1. Chromosomes and Gene Expression
Download icon

Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposures

  1. Joshua M Galanter  Is a corresponding author
  2. Christopher R Gignoux
  3. Sam S Oh
  4. Dara Torgerson
  5. Maria Pino-Yanes
  6. Neeta Thakur
  7. Celeste Eng
  8. Donglei Hu
  9. Scott Huntsman
  10. Harold J Farber
  11. Pedro C Avila
  12. Emerita Brigino-Buenaventura
  13. Michael A LeNoir
  14. Kelly Meade
  15. Denise Serebrisky
  16. William Rodríguez-Cintrón
  17. Rajesh Kumar
  18. Jose R Rodríguez-Santana
  19. Max A Seibold
  20. Luisa N Borrell
  21. Esteban G Burchard  Is a corresponding author
  22. Noah Zaitlen  Is a corresponding author
  1. University of California, United States
  2. University of California, San Francisco, United States
  3. Stanford University, United States
  4. Hospital Universitario Nuestra Señora de Candelaria, Spain
  5. Instituto de Salud Carlos III, Spain
  6. Baylor College of Medicine and Texas Children’s Hospital, Texas
  7. Feinberg School of Medicine, Northwestern University, Illinois
  8. Kaiser Permanente-Vallejo Medical Center, United States
  9. Bay Area Pediatrics, United States
  10. Children’s Hospital and Research Center, United States
  11. Jacobi Medical Center, United States
  12. Veterans Caribbean Health System, United States
  13. The Ann and Robert H Lurie Children’s Hospital of Chicago, United States
  14. Centro de Neumología Pediátrica, United States
  15. National Jewish Health, United States
  16. City University of New York, United States
Research Article
Cite this article as: eLife 2017;6:e20532 doi: 10.7554/eLife.20532
8 figures, 2 tables and 1 additional file

Figures

Ancestry estimates for GALA II participants, by ethnic group.

Mexicans, on average, had a greater proportion of Native American ancestry than Puerto Ricans; Puerto Ricans had a greater proportion of European and African ancestry. Mixed and other Latinos were intermediate.

https://doi.org/10.7554/eLife.20532.003
Patterns of global methylation.

(A) Distribution of the first 10 principal coordinates of the methylation data. Plots in the diagonal show the univariate distribution; those in the lower left triangle show bivariate relationship between each pair of PCs, while those in the upper right show the bivariate density. (B) Bivariate or ANOVA associations between principal coordinates and technical factors (chip, position), cell counts, genetic ancestry (European, Native American, African), recruitment site (New York, NY, San Francisco, CA, Chicago, IL, Houston, TX, and Puerto Rico), demographic factors (ethnicity, age, sex), and case status. (C) Correlation coefficients between the various factors and principal coordinates.

https://doi.org/10.7554/eLife.20532.005
Associations between ethnicity, ancestry and global methylation.

(A) Association between ethnicity and principal coordinate 7. (B) Association between Native American ancestry proportion and PC7, colored by ethnicity. Native American ancestry explains approximately 81% of the association between PC7 and ethnicity.

https://doi.org/10.7554/eLife.20532.006
Associations between ethnicity and methylation (A) Manhattan plot showing the associations between ethnicity and methylation at individual CpG loci.

(B) Violin plot showing one such locus, cg19145607. Mexicans are relatively hypermethylated compared to Puerto Ricans (p=1.4×10–19). (C) Plot showing the association between Native American ancestry at the locus and methylation levels at the locus colored by ethnicity; Native American ancestry accounts for 58% of the association between ethnicity and methylation at the locus.

https://doi.org/10.7554/eLife.20532.007
Relationship between genomic ancestry and the association between ethnicity and methylation.

(A) Venn diagram showing the effect of adjustment for ancestry on the association between ethnicity and methylation. The components of the diagram represent the number of CpG’s that remained associated with ethnicity after adjustment for ancestry and the number of CpG’s that were associated with ancestry. (B) Relative proportion of variance in methylation explained by ethnicity and genomic ancestry across loci significantly associated with ethnicity. Mediation analysis of associations between ethnicity and methylation M-values for (C) Native American ancestry and (D) African ancestry. For simplicity, only significant mediation effects are shown.

https://doi.org/10.7554/eLife.20532.008
Associations between genomic ancestry and individual methylation loci.

(A) Manhattan plot showing the associations between genomic ancestry and methylation at individual CpG loci. (B) Plot showing one such locus, cg04922029, and genomic African ancestry, showing a strong correlation between African ancestry and hypermethylation at that site.

https://doi.org/10.7554/eLife.20532.010
Association between local ancestry and methylation.

