Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity

Walters, Robin G., Coin, Lachlan J. M., Ruokonen, Aimo, de Smith, Adam J., Moustafa, Julia S. El-Sayed, Jacquemont, Sebastien, Elliott, Paul, Esko, Tonu, Hartikainen, Anna-Liisa, Laitinen, Jaana, Maennik, Katrin, Martinet, Danielle, Meyre, David, Nauck, Matthias, Schurmann, Claudia, Sladek, Rob, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Valsesia, Armand, Waeber, Gerard, Zufferey, Flore, Balkau, Beverley, Pattou, Francois, Metspalu, Andres, Voelzke, Henry, Vollenweider, Peter, Stefansson, Kari, Jarvelin, Marjo-Riitta, Beckmann, Jacques S., Froguel, Philippe and Blakemore, Alexandra I. F. (2013) Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity. Plos One, 8 3: e58048.1-e58048.11. doi:10.1371/journal.pone.0058048

Author Walters, Robin G.
Coin, Lachlan J. M.
Ruokonen, Aimo
de Smith, Adam J.
Moustafa, Julia S. El-Sayed
Jacquemont, Sebastien
Elliott, Paul
Esko, Tonu
Hartikainen, Anna-Liisa
Laitinen, Jaana
Maennik, Katrin
Martinet, Danielle
Meyre, David
Nauck, Matthias
Schurmann, Claudia
Sladek, Rob
Thorleifsson, Gudmar
Thorsteinsdottir, Unnur
Valsesia, Armand
Waeber, Gerard
Zufferey, Flore
Balkau, Beverley
Pattou, Francois
Metspalu, Andres
Voelzke, Henry
Vollenweider, Peter
Stefansson, Kari
Jarvelin, Marjo-Riitta
Beckmann, Jacques S.
Froguel, Philippe
Blakemore, Alexandra I. F.
Title Rare Genomic Structural Variants in Complex Disease: Lessons from the Replication of Associations with Obesity
Journal name Plos One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-03-01
Year available 2013
Sub-type Article (original research)
DOI 10.1371/journal.pone.0058048
Open Access Status DOI
Volume 8
Issue 3
Start page e58048.1
End page e58048.11
Total pages 11
Place of publication San Francisco, CA United States
Publisher Public Library of Science
Language eng
Formatted 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.
Keyword Copy Number Variation
Circular Binary Segmentation
Hidden Markov Model
Snp Genotyping Data
Body Mass Index (bmi)
Wide Association
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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