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@article{Walters:2013:10.1371/journal.pone.0058048,
author = {Walters, RG and Coin, LJ and Ruokonen, A and de, Smith AJ and El-Sayed, Moustafa JS and Jacquemont, S and Elliott, P and Esko, T and Hartikainen, AL and Laitinen, J and Mannik, K and Martinet, D and Meyre, D and Nauck, M and Schurmann, C and Sladek, R and Thorleifsson, G and Thorsteinsdottir, U and Valsesia, A and Waeber, G and Zufferey, F and Balkau, B and Pattou, F and Metspalu, A and Volzke, H and Vollenweider, P and Stefansson, K and Jarvelin, MR and Beckmann, JS and Froguel, P and Blakemore, AI},
doi = {10.1371/journal.pone.0058048},
journal = {PLoS One},
title = {Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity},
url = {http://dx.doi.org/10.1371/journal.pone.0058048},
volume = {8},
year = {2013}
}

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TY  - JOUR
AB  - 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 2x10(-4) (95% confidence interval [9.6x10(-5)-3.1x10(-4)]); accounts overall for 0.5% [0.19%-0.82%] of severe childhood obesity cases (P = 3.8x10(-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 th
AU  - Walters,RG
AU  - Coin,LJ
AU  - Ruokonen,A
AU  - de,Smith AJ
AU  - El-Sayed,Moustafa JS
AU  - Jacquemont,S
AU  - Elliott,P
AU  - Esko,T
AU  - Hartikainen,AL
AU  - Laitinen,J
AU  - Mannik,K
AU  - Martinet,D
AU  - Meyre,D
AU  - Nauck,M
AU  - Schurmann,C
AU  - Sladek,R
AU  - Thorleifsson,G
AU  - Thorsteinsdottir,U
AU  - Valsesia,A
AU  - Waeber,G
AU  - Zufferey,F
AU  - Balkau,B
AU  - Pattou,F
AU  - Metspalu,A
AU  - Volzke,H
AU  - Vollenweider,P
AU  - Stefansson,K
AU  - Jarvelin,MR
AU  - Beckmann,JS
AU  - Froguel,P
AU  - Blakemore,AI
DO  - 10.1371/journal.pone.0058048
PY  - 2013///
SN  - 1932-6203
TI  - Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity
T2  - PLoS One
UR  - http://dx.doi.org/10.1371/journal.pone.0058048
UR  - http://hdl.handle.net/10044/1/28722
VL  - 8
ER  -

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