Analysis of Loss-of-Function Variants in 8,612 Deeply-Phenotyped Individuals Identifies Novel Loci for Common Chronic Disease. A. H. Li1, A. C. Morrison1, G. Metcalf2, L. A. Cupples3,4, J. A. Brody5, L. M. Polfus1, B. Yu1, N. Veeraraghavan2, X. Liu1, T. Lumley5,6, D. Muzny2, T. H. Mosley7, R. A. Gibbs2, E. Boerwinkle1,2 1) Human Genetics Center, University of Texas Health Science Center, Houston, TX; 2) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; 3) National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA; 4) Department of Biostatistics, Boston University School of Public Health, Boston, MA; 5) Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA; 6) Department of Statistics, University of Auckland, Auckland, New Zealand; 7) The Memory Impairment and Neurodegenerative Dementia Research Center, University of Mississippi, Jackson, MS.

   A typical human exome analysis reveals more than 100 loss-of-function (LOF) variants, approximately 20 of which are homozygous and predicted to abolish gene function. The effects of these variants have been explored in clinical samples ascertained for rare phenotypes but have not been examined in population-based samples measured for a broad spectrum of common risk factor phenotypes and clinical outcomes. We sequenced the exomes of 8,612 ethnically-diverse individuals (2,849 African American, 5,763 European American) and identified 50,259 predicted LOF variants (splice, stopgain, frameshift indel). Gene-based burden analyses were performed on over 40 chronic disease risk factor phenotypes including serum electrolytes, liver enzymes, serum lipids, diabetes biomarker, markers of lung function and anthropomorphic measurements. Our analysis framework replicated known phenotypic associations of two well-studied genes (PCSK9, APOC3) and identified more than 11 novel associations. For example, individuals with LOF variants in SCNN1D, which encodes the delta subunit of the non-voltage-gated sodium channel 1 protein, presented elevated creatinine across multiple clinical visits (T5 burden, 2.5 x 10-8). We also demonstrate evidence for recessive effects, as demonstrated by the presentation of abnormal fasting glucose in samples with homozygous LOF genotypes in TYW1B, a gene within the Williams-Beuren syndrome deletion (MIM: 194050; 7q11.23), while heterozygotes appear normal (Wilcoxon, 2.6x10-4). These data demonstrate the utility of applying detailed functional annotation of whole exome sequence to a large sample of deeply-phenotyped individuals for novel gene discovery.

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