta (95% CI), pBeta (95% CI), p
Mother’s: BMI0.23 (0.22,0.25) p<0.0010.01 (-0.00,0.02) p=0.090.03 (0.02,0.05) p<0.001
Mother’s: Depressive symptoms0.00 (-0.01,0.01), p=0.850.18 (0.16,0.20) p<0.0010.10 (0.09,0.12), P<0.001
Mother’s: ADHD symptoms0.01 (-0.02,0.01) p=0.320.05 (0.05,0.06) p<0.0010.11 (0.09,0.13) p<0.001
Polygenic scores: regression of father’s PGS for BMI, depression, and ADHD: regression of father’s PGS on mother’s PGS
Father’s: Adult BMI PGSFather’s: Childhood body size PGSFather’s: Depression PGSFather’s: ADHD PGS
Beta (95% CI), pBeta (95% CI), pBeta (95% CI), pBeta (95% CI)
Mother’s: Adult BMI PGS0.01 (0.00,0.02), p=0.020.01 (0.00,0.02), p=0.008–0.00 (-0.01,0.01), p=0.62–0.00 (-0.01,0.01), p=0.49
Mother’s: Childhood body size PGS0.01 (-0.00,0.02), p=0.100.01 (-0.00,0.02), p=0.150.00 (-0.00,0.01), p=0.330.01 (0.00,0.02), p=0.03
Mother’s: Depression PGS–0.01 (−0.02–0.00), p=0.11–0.00 (-0.01,0.01), p=0.76–0.00 (-0.01,0.01), p=0.44–0.00 (-0.01,0.01), p=0.47
Mother’s: ADHD PGS–0.00 (-0.01,0.01), p=0.580.01 (-0.00,0.02), p=0.24–0.00 (-0.01,0.01), p=0.42–0.00 (-0.01,0.01), p=0.93
  1. *

    All models adjusted for the first 20 principal components of ancestry, genotyping centre and genotyping chip of the mother and father.

Appendix 1—table 6
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, adult BMI PGS, log-transformed outcomes (N=40,949)*.
Non-genetic estimate†MR estimate ‡Within-families MR estimate ‡
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: log-transformed SMFQ§ scoreChild BMI0.030.01,0.060.020.310.18,0.45<0.0010.16–0.04,0.350.12
Mother’s BMI0.040.03,0.05<0.0010.080.02,0.140.01
Father’s BMI0.01–0.01,0.020.560.03–0.05,0.100.52
Anxiety symptoms: log-transformed SCARED scoreChild BMI–0.03−0.05,–0.010.001–0.04–0.14,0.050.38–0.00–0.14,0.130.97
Mother’s BMI0.00–0.01,0.010.60–0.02–0.06,0.020.35
Father’s BMI–0.00–0.01,0.011.00–0.01–0.06,0.050.79
ADHD symptoms: log-transformed RS-DBD** scoreChild BMI–0.05−0.08,–0.020.0020.270.13,0.40<0.0010.280.08,0.490.006
Mother’s BMI0.030.02,0.05<0.0010.00–0.06,0.070.90
Father’s BMI0.02–0.00,0.030.07–0.02–0.10,0.060.66
ADHD-inattention symptoms: log-transformed RS-DBD** score, inattention itemsChild BMI–0.04−0.07,–0.010.0070.220.09,0.340.0010.290.10,0.470.003
Mother’s BMI0.030.02,0.05<0.0010.00–0.06,0.070.92
Father’s BMI0.020.00,0.030.05–0.06–0.14,0.020.13
ADHD-hyperactivity symptoms: log-transformed RS-DBD** score, hyperactivity itemsChild BMI–0.05−0.08,–0.010.0040.240.10,0.390.0010.18–0.04,0.400.10
Mother’s BMI0.020.00,0.040.010.00–0.07,0.071.00
Father’s BMI0.01–0.01,0.030.250.05–0.04,0.140.29
  1. *

    Coefficients represent change in symptoms, log-transformed after adding 1, per 5 kg/m2 increase in BMI.

