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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.

TitleTrans-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.
Publication TypePublication
Year2017
AuthorsFernández-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, C Gu C, Ehret G, Nguyen K-DH, 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-H, Guo X, Lee W-J, Hai Y, Hung Y-J, Absher D, Wu I-C, Taylor KD, Lee I-T, Liu Y, Wang T-D, Quertermous T, Juang J-MJ, Rotter JI, Assimes T, Hsiung CA, Chen Y-DIda, Prentice R, Kuller LH, Manson JAE, Kooperberg C, Smokowski P, Robinson WR, Gordon-Larsen P, Li R, Hindorff L, Buyske S, Matise TC, Peters U, North KE
JournalHum Genet
Volume136
Issue6
Pagination771-800
Date Published2017 06
ISSN1432-1203
KeywordsBody mass index, ethnic groups, Genetics, Population, Humans, Obesity
Abstract

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) 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.

DOI10.1007/s00439-017-1787-6
Alternate JournalHum Genet
PubMed ID28391526
PubMed Central IDPMC5485655
Grant ListUL1 TR000445 / TR / NCATS NIH HHS / United States
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R01 HL080295 / HL / NHLBI NIH HHS / United States
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U01 HG007376 / HG / NHGRI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
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MS#: 
0155B
Manuscript Lead/Corresponding Author Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
ECI: 
Manuscript Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
Manuscript Status: 
Published