Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.
Emdin CA., Khera AV., Chaffin M., Klarin D., Natarajan P., Aragam K., Haas M., Bick A., Zekavat SM., Nomura A., Ardissino D., Wilson JG., Schunkert H., McPherson R., Watkins H., Elosua R., Bown MJ., Samani NJ., Baber U., Erdmann J., Gupta N., Danesh J., Chasman D., Ridker P., Denny J., Bastarache L., Lichtman JH., D'Onofrio G., Mattera J., Spertus JA., Sheu WH-H., Taylor KD., Psaty BM., Rich SS., Post W., Rotter JI., Chen Y-DI., Krumholz H., Saleheen D., Gabriel S., Kathiresan S.
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