A Multi-SNP Locus-Association Method Reveals a Substantial Fraction of the Missing Heritability.

Details

Serval ID
serval:BIB_D4DFE0570968
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A Multi-SNP Locus-Association Method Reveals a Substantial Fraction of the Missing Heritability.
Journal
American Journal of Human Genetics
Author(s)
Ehret G.B., Lamparter D., Hoggart C.J., Whittaker J.C., Whittaker J.C., Beckmann J.S., Kutalik Z.
Working group(s)
Genetic Investigation of Anthropometric Traits Consortium
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
2012
Volume
91
Number
5
Pages
863-871
Language
english
Notes
Publication types: Journal Article WOS Document Type: Article
Abstract
There are many known examples of multiple semi-independent associations at individual loci; such associations might arise either because of true allelic heterogeneity or because of imperfect tagging of an unobserved causal variant. This phenomenon is of great importance in monogenic traits but has not yet been systematically investigated and quantified in complex-trait genome-wide association studies (GWASs). Here, we describe a multi-SNP association method that estimates the effect of loci harboring multiple association signals by using GWAS summary statistics. Applying the method to a large anthropometric GWAS meta-analysis (from the Genetic Investigation of Anthropometric Traits consortium study), we show that for height, body mass index (BMI), and waist-to-hip ratio (WHR), 3%, 2%, and 1%, respectively, of additional phenotypic variance can be explained on top of the previously reported 10% (height), 1.5% (BMI), and 1% (WHR). The method also permitted a substantial increase (by up to 50%) in the number of loci that replicate in a discovery-validation design. Specifically, we identified 74 loci at which the multi-SNP, a linear combination of SNPs, explains significantly more variance than does the best individual SNP. A detailed analysis of multi-SNPs shows that most of the additional variability explained is derived from SNPs that are not in linkage disequilibrium with the lead SNP, suggesting a major contribution of allelic heterogeneity to the missing heritability.
Pubmed
Web of science
Open Access
Yes
Create date
13/12/2012 19:21
Last modification date
20/08/2019 16:54
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