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.
Highlights
Genome-wide association studies (GWAS) of common single nucleotide polymorphisms (SNPs) have identified loci accounting for only a modest proportion of the heritability of most complex diseases
Using existing genotyping data from cohorts of severely obese French children and adults, similar numbers of nonoverweight controls, and a general population cohort from northern Finland [17,18], each genomic region was analysed for the presence of genomic structural variants (GSVs)
The analysis of rare GSVs for association with complex traits represents a complementary approach to SNP- or sequence-based methods for identifying novel loci that can account for the ‘missing heritability’ of multiple complex traits [3,9]
Summary
Genome-wide association studies (GWAS) of common single nucleotide polymorphisms (SNPs) have identified loci accounting for only a modest proportion of the heritability of most complex diseases. Some of this ‘missing heritability’ may be ascribed to a large number of SNPs with weak effect [1,2], it is becoming increasingly likely that there is a substantial contribution from rare variants with large effect that are not readily identifiable by SNP-based methods [3,4,5]. .0.5 Mb) compared to the general population [10,11], strongly suggesting that some of the GSVs carried by these unusual patients are responsible for a pronounced, readily-identifiable phenotype with high penetrance. Genes within the regions delineated by such GSVs may be of direct relevance to obesity in the general population
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