Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.


Fernández-Rhodes L, Gong J, Haessler J, Franceschini N, Graff M, Nishimura KK, Wang Y, Highland HM, Yoneyama S, Bush WS, Goodloe R, Ritchie MD, Crawford D, Gross M, Fornage M, Buzkova P, Tao R, Isasi C, Avilés-Santa L, Daviglus M, Mackey RH, Houston D, Gu CC, Ehret G, Nguyen KH, Lewis CE, Leppert M, Irvin MR, Lim U, Haiman CA, Le Marchand L, Schumacher F, Wilkens L, Lu Y, Bottinger EP, Loos RJL, Sheu WH, Guo X, Lee WJ, Hai Y, Hung YJ, Absher D, Wu IC, Taylor KD, Lee IT, Liu Y, Wang TD, Quertermous T, Juang JJ, Rotter JI, Assimes T, Hsiung CA, Chen YI, Prentice R, Kuller LH, Manson JE, Kooperberg C, Smokowski P, Robinson WR, Gordon-Larsen P, Li R, Hindorff L, Buyske S, Matise TC, Peters U, North KE,.

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of 102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p  0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

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Will Bush

William S. Bush, Ph.D., is a human geneticist and bioinformatician, and Assistant Professor within the Cleveland Institute for Computational Biology and the Department of Population and Quantitative Health Sciences at Case Western Reserve University.