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

Nat Genet. 2022 Mar;54(3):240-250. doi: 10.1038/s41588-021-01011-w. Epub 2022 Feb 17.


Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3, LDLR, GCK, PKD1 and TTN. Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Specimen Banks
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / genetics
  • Carrier Proteins / genetics
  • Diabetes Mellitus, Type 2* / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation / genetics
  • Humans
  • United Kingdom


  • Carrier Proteins
  • GIGYF1 protein, human