Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

• Published in: Nature genetics Vol. 54; no. 3; pp. 240 - 3
• Main Authors: Jurgens, Sean J, Choi, Seung Hoan, Morrill, Valerie N, Chaffin, Mark, Pirruccello, James P, Halford, Jennifer L, Weng, Lu-Chen, Nauffal, Victor, Roselli, Carolina, Hall, Amelia W, Oetjens, Matthew T, Lagerman, Braxton, Vanmaanen, David P, Aragam, Krishna G, Lunetta, Kathryn L, Haggerty, Christopher M, Lubitz, Steven A, Ellinor, Patrick T, Abecasis, Goncalo, Bai, Xiaodong, Balasubramanian, Suganthi, Baras, Aris, Beechert, Christina, Boutkov, Boris, Cantor, Michael, Coppola, Giovanni, De, Tanima, Deubler, Andrew, Economides, Aris, Eom, Gisu, Ferreira, Manuel A R, sythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Habegger, Lukas, Hawes, Alicia, Jones, Marcus B, Karalis, Katia, Khalid, Shareef, Krasheninina, Olga, Lanche, Rouel, Lattari, Michael, Li, Dadong, Lopez, Alexander, Lotta, Luca A, Manoochehri, Kia, Mansfield, Adam J, Maxwell, Evan K, Mighty, Jason, Mitnaul, Lyndon J, Nafde, Mona, Nielsen, Jonas, O'Keeffe, Sean, Orelus, Max, Overton, John D, Padilla, Maria Sotiropoulos, Panea, Razvan, Polanco, Tommy, Pradhan, Manasi, Rasool, Ayesha, Reid, Jeffrey G, Salerno, William, Schleicher, Thomas D, Shuldiner, Alan, Siminovitch, Katherine, Staples, Jeffrey C, Ulloa, Ricardo H, Verweij, Niek, Widom, Louis, Wolf, Sarah E
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 01.03.2022
• Subjects: Biobanks; Cardiovascular diseases; Diabetes; Diabetes mellitus; Genes; Genetic analysis; Genetic diversity; Genetic variability; Genomes; Genotype & phenotype; High density lipoprotein; Hypothyroidism; Metabolism; Mutation; Phenotypes; Proteins; Quality control; Therapeutic targets; Thyroid diseases; United Kingdom > UK
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-02101011-w

[...]exome sequencing-which is focused on the protein-coding regions of the genome-may directly implicate genes in phenotype variability through burden testing of multiple rare protein-coding variants15. [...]analysis of rare coding variation can help establish the directionality of impaired gene function through the analysis of loss-of-function (LOF) alleles, a feature that can be informative both for understanding disease mechanisms and for potential therapeutic targeting. [...]we describe the frequency of mutations in genes underlying cardiovascular diseases and monogenic diabetes. Importantly, the novel associations that we identified remained robust in a LOVO analysis (Supplementary Fig. 10). [...]the genes significantly associated with diseases or traits were identified due to a burden of multiple contributing rare variants, although in certain cases-such as the associations of ANGPTL2 with height and NR1H3 with HDL-single variants were important.