Epigenome-wide association study meta-analysis of BMI in African Americans.

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Despite considerable advances in identifying risk factors for obesity development, there remains substantial gaps in our knowledge about its etiology. Variation in obesity (defined by BMI) is thought to be due in part to heritable factors; however, obesity-associated genetic variants only account for a small portion of heritability. Epigenetic regulation, defined by genetic and/or environmental factors with changes in gene expression, may account for some of this "missing heritability". Epigenetic studies of obesity have largely been conducted in populations of European ancestry, despite the disproportionate burden of obesity in African Americans (AAs). To address race/ethnic (RE)-differences in obesity, we conducted a BMI epigenome-wide association study (EWAS) meta-analysis using AA participants from the Jackson Heart Study (JHS, n=1604) and the Multi-Ethnic Study of Atherosclerosis (MESA, n=179). Analyses using a linear regression model with methylation as the outcome and continuous BMI as the predictor were stratified by study and sex, then meta-analyzed. There were 208 methylation sites (CpGs) that reached epigenome-wide significance (p< 8.72×10 -8 ); 151 of these were novel. Of the novel CpGs, 29 CpGs were available for replication testing in a separate sample of AA and 20 replicated. Differentially methylated region (DMR) analysis resulted in 54 DMRs significantly associated with BMI. Several regions are proximal to, or include, genes previously associated with obesity traits (e.g., SOCS3, ABCG1 , and TGFB1 ) in GWAS. Gene and trait enrichment and pathway analysis showed enrichment for genes in immune system and inflammation related pathways (e.g., the IL-6/JAK/STAT pathway). In conclusion, EWAS of BMI in AAs replicated previously known associations identified in European ancestry and multi-ethnic EWAS and identified novel obesity-associated CpGs.