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<5x10^-08; main-analysis) and two subthreshold signals (significant at a Bonferroni-corrected p<1.3x10^-06). We found strong statistical evidence of causal association for nonsynonymous alleles in CALCRL (p.L87P, pconditional=5.9x10^-12; posterior-probability of association [PPA]=52%), PLIN1 (p.L90P, pconditional=5.5x10^-13; PPA>99%), PDE3B (p.R783X, pconditional=6.2x10^-15; PPA>99%), ACVR1C (p.I195T; pconditional=5.4x10^-12; PPA>99%), and FGF1 (p.G21E, pconditional=1.6x10^-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.

Genome-wide scan and fine-mapping of rare nonsynonymous associations implicates intracellular lipolysis genes in fat distribution and cardio-metabolic risk