“Fine-Scale Population Structure and Demographic History of British Pakistanis”, 2021-12-10 (; similar):
Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy.
Here, we investigate fine-scale population structure, history and consanguinity patterns using genotype chip data from 2,200 British Pakistanis.
We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low recent effective population sizes (Ne), with some showing a decrease 15‒20 generations ago that has resulted in extensive identity-by-descent sharing and homozygosity, increasing the risk of recessive disorders. Our results from 2 orthogonal methods (one using machine learning and the other coalescent-based) 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.
…57% of the BiB Pakistani mothers reported that their parents were related, and 63% reported being related to their child’s father (Supplementary Data 13 & 14). As expected, a much higher fraction of the genome was homozygous (FROH) in the Pakistani mothers than the White British (mean = 0.048 versus 0.0004, 2-sided t.test p < 1 × 10−15).
…Our results suggest that, even in the absence of close consanguinity, increased homozygosity due to endogamy is likely to be contributing to recessive disease burden and the elevated frequency of rare homozygous knockouts in this population. To investigate the relative impact of endogamy versus consanguinity on recessive disease risk, we used exome-sequence data from 2,484 Bradford Pakistani mothers, in which we ascertained pathogenic/likely pathogenic (P/LP) variants in autosomal recessive developmental disorder genes. We then simulated intra-biraderi (endogamous) and inter-biraderi (exogamous) couples, and unions between pairs of individuals whose IBD distribution matches that of self-reported first cousins within the dataset (see ‘Methods’). We then scored each couple as being ‘at risk’ of having an affected child if both individuals were carriers of a P/LP variant in the same gene, similar to the approach in ref. 58. The results (Figure 6) indicate that intra-biraderi unions incur statistically-significantly higher risk than inter-biraderi unions (particularly for the Bains and Jatts; one-sided permutation tests p = 2 × 10−4 and p < 1 × 10−4 respectively), but first cousin unions incur more than ten-fold higher risk than intra-biraderi unions.
…Our findings suggest that clinicians should consider recording parents’ biraderi groups as well as close relatedness in genetic consultations. This will be particularly useful as research becomes more focused on clinical sequencing datasets such as that held by Genomics England. Recording biraderi information would enable further research into the prevalence of different diseases in different biraderi groups, the impacts of endogamy and the possible presence of disease-causing founder mutations. The results from such research will be important to inform and design targeted genomic health services for Pakistani-ancestry populations. However, great care needs to be taken to ensure this research and any application of it is carried out in a culturally sensitive way.