Influence of autozygosity on common disease risk across the phenotypic spectrum

• Published in: Cell Vol. 186; no. 21; pp. 4514 - 4527.e14
• Main Authors: Malawsky, Daniel S., van Walree, Eva, Jacobs, Benjamin M., Heng, Teng Hiang, Huang, Qin Qin, Sabir, Ataf H., Rahman, Saadia, Sharif, Saghira Malik, Khan, Ahsan, Mirkov, Maša Umićević, Kuwahara, Hiroyuki, Gao, Xin, Alkuraya, Fowzan S., Posthuma, Danielle, Newman, William G., Griffiths, Christopher J., Mathur, Rohini, van Heel, David A., Finer, Sarah, O’Connell, Jared, Martin, Hilary C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.10.2023; Cell Press
• Subjects: autozygosity; Biological Specimen Banks; common diseases; Consanguinity; Diabetes Mellitus, Type 2 - genetics; diverse cohorts; Genetic Predisposition to Disease; Genome, Human; Homozygote; Humans; medical genetics; Phenotype; Polymorphism, Single Nucleotide; recessive; United Kingdom; United Kingdom; common diseases; medical genetics; consanguinity; diverse cohorts; autozygosity; recessive
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2023.08.028

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. [Display omitted] •Robust method to reduce confounding in autozygosity-phenotype association studies•Higher autozygosity associated with increased risk for common diseases such as T2D•Replication of findings including a within-sibling analysis•Consanguinity explains ∼10% of T2D cases in British Pakistanis Autozygosity resulting from consanguinity is causally associated with several complex diseases, including type 2 diabetes.