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FTO genotype is associated with phenotypic variability of body mass index.

TitleFTO genotype is associated with phenotypic variability of body mass index.
Publication TypeJournal Article
Year of Publication2012
AuthorsYang J, Loos RJF, Powell JE, et al.
Secondary AuthorsVisscher PM
JournalNature
Volume490
Issue7419
Pagination267-72
Date Published2012 Oct 11
ISSN1476-4687
KeywordsAlpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Height, Body Mass Index, Co-Repressor Proteins, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, Proteins, Repressor Proteins
Abstract

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

DOI10.1038/nature11401
Alternate JournalNature
PubMed ID22982992
PubMed Central IDPMC3564953
Grant ListR01 LM010098 / LM / NLM NIH HHS / United States
AA014041 / AA / NIAAA NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
RL1 MH083268 / MH / NIMH NIH HHS / United States
R01 AA013320 / AA / NIAAA NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
CZB/4/710 / CSO_ / Chief Scientist Office / United Kingdom
R01 DK073490 / DK / NIDDK NIH HHS / United States
K23 DK080145 / DK / NIDDK NIH HHS / United States
R01 MH063706 / MH / NIMH NIH HHS / United States
R01 AA007535 / AA / NIAAA NIH HHS / United States
R01 HL075366 / HL / NHLBI NIH HHS / United States
R01 AA014041 / AA / NIAAA NIH HHS / United States
K05 AA017688 / AA / NIAAA NIH HHS / United States
N01 AG012100 / AG / NIA NIH HHS / United States
R01 HL087647 / HL / NHLBI NIH HHS / United States
U01 HL084729 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
N01 HG065403 / HG / NHGRI NIH HHS / United States
AA13320 / AA / NIAAA NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
U01 HL054527 / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
R01 HL087679 / HL / NHLBI NIH HHS / United States
R01 HL087676 / HL / NHLBI NIH HHS / United States
R01 HG002651 / HG / NHGRI NIH HHS / United States
N01 HC075150 / HC / NHLBI NIH HHS / United States
R01 HL043851 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HG006513 / HG / NHGRI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
MC_U127561128 / MRC_ / Medical Research Council / United Kingdom
DA12854 / DA / NIDA NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
AA13321 / AA / NIAAA NIH HHS / United States
AA10248 / AA / NIAAA NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
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R01 AA013326 / AA / NIAAA NIH HHS / United States
G1000143 / MRC_ / Medical Research Council / United Kingdom
Z01 HG000024-14 / ImNIH / Intramural NIH HHS / United States
R56 DA012854 / DA / NIDA NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
F32 DK079466 / DK / NIDDK NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
R01 DK075787 / DK / NIDDK NIH HHS / United States
R01 DK075681 / DK / NIDDK NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
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R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_U106179471 / MRC_ / Medical Research Council / United Kingdom
U01 HL084756 / HL / NHLBI NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
14136 / CRUK_ / Cancer Research UK / United Kingdom
GM057091 / GM / NIGMS NIH HHS / United States
N01 HC055222 / HC / NHLBI NIH HHS / United States
G0401527 / MRC_ / Medical Research Council / United Kingdom
090532 / WT_ / Wellcome Trust / United Kingdom
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
U01 HL072515 / HL / NHLBI NIH HHS / United States
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R01 DA012854 / DA / NIDA NIH HHS / United States
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