PT - JOURNAL ARTICLE AU - Sean J. Jurgens AU - Seung Hoan Choi AU - Valerie N. Morrill AU - Mark Chaffin AU - James P. Pirruccello AU - Jennifer L. Halford AU - Lu-Chen Weng AU - Victor Nauffal AU - Carolina Roselli AU - Amelia W. Hall AU - Krishna G. Aragam AU - Kathryn L. Lunetta AU - Steven A. Lubitz AU - Patrick T. Ellinor TI - Rare Genetic Variation Underlying Human Diseases and Traits: Results from 200,000 Individuals in the UK Biobank AID - 10.1101/2020.11.29.402495 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.11.29.402495 4099 - http://biorxiv.org/content/early/2020/11/29/2020.11.29.402495.short 4100 - http://biorxiv.org/content/early/2020/11/29/2020.11.29.402495.full AB - Background Many human diseases are known to have a genetic contribution. While genome-wide studies have identified many disease-associated loci, it remains challenging to elucidate causal genes. In contrast, exome sequencing provides an opportunity to identify new disease genes and large-effect variants of clinical relevance. We therefore sought to determine the contribution of rare genetic variation in a curated set of human diseases and traits using a unique resource of 200,000 individuals with exome sequencing data from the UK Biobank.Methods and Results We included 199,832 participants with a mean age of 68 at follow-up. Exome-wide gene-based tests were performed for 64 diseases and 23 quantitative traits using a mixed-effects model, testing rare loss-of-function and damaging missense variants. We identified 51 known and 23 novel associations with 26 diseases and traits at a false-discovery-rate of 1%. There was a striking risk associated with many Mendelian disease genes including: MYPBC3 with over a 100-fold increased odds of hypertrophic cardiomyopathy, PKD1 with a greater than 25-fold increased odds of chronic kidney disease, and BRCA2, BRCA1, ATM and PALB2 with 3 to 10-fold increased odds of breast cancer. Notable novel findings included an association between GIGYF1 and type 2 diabetes (OR 5.6, P=5.35×10−8), elevated blood glucose, and lower insulin-like-growth-factor-1 levels. Rare variants in CCAR2 were also associated with diabetes risk (OR 13, P=8.5×10−8), while COL9A3 was associated with cataract (OR 3.4, P=6.7×10−8). Notable associations for blood lipids and hypercholesterolemia included NR1H3, RRBP1, GIGYF1, SCGN, APH1A, PDE3B and ANGPTL8. A number of novel genes were associated with height, including DTL, PIEZO1, SCUBE3, PAPPA and ADAMTS6, while BSN was associated with body-mass-index. We further assessed putatively pathogenic variants in known Mendelian cardiovascular disease genes and found that between 1.3 and 2.3% of the population carried likely pathogenic variants in known cardiomyopathy, arrhythmia or hypercholesterolemia genes.Conclusions Large-scale population sequencing identifies known and novel genes harboring high-impact variation for human traits and diseases. A number of novel findings, including GIGYF1,represent interesting potential therapeutic targets. Exome sequencing at scale can identify a meaningful proportion of the population that carries a pathogenic variant underlying cardiovascular disease.Competing Interest StatementDr. Ellinor is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. Dr. Ellinor has also served on advisory boards or consulted for Bayer AG, MyoKardia, Quest Diagnostics, and Novartis. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb / Pfizer and Bayer AG.GWASGenome-wide association studiesMAFMinor allele frequencyWESWhole-exome sequencingLOFHigh-confidence loss-of-functionOROdds ratioSDStandard deviation