A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.
Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America. upeters@fhcrc.org
Ulrike
U
Peters
Kari E
KE
North
Praveen
P
Sethupathy
Steve
S
Buyske
Jeff
J
Haessler
Shuo
S
Jiao
Megan D
MD
Fesinmeyer
Rebecca D
RD
Jackson
Lew H
LH
Kuller
Aleksandar
A
Rajkovic
Unhee
U
Lim
Iona
I
Cheng
Fred
F
Schumacher
Lynne
L
Wilkens
Rongling
R
Li
Keri
K
Monda
Georg
G
Ehret
Khanh-Dung H
KD
Nguyen
Richard
R
Cooper
Cora E
CE
Lewis
Mark
M
Leppert
Marguerite R
MR
Irvin
C Charles
CC
Gu
Denise
D
Houston
Petra
P
Buzkova
Marylyn
M
Ritchie
Tara C
TC
Matise
Loic
L
Le Marchand
Lucia A
LA
Hindorff
Dana C
DC
Crawford
Christopher A
CA
Haiman
Charles
C
Kooperberg
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015992:Body Mass Index; D002874:Chromosome Mapping; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D056186:Metagenomics; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics; D044465:White People / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D011506:Proteins; C532826:RPGRIP1L protein, human; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human