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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 two 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., Little is known about the recent population history or the effects of endogamy on the Pakistani population. Here the authors examine the impact of the biraderi social stratification system on the population structure of individuals of British Pakistani ancestry in the Born in Bradford cohort.

BackgroundIndividuals with South Asian ancestry have higher risk of heart disease than other groups in Western countries; however, most genetic research has focused on European-ancestry (EUR) individuals. It is unknown whether reported genetic loci and polygenic scores (PGSs) for cardiometabolic traits are transferable to South Asians, and whether PGSs have utility in clinical settings.MethodsUsing data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort (G&H), we conducted genome-wide association studies (GWAS) and characterised the genetic architecture of coronary artery disease (CAD), body mass index (BMI), lipid biomarkers and blood pressure. We applied a new technique to assess the extent to which loci from GWAS in EUR samples were transferable. We tested how well existing findings from EUR studies performed in genetic risk prediction and Mendelian randomisation in G&H.ResultsTrans-ancestry genetic correlations between G&H and EUR samples for the tested traits were not significantly lower than 1, except for BMI (rg=0.85, p=0.02). We found evidence for transferability for the vast majority of loci from EUR discovery studies that were sufficiently powered to replicate in G&H. PGSs showed variable transferability in G&H, with the relative accuracy compared to EUR (ratio of incremental r2/AUC) ≥0.95 for HDL-C, triglycerides, and blood pressure, but lower for BMI (0.78) and CAD (0.42). We observed significant improvement in categorical net reclassification in G&H (NRI=3.9%; 95% CI 0.9–7.0) when adding a previously developed CAD PGS to clinical risk factors (QRISK3). We used transferable loci as genetic instruments in trans-ancestry Mendelian randomisation and found evidence of an increased CAD risk for higher LDL-C and BMI, and for lower HDL-C in G&H, consistent with our findings for EUR samples.ConclusionsThe genetic loci for CAD and its risk factors are largely transferable from EUR studies to British Pakistanis and Bangladeshis, whereas the transferability of PGSs varies greatly between traits. Our analyses suggest clinical utility for addition of PGS to existing clinical risk prediction tools for this population.Clinical PerspectiveWhat is new?This is the first study to explore the transferability of GWAS findings and PGSs for CAD and related cardiometabolic traits in British Pakistani and Bangladeshi individuals from a cohort with real-world electronic clinical data.We propose a new approach to assessing transferability of GWAS loci between populations, which can serve as a new methodological standard in this developing field.We find evidence of overall high transferability of GWAS loci in British Pakistanis and Bangladeshis. BMI, lipids and blood pressure show the highest transferability of loci, and CAD the lowest.The transferability of PGSs varied between traits, being high for HDL-C, triglycerides and blood pressure but more modest for CAD, BMI and LDL-C.Our results suggest that, for some traits, the use of transferable GWAS loci improves the robustness of Mendelian randomisation estimates in non-Europeans.What are the clinical implications?The polygenic score for CAD derived from genetic studies of European individuals improves reclassification on top of clinical risk factors in British Pakistanis and Bangladeshis. The improvement was driven by identification of more cases in younger individuals (25–54 years old), and of controls in older individuals (55–84 years old).Incorporation of the polygenic score for CAD into risk prediction models is likely to prevent cardiovascular events and deaths in this population.

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 genetic and questionnaire data from >4,000 British Pakistani individuals, mostly with roots in Azad Kashmir and Punjab. We reveal strong recent population structure driven by thebiraderisocial stratification system. We find that all subgroups have had low effective population sizes (Ne) over the last 50 generations, with some showing a decrease in Ne15-20 generations ago that has resulted in extensive identity-by-descent sharing and increased homozygosity. Using new theory, we show that the footprint of regions of homozygosity in the two largest subgroups is about twice that expected naively based on the self-reported consanguinity rates and the inferred historical Netrajectory. These results demonstrate the impact of the cultural practices of endogamy and consanguinity on population structure and genomic diversity in British Pakistanis, and have important implications for medical genetic studies.

Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20–60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting., This work was supported by The Wellcome Trust (098051). EA was supported by the Erasmus Lifelong Learning Programme (LLP). LP was supported by the ERC Starting Investigator grant FP7 – 261213.