title: Rare genomic structural variants in complex disease: lessons from the replication of associations with obesity.
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.
authors.affiliation: Department of Genomics of Common Disease, Imperial College London, London, United Kingdom.
authors.forename: Robin G
authors.initials: RG
authors.lastname: Walters
authors.forename: Lachlan J M
authors.initials: LJ
authors.lastname: Coin
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.forename: Julia S
authors.initials: JS
authors.lastname: El-Sayed Moustafa
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Hartikainen
authors.forename: Jaana
authors.initials: J
authors.lastname: Laitinen
authors.forename: Katrin
authors.initials: K
authors.lastname: Männik
authors.forename: Danielle
authors.initials: D
authors.lastname: Martinet
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Matthias
authors.initials: M
authors.lastname: Nauck
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.forename: Rob
authors.initials: R
authors.lastname: Sladek
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdóttir
authors.forename: Armand
authors.initials: A
authors.lastname: Valsesia
authors.forename: Gerard
authors.initials: G
authors.lastname: Waeber
authors.forename: Flore
authors.initials: F
authors.lastname: Zufferey
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.forename: Kári
authors.initials: K
authors.lastname: Stefansson
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Alexandra I F
authors.initials: AI
authors.lastname: Blakemore
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D016547:Kinesins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; C523507:KIF2B protein, human; D016547:Kinesins
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