Genome-wide scan and fine-mapping of rare nonsynonymous associations implicates intracellular lipolysis genes in fat distribution and cardio-metabolic risk
Year: 2018
Type: preprint
Study design: Observational Study
Abstract: Difficulties in identifying causal variants and genes underlying genetic associations have limited the translational potential of genetic studies of body fat distribution, an important, partly-heritable risk factor for cardio-metabolic disease. Rare variant associations facilitate fine-mapping of causal alleles, but their contribution to fat distribution is understudied. We performed a genome-wide scan of rare nonsynonymous variants for body mass index-adjusted waist-to-hip-ratio (BMI-adjusted WHR; a widely-used measure of fat distribution) in 450,562 European ancestry individuals, followed by systematic Bayesian fine-mapping at six genome-wide (p<5×10 −08 ; main-analysis) and two subthreshold signals (significant at a Bonferroni-corrected p<1.3×10 −06 ). We found strong statistical evidence of causal association for nonsynonymous alleles in CALCRL (p.L87P, p conditional =5.9×10 −12 ; posterior-probability of association [PPA]=52%), PLIN1 (p.L90P, p conditional =5.5×10 −13 ; PPA>99%), PDE3B (p.R783X, p conditional =6.2×10 −15 ; PPA>99%), ACVR1C (p.I195T; p conditional =5.4×10 −12 ; PPA>99%), and FGF1 (p.G21E, p conditional =1.6×10 −07 ; PPA=98%). Alleles at the four likely-causal main-analysis genes affected fat distribution primarily via larger hip-rather than smaller waist-circumference and six of nine conditionally-independent WHR-lowering index-variants were associated with protection from cardiovascular or metabolic disease. All four genes are expressed in adipose tissue and have been linked with the regulation of intracellular lipolysis, which controls fat retention in mature cells. Targeted follow-up analyses of key intracellular-lipolysis genes revealed associations for a variant in the initiator of intracellular lipolysis PNPLA2 (p.N252K) with higher BMI-adjusted-WHR and higher cardio-metabolic risk. This study provides human genetic evidence of a link between intracellular lipolysis, fat-distribution and its cardio-metabolic complications in the general population.
DOI: 10.1101/372128
Authors: Luca A. Lotta, Liang Dong, Chen Li, Satish Patel, Isobel D. Stewart, Koini Lim, Felix R. Day, Eleanor Wheeler, Craig A. Glastonbury, Marcel Van de Streek, Stephen J. Sharp, Jian’an Luan, Nicholas Bowkera, Martina Schweiger, Laura B. L. Wittemans, Nicola D. Kerrison, Lina Cai, Debora M. E. Lucarelli, Inês Barroso, Mark I. McCarthy, Robert A. Scott, Rudolf Zechner, John R. B. Perry, Vladimir Saudek, Kerrin S. Small, Stephen O’Rahilly, Nicholas J. Wareham, David B. Savage, Claudia Langenberg
Institutions: University of Cambridge, MRC Epidemiology Unit, Wellcome/MRC Institute of Metabolic Science, Wellcome Trust, King's College London, University of Oxford, University of Graz, Wellcome Sanger Institute, Centre for Human Genetics, Churchill Hospital, NIHR Oxford Biomedical Research Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Trust
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G1073258374, Aetiology of type 2 diabetes and related metabolic disorders, G1093531541, High Throughput Science - Investigating pathways to metabolic disease using "omic" approaches, G119964413, Insulin Resistance: Lessons from Extreme Phenotypes., G1553864662, G1745683494, High Throughput Science - Investigating the genetic determinants of healthy ageing: the MRC EPIC-Norfolk study, G2473961061, G2892497062, G301560378, G4960516925, G5787426001, G6382720711, G6830590702, MICA: Medical Bioinformatics: Data-Driven Discovery for Personalised Medicine, G8896647075, G8975348055
OpenAlex ID: W2883989129