I will describe two recent studies from my group focused on British cohorts with Pakistani and Bangladeshi ancestry which are enriched for consanguinity.
In the first, we investigated fine-scale population structure, history and consanguinity patterns using genotype chip data from 2,200 British Pakistanis in the Born in Bradford study. We found strong recent population structure driven by the biraderi social stratification system, and explored changes in effective population size across time that revealed strong bottlenecks. Our results from two orthogonal methods suggest that the detailed reporting of parental relatedness for mothers in the cohort under-represents the true levels of consanguinity. These results demonstrate the impact of cultural practices on population structure and genomic diversity in Pakistanis, and have important implications for medical genetic studies.
In the second study, we investigated associations between homozygosity resulting from consanguinity (autozygosity) and common diseases in 23,978 unrelated British Pakistani and Bangladeshi ancestry individuals from the Genes & Health cohort (G&H) and 397,184 individuals from UK Biobank with genetically-inferred European or South Asian ancestries. In a new approach to reduce confounding, we examined associations between FROH (the fraction of the genome in runs of homozygosity) and traits using only individuals who are offspring of first cousins or closer, in whom variation in FROH is primarily driven by stochastic recombination events and Mendelian segregation. We showed that subsetting to this group greatly attenuates confounding that hampered previous studies. Using electronic health records, we tested associations between common diseases and FROH within this highly consanguineous group, and found significant associations (FDR<5%) with several disorders, including type 2 diabetes (T2D), asthma, and anxiety-related disorders. We estimated that autozygosity due to consanguinity accounts for ~10% of the T2D and asthma cases observed in British-Pakistani individuals and ~3.5% in British-Bangladeshi individuals. Our work quantifies, for the first time, the impact of autozygosity on dozens of common diseases using a novel approach to control for confounding, and highlights the possibility of widespread non-additive effects across the disease phenotypic spectrum.