(A) Association between cg04922029 on the DARC locus and African ancestry, color coded by ethnic group. There is near perfect correlation between the two. (B) Association between SNPs located within 1 Mb of cg04922029 and methylation levels at that CpG. (C) Association between rs2814778 (Duffy null) genotype and methylation at cg04922029, color coded by the number of African alleles present. There is near perfect correlation between genotype, ancestry and methylation at the locus. (D) Allele frequency of rs2814778 by 1000 Genomes population. The C allele is nearly ubiquitous in African populations and nearly absent outside of African populations and their descendants.

https://doi.org/10.7554/eLife.20532.011
Relative proportion of variance in methylation explained by global and local ancestry across loci significantly associated with global ancestry.
https://doi.org/10.7554/eLife.20532.012

Tables

Table 1

Baseline characteristics of GALA II participants with methylation data, stratified by ethnicity. Continuous variables are reported with inter-quartile range in brackets.

https://doi.org/10.7554/eLife.20532.004

Mexican

Puerto rican

Mixed latino

Other latino

n

276

220

16

61

Males (%)

125 (45.3%)

127 (57.7%)

6 (37.5%)

28 (45.9%)

Age

11.4 [9.3: 14.7]

12.3 [10.4: 14.2]

11.8 [10.7: 14.9]

11.8 [10: 15.7]

Asthma cases (%)

124 (44.9%)

147 (66.8%)

9 (56.3%)

31 (50.8%)

Ancestry (n = 524)

African

4.3%

[2.9%: 6.0%)

22.8%

[16.6%: 29.4%)

8.5%

[5.6%: 19.2%)

12.3%

[6.3%: 25.8%)

Native American

55.4%

[44.5%: 65.7%)

11.2%

[9.8%: 13%)

31.5%

[20.9%: 45.6%)

32.8%

[10.4%: 49.3%)

European

40.5%

[29.9%: 50.2%)

65.7%

[59.2%: 71%)

50.5%

[44.6%: 57.6%)

48.9%

[40%: 58.5%)

Recruitment Site

Chicago

140 (50.7%)

15 (6.8%)

11 (68.9%)

15 (24.6%)

New York

18 (6.5%)

10 (4.5%)

1 (6.3%)

23 (37.7%)

Puerto Rico

0

193 (87.7%)

0

0

San Francisco

78 (28.3%)

0

2 (12.5%)

23 (37.7%)

Houston

40 (14.5%)

2 (0.9%)

2 (12.5%)

5 (8.2%)

Cell Counts (estimated)

Granulo cytes

51.2%

[46.0%: 55.7%)

51.6%

[46.8%: 57%)

51%

[43.6%: 57.2%)

49.1%

[43.8%: 55.8%)

Lympho cytes

41.9%

[36.9%: 46.6%)

41.8%

[36.9%: 46.5%)

41.9%

[36.1%: 51.6%)

43.9%

[36.8%: 49.6%)

Mono cytes

7.1%

[5.8%: 8.3%)

6.74%

[5.74%: 8.24%)

6.6%

[5.7%: 7.6%)

7.4%

[6.2%: 8.6%)

Table 2

Proportion of variance in methylation explained by ethnicity and ancestry. Numbers represent the median and interquartile range.

https://doi.org/10.7554/eLife.20532.009

Component

All CpG’s associated with ethnicity (n = 916)

CpG’s associated with ethnicity after adjusting for ancestry (n = 314)

CpG’s whose association with ethnicity is explained by ancestry (n = 520)

Joint

6.8% (4.5% to 10%)

6.2% (4.4% to 8.8%)

7.8% (5.3% to 11.1%)

Ethnicity

1.7% (0.78% to 3.0%)

3.5% (2.2% to 5.1%)

<1%

Ancestry

4.2% (1.8% to 8.3%)

1.8% (0.8% to 4.0%)

6.6% (4.0% to 10.2%)

Additional files

Supplementary file 1

(A) Methylation principal components and ethnicity and ancestry. (B) Significant associations between ethnicity and methylation. (C) Effect of adding cubic spline ancestry terms to the association between ethnicity and methylation. (D) Effect of adding quadratic and cubic ancestry terms to the association between ethnicity and methylation. (E) Effect of adding genetic principal components 3–10 to the association between ethnicity and methylation. (F) Significant associations between ethnicity and methylation (p<1.6×10–7), and effect of adjustment for ancestry on the association of ethnicity and methylation, excluding participants of ‘Mixed Latino’ ethnicity. (G) Association of ethnicity and methylation in loci previously associated with maternal smoking during pregnancy. (H) Significant associations between ethnicity and methylation loci previously associated with environmental exposures. (I) Significant associations between global ancestry and methylation.

https://doi.org/10.7554/eLife.20532.013

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)