  2. †

    Phenotypic models adjust for the child’s sex and birth year, the mother’s parity at the child’s birth, and the mother’s and father’s: educational qualifications, depressive/anxiety and ADHD symptoms, and smoking status during pregnancy. They also adjust for the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Genetic models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  4. §

    Short Mood and Feelings Questionnaire.

  5. Screen for Child Anxiety Related Disorders.

  6. **

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 7
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, childhood body size PGS, log-transformed outcomes (N=40,949)*.
Non-genetic estimate†MR estimate ‡Within-families MR estimate ‡
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: log-transformed SMFQ§ scoreChild BMI0.030.01,0.060.020.07–0.04,0.170.200.02–0.14,0.170.84
Mother’s BMI0.040.03,0.05<0.0010.02–0.06,0.100.67
Father’s BMI0.01–0.01,0.020.560.05–0.06,0.150.39
Anxiety symptoms: log-transformed SCARED scoreChild BMI–0.03−0.05,–0.010.001–0.03–0.10,0.050.490.01–0.10,0.120.89
Mother’s BMI0.00–0.01,0.010.60–0.01–0.07,0.040.69
Father’s BMI–0.00–0.01,0.011.00–0.03–0.10,0.040.43
ADHD symptoms: log-transformed RS-DBD** scoreChild BMI–0.05−0.08,–0.020.002–0.06–0.17,0.050.30–0.03–0.19,0.130.70
Mother’s BMI0.030.02,0.05<0.001–0.02–0.10,0.060.68
Father’s BMI0.02–0.00,0.030.07–0.01–0.11,0.090.79
ADHD-inattention symptoms: log-transformed RS-DBD** score, inattention itemsChild BMI–0.04−0.07,–0.010.007–0.03–0.14,0.070.52–0.05–0.19,0.100.52
Mother’s BMI0.030.02,0.05<0.0010.02–0.06,0.090.64
Father’s BMI0.020.00,0.030.05–0.01–0.10,0.090.87
ADHD-hyperactivity symptoms: log-transformed RS-DBD** score, hyperactivity itemsChild BMI–0.05−0.08,–0.010.004–0.07–0.19,0.040.21–0.00–0.18,0.170.98
Mother’s BMI0.020.00,0.040.01–0.06–0.15,0.030.22
Father’s BMI0.01–0.01,0.030.25–0.02–0.13,0.090.73
  1. *

    Coefficients represent change in symptoms, log-transformed after adding 1, per 5 kg/m2 increase in BMI.

  2. †

    Phenotypic models adjust for the child’s sex and birth year, the mother’s parity at the child’s birth, and the mother’s and father’s: educational qualifications, depressive/anxiety and ADHD symptoms, and smoking status during pregnancy. They also adjust for the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Genetic models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  4. §

    Short Mood and Feelings Questionnaire.

  5. Screen for Child Anxiety Related Disorders.

  6. **

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 8
Robustness checks based on SNP-specific associations with child’s BMI* and outcomes: SNPs in adult BMI polygenic score.
Inverse-variance weightedMR-Egger: slopeMR-Egger: interceptMR-MedianMR-Modal
For classic MR modelsBetapBetapBetapBetapBetap
Depressive symptoms: standardized SMFQ† score0.12<0.0010.090.180.000.560.11<0.0010.070.42
Anxiety symptoms: standardized SCARED‡ score–0.020.13–0.050.450.000.61–0.010.870.010.92
ADHD symptoms: standardized RS-DBD§ score0.10<0.0010.020.770.000.190.090.010.070.40
ADHD symptoms (inattention): standardized RS-DBD§ score0.09<0.001–0.020.730.000.070.090.01–0.020.81
ADHD symptoms (hyperactivity): standardized RS-DBD§ score0.08<0.0010.050.400.000.610.080.020.050.55
Inverse-variance weightedMR-Egger: slopeMR-Egger: interceptMR-MedianMR-Modal
For within-families MR modelsBetapBetapBetapBetapBetap
Depressive symptoms: standardized SMFQ† score0.06<0.0010.040.670.000.770.070.160.020.83
Anxiety symptoms: standardized SCARED‡ score0.001.000.050.580.000.570.030.570.030.76
ADHD symptoms: standardized RS-DBD§ score0.09<0.0010.070.410.000.800.090.070.130.24
ADHD symptoms (inattention): standardized RS-DBD§ score0.10<0.0010.000.970.000.210.100.030.050.63
ADHD symptoms (hyperactivity): standardized RS-DBD§ score0.07<0.0010.130.130.000.440.070.140.060.56
  1. *

