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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.

Authors :
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
Source :
Human genetics [Hum Genet] 2017 Jun; Vol. 136 (6), pp. 771-800. Date of Electronic Publication: 2017 Apr 08.
Publication Year :
2017

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 <superscript>2</superscript> ) 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.

Details

Language :
English
ISSN :
1432-1203
Volume :
136
Issue :
6
Database :
MEDLINE
Journal :
Human genetics
Publication Type :
Academic Journal
Accession number :
28391526
Full Text :
https://doi.org/10.1007/s00439-017-1787-6