Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease

作者:Emdin Connor A; Khera Amit V; Chaffin Mark; Klarin Derek; Natarajan Pradeep; Aragam Krishna; Haas Mary; Bick Alexander; Zekavat Seyedeh M; Nomura Akihiro; Ardissino Diego; Wilson James G; Schunkert Heribert; McPherson Ruth; Watkins Hugh; Elosua Roberto; Bown Matthew J; Samani Nilesh J; Baber Usman; Erdmann Jeanette; Gupta Namrata; Danesh John; Chasman Daniel; Ridker Paul; Denny Joshua; Bastarache Lisa; Lichtman Judith H; D'Onofrio Gail; Mattera Jennifer
来源:Nature Communications, 2018, 9(1): 1613.
DOI:10.1038/s41467-018-03911-8

摘要

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In > 400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency <5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

  • 出版日期2018-4-24