    In the main analyses, all coefficients are expressed in terms of S.D. change in symptoms per 5 kg/m2 increase in BMI. In robustness checks, SNP-exposure associations were taken directly from the relevant GWAS. Coefficients above for BMI-outcome associations are therefore on the scale of kg/m2.

  2. †

    Short Mood and Feelings Questionnaire.

  3. ‡

    Screen for Child Anxiety Related Disorders.

  4. §

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 9
Robustness checks based on SNP-specific associations with child’s BMI* and outcomes: SNPs in childhood body size polygenic score.
Inverse-variance weightedMR-Egger: slopeMR-Egger: interceptMR-MedianMR-Modal
For classic MR modelsBetapBetapBetapBetapBetap
Depressive symptoms: standardized SMFQ† score0.060.030.100.300.000.570.050.520.040.67
Anxiety symptoms: standardized SCARED‡ score–0.020.400.010.900.000.66–0.020.74–0.010.95
ADHD symptoms: standardized RS-DBD§ score–0.040.14–0.020.850.000.75–0.060.36–0.050.65
ADHD symptoms (inattention): standardized RS-DBD§ score–0.020.47–0.040.640.000.81–0.080.28–0.080.42
ADHD symptoms (hyperactivity): standardized RS-DBD§ score–0.050.050.010.900.000.42–0.050.48–0.040.68
Inverse-variance weightedMR-Egger: slopeMR-Egger: interceptMR-MedianMR-Modal
For within-families MR modelsBetapBetapBetapBetapBetap
Depressive symptoms: standardized SMFQ† score0.020.590.050.700.000.750.030.760.040.79
Anxiety symptoms: standardized SCARED‡ score0.020.600.070.640.000.690.040.660.050.74
ADHD symptoms: standardized RS-DBD§§ score–0.020.530.090.490.000.35–0.010.940.030.85
ADHD symptoms (inattention): standardized RS-DBD§ score–0.040.280.060.650.000.41–0.040.680.010.95
ADHD symptoms (hyperactivity): standardized RS-DBD§ score0.000.980.110.430.000.390.020.800.060.67
  1. *

    In the main analyses, all coefficients are expressed in terms of S.D. change in symptoms per 5 kg/m2 increase in BMI. In robustness checks, SNP-exposure associations were taken directly from the relevant GWAS. Coefficients above for BMI-outcome associations are therefore on the scale of kg/m2.

  2. †

    Short Mood and Feelings Questionnaire.

  3. ‡

    Screen for Child Anxiety Related Disorders.

