TY - JOUR T1 - Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposures JF - bioRxiv DO - 10.1101/036822 SP - 036822 AU - Joshua M. Galanter, MD, MAS AU - Christopher R. Gignoux, PhD AU - Sam S. Oh, PhD AU - Dara Torgerson, PhD AU - Maria Pino-Yanes, PhD AU - Neeta Thakur, MD, MPH AU - Celeste Eng, BS AU - Donglei Hu, PhD AU - Scott Huntsmann, MS AU - Harold J. Farber MD AU - Pedro C Avila MD AU - Emerita Brigino-Buenaventura MD AU - Michael A LeNoir MD AU - Kelly Meade MD AU - Denise Serebrisky MD AU - William Rodríguez-Cintrón MD AU - Rajesh Kumar MD AU - Jose R Rodríguez-Santana MD AU - Max A. Seibold, PhD AU - Luisa N. Borrell, DDS, PhD AU - Esteban G. Burchard, MD, MPH AU - Noah Zaitlen, PhD Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/19/036822.abstract N2 - In clinical practice and biomedical research populations are often divided categorically into distinct racial and ethnic groups. In reality, these categories, which are based on social rather than biological constructs, comprise diverse groups with highly heterogeneous histories, cultures, traditions, religions, as well as social and environmental exposures. While the factors captured by these categories contribute to clinical practice and biomedical research, the use of race/ ethnicity is widely debated. As a response to this debate, genetic ancestry has been suggested as a complement or alternative to this categorization. However, few studies have examined the effect of genetic ancestry, racial/ethnic identity, and environmental exposures on biological processes. Herein, we examine the associations between self-identified ethnicity and epigenetic modification of DNA methylation, a phenomenon affected by both genetic and environmental factors. We also assess the relative contributions of genetic ancestry and environmental factors on these associations. We typed over 450,000 variably methylated CpG sites in primary whole blood of 573 individuals of Mexican and Puerto Rican descent who also had high-density genotype data. We found that both genetically determined ancestry and self-identified ethnicity were significantly associated with methylation levels at a large number of CpG sites. In addition, we found an enrichment of ethnicity-associated sites amongst loci previously associated with environmental and social exposures, particularly maternal smoking during pregnancy. This suggests that ethnic self-identification may function as a proxy for environmental exposures. Overall we conclude that race and ethnicity provide important and relevant clinical and biomedical information above and beyond and individual’s genetic ancestry.Sources of Funding This research was supported in part by the Sandler Family Foundation, the American Asthma Foundation, National Institutes of Health (P60 MD006902, R01 HL117004, R21ES24844, U54MD009523, R01 ES015794, R01 HL088133, M01 RR000083, R01 HL078885, R01 HL104608, U19 AI077439, M01 RR00188), ARRA grant RC2 HL101651, and TRDRP 24RT-0025; EGB was supported in part through grants from the Flight Attendant Medical Research Institute (FAMRI), and NIH (K23 HL004464); NZ was supported in part by an NIH career development award from the NHLBI (K25HL121295). JMG was supported in part by NIH Training Grant T32 (T32GM007546) and career development awards from the NHLBI (K23HL111636) and NCATS (KL2TR000143) as well as the Hewett Fellowship; N.T. was supported in part by an institutional training grant from the NIGMS (T32-GM007546) and career development awards from the NHLBI (K12-HL119997 and K23-HL125551), Parker B. Francis Fellowship Program, and the American Thoracic Society; CRG was supported in part by NIH Training Grant T32 (GM007175) and the UCSF Chancellor’s Research Fellowship and Dissertation Year Fellowship; RK was supported with a career development award from the NHLBI (K23HL093023); HJF was supported in part by the GCRC (RR00188); PCA was supported in part by the Ernest S. Bazley Grant; MAS was supported in part by 1R01HL128439-01. This publication was supported by various institutes within the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.Significance Statement Race, ethnicity, and genetic ancestry have had a complex and often controversial history within biomedical research and clinical practice. For example, race‐ and ethnicityspecific clinical reference standards are based on an average derived from statistical modeling applied to population-based sampling on a given physical trait such as pulmonary function. However, because race and ethnicity are social constructs, they ignore the heterogeneity within the categories. To account for these heterogeneities and avoid social and political controversies, the genetics community has integrated the use of genetic ancestry as a proxy because genetic sequence is not altered by environmental or social factors. We explore the relative contributions of ancestry, ethnicity and environment to variation in methylation, a fundamental biological process. ER -