Influence of autozygosity on common disease risk across the phenotypic spectrum

Cell. 2023 Oct 12;186(21):4514-4527.e14. doi: 10.1016/j.cell.2023.08.028. Epub 2023 Sep 26.


Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.

Keywords: autozygosity; common diseases; consanguinity; diverse cohorts; medical genetics; recessive.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Specimen Banks
  • Consanguinity*
  • Diabetes Mellitus, Type 2* / genetics
  • Genetic Predisposition to Disease
  • Genome, Human
  • Homozygote
  • Humans
  • Phenotype
  • Polymorphism, Single Nucleotide
  • United Kingdom