  4. §

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 10
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, adult BMI PGS, complete-case analysis*.
Non-genetic estimate†MR estimate ‡Within-families MR estimate ‡
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: standardized SMFQ § score.
N=5,158		Child BMI0.080.00,0.150.050.380.00,0.770.050.16–0.35,0.660.55
Mother’s BMI0.070.03,0.11<0.0010.10–0.06,0.260.21
Father’s BMI0.01–0.04,0.050.790.04–0.15,0.230.66
Anxiety symptoms: standardized SCARED score.
N=5,177		Child BMI–0.04–0.12,0.030.26–0.15–0.54,0.240.45–0.07–0.62,0.480.80
Mother’s BMI0.02–0.02,0.060.260.06–0.11,0.220.48
Father’s BMI0.01–0.04,0.050.69–0.13–0.34,0.080.24
ADHD symptoms: standardized RS-DBD** score, ADHD items. N=5,174Child BMI–0.03–0.11,0.040.380.41–0.00,0.830.050.540.01,1.080.04
Mother’s BMI0.090.05,0.12<0.001–0.01–0.16,0.150.93
Father’s BMI–0.01–0.05,0.030.60–0.09–0.29,0.120.41
ADHD-inattention symptoms: standardized RS-DBD** score, inattention items. N=5,171Child BMI–0.02–0.10,0.050.550.440.04,0.850.030.730.20,1.250.01
Mother’s BMI0.090.05,0.12<0.001–0.02–0.18,0.140.84
Father’s BMI–0.00–0.05,0.040.83–0.18–0.39,0.030.09
ADHD-hyperactivity symptoms: standardized RS-DBD** score, hyperactivity items. N=5,167Child BMI–0.04–0.11,0.030.290.28–0.13,0.700.180.21–0.32,0.750.43
Mother’s BMI0.070.03,0.110.0010.01–0.15,0.170.87
Father’s BMI–0.01–0.06,0.030.510.03–0.17,0.240.75
  1. *

    Coefficients represent S.D. change in symptoms per 5 kg/m2 increase in BMI.

  2. †

    Phenotypic models adjust for the child’s sex and birth year, the mother’s parity at the child’s birth, and the mother’s and father’s: educational qualifications, depressive/anxiety and ADHD symptoms, and smoking status during pregnancy. They also adjust for the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Genetic models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  4. §

    Short Mood and Feelings Questionnaire

  5. Screen for Child Anxiety Related Disorders

  6. **

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 11
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, childhood body size PGS, complete-case analysis*.
Non-genetic estimate†MR estimate‡Within-families MR estimate‡
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: standardized SMFQ§ score
N=5,158		Child BMIa0.080.00,0.150.050.13–0.15,0.420.370.10–0.34,0.540.65
Mother’s BMI0.070.03,0.11<0.001–0.06–0.26,0.140.57
Father’s BMI0.01–0.04,0.050.790.10–0.20,0.400.52
Anxiety symptoms: standardized SCARED score
N=5,177		Child BMI–0.04–0.12,0.030.26–0.03–0.32,0.270.850.06–0.37,0.480.79
Mother’s BMI0.02–0.02,0.060.260.02–0.19,0.240.85
Father’s BMI0.01–0.04,0.050.69–0.13–0.43,0.180.42
ADHD symptoms: standardized RS-DBD** score, ADHD items
N=5,174		Child BMI–0.03–0.11,0.040.380.00–0.29,0.300.980.13–0.31,0.560.57
Mother’s BMI0.090.05,0.12<0.001–0.05–0.25,0.150.61
Father’s BMI–0.01–0.05,0.030.60–0.09–0.40,0.220.56
ADHD-inattention symptoms: standardized RS-DBD** score, inattention items
N=5,171		Child BMI–0.02–0.10,0.050.55–0.00–0.29,0.290.990.13–0.29,0.550.55
Mother’s BMI0.090.05,0.12<0.0010.04–0.17,0.240.72
Father’s BMI–0.00–0.05,0.040.83–0.20–0.51,0.110.20
ADHD-hyperactivity symptoms: standardized RS-DBD** score, hyperactivity items
N=5,167		Child BMI–0.04–0.11,0.030.290.00–0.30,0.300.990.10–0.35,0.550.67
Mother’s BMI0.070.03,0.110.001–0.14–0.34,0.060.18
Father’s BMI–0.01–0.06,0.030.510.03–0.28,0.340.84
  1. *

    Coefficients represent S.D. change in symptoms per 5 kg/m2 increase in BMI.

