Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistanis and Bangladeshis

Abstract

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 PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIThis 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. C_LIO_LIWe propose a new approach to assessing transferability of GWAS loci between populations, which can serve as a new methodological standard in this developing field. C_LIO_LIWe 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. C_LIO_LIThe transferability of PGSs varied between traits, being high for HDL-C, triglycerides and blood pressure but more modest for CAD, BMI and LDL-C. C_LIO_LIOur results suggest that, for some traits, the use of transferable GWAS loci improves the robustness of Mendelian randomisation estimates in non-Europeans. C_LI What are the clinical implications?O_LIThe 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). C_LIO_LIIncorporation of the polygenic score for CAD into risk prediction models is likely to prevent cardiovascular events and deaths in this population. C_LI