Large duplications are associated with increased risk of obesity. J. S. El-Sayed Moustafa1, M. Falchi1, R. G. Walters2, I. Prokopenko1, A. I. F. Blakemore3, L. J. M. Coin1,4, P. Froguel1,5 1) Department of Genomics of Common Disease, Imperial College London, London, United Kingdom; 2) Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK; 3) Section of Investigative Medicine, Imperial College London, London, UK; 4) Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; 5) Centre National de la Recherche Scientifique (CNRS) - Unité Mixte de Recherche de lUniversité Lille 2 (UMR) 8199, Institut Pasteur, Lille, France.
Obesity is rapidly becoming an increasingly serious public health concern, placing affected individuals at increased risk of various other health conditions. Despite an estimated heritability of 40-70%, much of the genetic variance of adiposity remains unexplained. We have investigated the contribution of large, rare genomic structural variants above 500kb to obesity susceptibility. We employed our copy number variant (CNV) prediction algorithm cnvHap to conduct genome-wide CNV prediction in a child obesity sample of 683 cases and 655 controls, and an adult obesity sample of 695 cases and 197 controls, all genotyped on the Illumina Human CNV370 Duo platform. Analyses were limited to CNVs of a minimum length of 500kb, and of a frequency below 1% in control subjects. All identified CNVs were confirmed visually, as well as using an alternative CNV prediction algorithm (pennCNV), with a subset of CNVs also experimentally validated using non-array-based methods including multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR (qPCR). A total of 188 rare CNVs above 500kb were identified in our study sample. Permutation-based global large CNV burden analysis was conducted using PLINK v1.07. We found rare duplications above 500kb to be significantly enriched in child and adult obese cases compared to normal-weight controls (P=8.89×10-3 and P= 5.05×10-3, respectively, pooled analysis P=1.07×10-3). Functional annotation analysis also revealed enrichment for genes associated with schizophrenia within GSVs identified in obese subjects (P=2.2×10-5). These results provide novel evidence that large duplications above 500kb may contribute to the "missing heritability" of obesity. The overlap between genes located within large CNVs above 500kb in obese subjects and genes associated with psychiatric disorders such as schizophrenia may also help explain the observed clinical and genetic overlap between these disorders.
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