  2. †

    Phenotypic models adjust for the child’s sex and birth year, the mother’s parity at the child’s birth, and the mother’s and father’s: educational qualifications, depressive/anxiety and ADHD symptoms, and smoking status during pregnancy. They also adjust for the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Genetic models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  4. §

    Short Mood and Feelings Questionnaire.

  5. Screen for Child Anxiety Related Disorders.

  6. **

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 12
Multivariable-adjusted associations* of BMI quintiles with symptoms of depression, anxiety, and ADHD at age 8 in MoBa.
Depressive symptoms: standardized SMFQ† scoreAnxiety symptoms: standardized SCARED ‡ scoreADHD symptoms: standardized RS-DBD § score, ADHD itemsADHD-inattention symptoms: standardized RS-DBD § score, inattention itemsADHD-hyperactivity symptoms: standardized RS-DBD § score, hyperactivity items
BMI quintileBeta (95% CI)pBeta (95% CI)pBeta (95% CI)pBeta (95% CI)pBeta (95% CI)p
10.00 (-0.04,0.04)0.990.04 (0.00,0.09)0.040.05 (0.01,0.09)0.010.05 (0.01,0.09)0.020.04 (-0.00,0.08)0.05
2–0.01 (-0.05,0.03)0.700.02 (-0.03,0.06)0.470.02 (-0.02,0.06)0.290.02 (-0.02,0.06)0.380.02 (-0.02,0.06)0.30
3 (ref)11111
40.01 (-0.03,0.05)0.62–0.03 (-0.07,0.01)0.16–0.01 (-0.04,0.03)0.66–0.01 (-0.05,0.02)0.54–0.00 (-0.04,0.03)0.87
50.04 (0.00,0.08)0.03–0.03 (-0.07,0.01)0.09–0.02 (-0.06,0.02)0.27–0.01 (-0.05,0.03)0.51–0.03 (-0.06,0.01)0.20
  1. *

    Models adjust for the child’s sex and birth year, the mother’s parity at the child’s birth, and the mother’s and father’s: educational qualifications, depressive/anxiety and ADHD symptoms, and smoking status during pregnancy. They also adjust for the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  2. †

    Short Mood and Feelings Questionnaire.

  3. ‡

    Screen for Child Anxiety Related Disorders.

  4. §

    Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

  5. Coefficients represent S.D. difference in symptoms between quintiles of child’s BMI.

Appendix 1—table 13
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, adult BMI PGS, genetic models adjusted for parental education (N=40,949)*.
MR estimate†Within-families MR estimate†
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: standardized SMFQ‡ scoreChild BMI0.380.19,0.58<0.0010.26–0.01,0.530.06
Mother’s BMI0.09–0.00,0.170.05
Father’s BMI–0.00–0.11,0.110.97
Anxiety symptoms: standardized SCARED§ scoreChild BMI–0.08–0.26,0.110.430.01–0.25,0.270.95
Mother’s BMI–0.04–0.12,0.050.40
Father’s BMI–0.03–0.14,0.080.64
ADHD symptoms: standardized RS-DBD score, ADHD itemsChild BMI0.270.09,0.450.0030.370.10,0.640.007
Mother’s BMI–0.03–0.12,0.060.52
Father’s BMI–0.05–0.16,0.060.37
ADHD-inattention symptoms: standardized RS-DBD score, inattention itemsChild BMI0.250.07,0.420.0070.390.13,0.660.004
Mother’s BMI–0.02–0.11,0.070.64
Father’s BMI–0.10–0.21,0.010.08
ADHD-hyperactivity symptoms: standardized RS-DBD score, hyperactivity itemsChild BMI0.240.06,0.420.0090.270.00,0.550.05
Mother’s BMI–0.03–0.12,0.060.49
Father’s BMI0.01–0.10,0.120.85
  1. *

    Coefficients represent S.D. change in symptoms per 5 kg/m2 increase in BMI.

