Fine-scale population structure and demographic history of British Pakistanis

Elena Arciero,Eamonn Sheridan,Massimo Mezzavilla,Neil Small,Daniel S Malawsky,Karen A Hunt,Theofanis Tsismentzoglou,Hilary C Martin,Dan Mason,Sufyan A Dogra,John Wright,David A Van Heel,Saghira Malik Sharif,Qin Qin Huang,Shai Carmi,Mark M Iles

doi:10.1038/s41467-021-27394-2

Abstract

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.

Highlights

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
We assembled a large dataset of 7180 individuals with Pakistani ancestry (Supplementary Data 1 and 2) from the Born in Bradford (BiB) project, of which 5669 had been genotyped on the Illumina CoreExome array and 1511 on the Illumina Global Screening Array (GSA); 2484 of these had exome-sequence data
The biraderi system is culturally characterised by patrilineal kinship ties, so we examined GSA data on 228 unrelated Pakistani fathers from BiB to test whether males from the same subgroups did carry the same or similar Y haplogroups (Supplementary Data 5), using 1056 Y chromosomal single-nucleotide polymorphisms (SNPs)

Summary

Introduction

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. Our results from two orthogonal methods (one using machine learning and the other coalescentbased) 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. Pakistanis have rates of type 2 diabetes and heart disease that are two to four times higher than the white British population[9,10,11], as well as an increased risk of congenital anomalies due to the prevalence of consanguinity[12] These factors, combined with the drive to increase the number of genetic studies on people with non-European ancestry[13], have spurred the creation of several cohort studies whose aims include exploring the environmental and genetic contributions to various phenotypes in Pakistaniancestry individuals and the impact of homozygous gene knockouts[14]. North-west Indians and Pakistanis have a greater proportion of the ANI component[18,19]

Methods

Results

Conclusion