Influence of autozygosity on common disease risk across the phenotypic spectrum.

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 (F _ROH ) 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 F _ROH . Within this group in G&H+UK Biobank, we found experiment-wide significant associations between F _ROH 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.
Competing Interests: Declaration of interests J.O. and members of the 23andMe Research Team are employed by and hold stock or stock options in 23andMe, Inc. H.C.M. is a member of Cell’s advisory board. D.A.v.H., S.F., and H.C.M. have received salary contributions via the Genes & Health Industry Consortium of AstraZeneca PLC, Bristol-Myers Squibb Company, GlaxoSmithKline Research and Development Limited, Maze Therapeutics Inc., Merck Sharp & Dohme LLC, Novo Nordisk A/S, Pfizer Inc., and Takeda Development Centre Americas Inc.
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