  2. †

    Models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Short Mood and Feelings Questionnaire.

  4. §

    Screen for Child Anxiety Related Disorders.

  5. Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Appendix 1—table 14
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, childhood body size PGS, genetic models adjusted for parental education (N=40,949)*.
MR estimate†Within-families MR estimate†
OutcomeBeta (per 5 kg/m2)CIpBeta (per 5 kg/m2)CIp
Depressive symptoms: standardized SMFQ‡ scoreChild BMI0.07–0.07,0.220.330.01–0.20,0.230.90
Mother’s BMI0.02–0.10,0.130.76
Father’s BMI0.05–0.09,0.200.48
Anxiety symptoms: standardized SCARED§ scoreChild BMI–0.03–0.18,0.110.650.03–0.18,0.230.81
Mother’s BMI–0.02–0.13,0.090.76
Father’s BMI–0.06–0.19,0.080.44
ADHD symptoms: standardized RS-DBD score, ADHD itemsChild BMI–0.08–0.22,0.060.27–0.03–0.23,0.160.75
Mother’s BMI–0.03–0.13,0.070.50
Father’s BMI–0.02–0.15,0.110.79
ADHD-inattention symptoms: standardized RS-DBD score, inattention itemsChild BMI–0.05–0.20,0.100.52–0.06–0.25,0.140.57
Mother’s BMI0.02–0.08,0.120.74
Father’s BMI–0.01–0.14,0.120.87
ADHD-hyperactivity symptoms: standardized RS-DBD score, hyperactivity itemsChild BMI–0.10–0.23,0.040.18–0.00–0.21,0.211.00
Mother’s BMI–0.08–0.19,0.030.15
Father’s BMI–0.02–0.15,0.120.77
  1. *

    Coefficients represent S.D. change in symptoms per 5 kg/m2 increase in BMI.

  2. †

    Models adjust for the child’s sex and birth year and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry.

  3. ‡

    Short Mood and Feelings Questionnaire.

  4. §

    Screen for Child Anxiety Related Disorders.

