Exome chip scan of 74,000 subjects of European descent and 18,000 subjects of African descent identify novel genes with functional mutations influencing adiposity traits. I. B. Borecki, The CHARGE Adiposity Working Group Div Statistical Genomics, Washington Univ Sch Med, St Louis, MO.

   The rapid increase in prevalence of obesity in the industrialized world along with associated metabolic derangements is a major public health concern costing billions of dollars each year. An understanding of the biological pathways that regulate adiposity is crucial to the development of intervention strategies. Published genome-wide association studies have revealed 40 and 14 loci across ethnicities influencing body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRaBMI), respectively, many of which are annotated as having potential regulatory function. Here, we test the hypothesis that putatively functional exonic variants (missense and splice) also influence variation in these adiposity traits,. We organized a meta-analysis effort within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium including 73,768 European descent (EU) and 17,713 African descent (AF) subjects for BMI, and 50,601 EU and 13,224 AF subjects for WHRaBMI, across 18 studies. The subjects were genotyped using the Illumina HumanExome v1.0 BeadChip, which covers ~18,500 genes. Variant-wise association tests were combined using fixed effects meta-analysis as implemented in METAL, and two gene-wise burden tests were implemented using the sequence kernel association test in the SKAT package. Using a criterion of -logP >6, variants in 9 genes were associated with BMI in EU: BDNG, GIPR, MPR17L2, IFI30, ANAPC4, ADCY3, SLC39A8, KCNH2 and MAST3; and 1 gene in AF, PLS1. Some of these are novel genes that have not been previously recognized in association with adiposity (ANAPC4, KCNH2 and MAST3), and they function in the cell cycle, in mitochondrial membranes, modulating gene expression in intestinal mucosa with inflammatory response, and in assembly of intestinal epithelium. Five variants in 4 genes were associated with WHRaBMI in EU: RSPO3 and COBLL1 and in novel genes CCDC92, RAPGEF3. These genes have been associated with Wnt signaling, adiponectin levels, and anxiety and depression using GWAS markers. Here we demonstrate for the first time, association of exonic mutations with a measure of fat distribution in population-based samples. These results support the value of exon screening as a means of identifying novel genes and variants influencing adiposity traits. A deeper understanding of adiposity-related pathways and processes they influence can potentially lead to novel therapeutic strategies.

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