Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.

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Serval ID
serval:BIB_0257103FC0D5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.
Journal
Plos One
Author(s)
Walters R.G., Coin L.J., Ruokonen A., de Smith A.J., El-Sayed Moustafa J.S., Jacquemont S., Elliott P., Esko T., Hartikainen A.L., Laitinen J., Männik K., Martinet D., Meyre D., Nauck M., Schurmann C., Sladek R., Thorleifsson G., Thorsteinsdóttir U., Valsesia A., Waeber G., Zufferey F., Balkau B., Pattou F., Metspalu A., Völzke H., Vollenweider P., Stefansson K., Järvelin M.R., Beckmann J.S., Froguel P., Blakemore A.I.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2013
Volume
8
Number
3
Pages
e58048
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
The limited ability of common variants to account for the genetic contribution to complex disease has prompted searches for rare variants of large effect, to partly explain the 'missing heritability'. Analyses of genome-wide genotyping data have identified genomic structural variants (GSVs) as a source of such rare causal variants. Recent studies have reported multiple GSV loci associated with risk of obesity. We attempted to replicate these associations by similar analysis of two familial-obesity case-control cohorts and a population cohort, and detected GSVs at 11 out of 18 loci, at frequencies similar to those previously reported. Based on their reported frequencies and effect sizes (OR≥25), we had sufficient statistical power to detect the large majority (80%) of genuine associations at these loci. However, only one obesity association was replicated. Deletion of a 220 kb region on chromosome 16p11.2 has a carrier population frequency of 2×10(-4) (95% confidence interval [9.6×10(-5)-3.1×10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8×10(-10); odds ratio = 25.0 [9.9-60.6]); and results in a mean body mass index (BMI) increase of 5.8 kg.m(-2) [1.8-10.3] in adults from the general population. We also attempted replication using BMI as a quantitative trait in our population cohort; associations with BMI at or near nominal significance were detected at two further loci near KIF2B and within FOXP2, but these did not survive correction for multiple testing. These findings emphasise several issues of importance when conducting rare GSV association, including the need for careful cohort selection and replication strategy, accurate GSV identification, and appropriate correction for multiple testing and/or control of false discovery rate. Moreover, they highlight the potential difficulty in replicating rare CNV associations across different populations. Nevertheless, we show that such studies are potentially valuable for the identification of variants making an appreciable contribution to complex disease.
Pubmed
Web of science
Open Access
Yes
Create date
18/04/2013 8:58
Last modification date
20/08/2019 12:24
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