  5. Parent/Teacher Rating Scale for Disruptive Behaviour Disorders.

Author response table 1
BMI and symptoms of depression, anxiety, and ADHD at age 8 in MoBa, using adult and childhood body size PGS with a p-value threshold of 1.
Adult BMI PGS, p-value threshold of 1aChildhood body size PGS, p-value threshold of 1a
MR estimatebWithin-families MR estimatebMR estimatebWithin-families MR estimateb
BetaCIpBetaCIpBetaCIpBetaCIp
Depressive symptoms: SMFQc scoreChild BMIa0.430.26,0.60<0.0010.310.06,0.570.020.1–0.05,0.240.18–0.06–0.26,0.140.57
Mother’s BMI0.04–0.03,0.120.270.10–0.01,0.210.09
Father’s BMI0.03–0.07,0.140.520.10–0.05,0.250.18
Anxiety symptoms: SCAREDd scoreChild BMI–0.25–0.42,0.080.004–0.34−0.59,–0.100.005–0.1–0.24,0.040.16–0.24−0.43,–0.050.01
Mother’s BMI0.03–0.05,0.100.480.120.01,0.230.03
Father’s BMI0.04–0.06,0.140.420.05–0.09,0.190.48
ADHD symptoms: RS-DBDe scoreChild BMI0.480.31,0.65<0.0010.690.43,0.95<0.001–0.09–0.23,0.060.24–0.15–0.35,0.050.15
Mother’s BMI–0.05–0.13,0.030.190.07–0.04,0.180.24
Father’s BMI–0.10–0.20,0.000.060.01–0.13,0.150.93
ADHD-inattention symptoms: RS-DBDe score, inattention itemsChild BMI0.440.26,0.61<0.0010.650.39,0.92<0.001–0.07–0.21,0.080.37–0.15–0.35,0.050.15
Mother’s BMI–0.06–0.14,0.020.130.10–0.01,0.210.09
Father’s BMI–0.09–0.19,0.010.08–0.01–0.15,0.140.93
ADHD-hyperactivity symptoms: RS-DBDe score, hyperactivity itemsChild BMI0.420.25,0.60<0.0010.590.32,0.85<0.001–0.09–0.24,0.060.24–0.12–0.33,0.080.25
Mother’s BMI–0.03–0.11,0.050.420.02–0.09,0.130.70
Father’s BMI–0.08–0.19,0.020.120.02–0.12,0.160.80
aCoefficients represent change in symptoms, log-transformed after adding 1, per 5 kg/m2 increase in BMI. bGenetic models adjust for child’s sex, genotyping batch, and the first 20 principal components of ancestry. cShort Mood and Feelings Questionnaire. dScreen for Child Anxiety Related Disorders. eParent/Teacher Rating Scale for Disruptive Behaviour Disorders.
Author response table 2
Non-genetic associations of BMI and symptoms of depression, anxiety, and ADHD at age 8
Full adjustmentbLess adjustmentc
BetaCIpBetaCIp
Depressive symptoms: SMFQd scoreChild BMIa0.050.01,0.090.020.050.01,0.090.02
Mother’s BMI0.050.03,0.07<0.0010.050.03,0.07<0.001
Father’s BMI0.01–0.02,0.030.670.01–0.02,0.030.58
Anxiety symptoms: SCAREDe scoreChild BMI–0.07−0.11,–0.030.001–0.07−0.11,–0.03<0.001
Mother’s BMI0.01–0.01,0.030.470.01–0.01,0.030.45
Father’s BMI–0.00–0.02,0.020.89–0.00–0.02,0.020.91
ADHD symptoms: RS-DBDf scoreChild BMI–0.07−0.11,–0.030.001–0.07−0.10,–0.030.001
Mother’s BMI0.040.02,0.06<0.0010.040.02,0.06<0.001
Father’s BMI0.02–0.00,0.040.100.02–0.00,0.050.07
aCoefficients represent S.D. change in symptoms per 5 kg/m2 increase in BMI. bAdjusted for child’s sex, mother’s and father’s educational qualifications, mother’s and father’s depressive/anxiety symptoms and ADHD symptoms, mother’s and father’s smoking status during pregnancy, and maternal parity, and the child’s, mother’s, and father’s genotyping centre, genotyping chip, and first 20 principal components of ancestry. cAdjusted for the child’s sex, mother’s and father’s educational qualifications, mother’s and father’s depressive/anxiety symptoms and ADHD symptoms, mother’s and father’s smoking status during pregnancy, and maternal parity. dShort Mood and Feelings Questionnaire. eScreen for Child Anxiety Related Disorders. fParent/Teacher Rating Scale for Disruptive Behaviour Disorders

Additional files

Supplementary file 1

(a) SNPs used in the polygenic score for adult BMI. (b) SNPs used in the polygenic score for childhood body size BMI. (c) SNPs used in the polygenic score for depression. (d) SNPs used in the polygenic score for ADHD.

https://cdn.elifesciences.org/articles/74320/elife-74320-supp1-v2.xlsx
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  1. Amanda M Hughes
  2. Eleanor Sanderson
  3. Tim Morris
  4. Ziada Ayorech
  5. Martin Tesli
  6. Helga Ask
  7. Ted Reichborn-Kjennerud
  8. Ole A Andreassen
  9. Per Magnus
  10. Øyvind Helgeland
  11. Stefan Johansson
  12. Pål Njølstad
  13. George Davey Smith
  14. Alexandra Havdahl
  15. Laura D Howe
  16. Neil M Davies
(2022)
Body mass index and childhood symptoms of depression, anxiety, and attention-deficit hyperactivity disorder: A within-family Mendelian randomization study
eLife 11:e74320.
https://doi.org/10.7554/eLife.74320