Fine mapping of the association with obesity at the FTO locus in African-derived populations.
Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 x 10(-6) and 3.61 x 10(-6) in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.
Hassanein
Mohamed T
MT
Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
Lyon
Helen N
HN
Nguyen
Thutrang T
TT
Akylbekova
Ermeg L
EL
Waters
Kevin
K
Lettre
Guillaume
G
Tayo
Bamidele
B
Forrester
Terrence
T
Sarpong
Daniel F
DF
Stram
Dan O
DO
Butler
Johannah L
JL
Wilks
Rainford
R
Liu
Jiankang
J
Le Marchand
Loic
L
Kolonel
Laurence N
LN
Zhu
Xiaofeng
X
Henderson
Brian
B
Cooper
Richard
R
McKenzie
Colin
C
Taylor
Herman A
HA
Haiman
Christopher A
CA
Hirschhorn
Joel N
JN
D000293:Adolescent; D000328:Adult; D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D044383:Black People / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D056426:Genetic Loci; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D055815:Young Adult
D011506:Proteins; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human