Individuals with South Asian ancestry have a higher risk of heart disease than other groups but have been largely excluded from genetic research. Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort, we conducted genome-wide association studies of coronary artery disease and its key risk factors. Using power-adjusted transferability ratios, we found evidence for transferability for the majority of cardiometabolic loci powered to replicate. The performance of polygenic scores was high for lipids and blood pressure, but lower for BMI and coronary artery disease. Adding a polygenic score for coronary artery disease to clinical risk factors showed significant improvement in reclassification. In Mendelian randomisation using transferable loci as instruments, our findings were consistent with results in European-ancestry individuals. Taken together, trait-specific transferability of trait loci between populations is an important consideration with implications for risk prediction and causal inference.

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Background: Individuals 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. Methods: Using 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. Results: Trans-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. Conclusions: The 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.

Background: Cholesteryl ester transfer protein (CETP) is a lipid drug target under development for coronary heart disease (CHD) in both European and East Asian populations. Previous drug target Mendelian randomization (MR) studies conducted in East Asians failed to show a CHD effect, which has been interpreted as lack of effectiveness of CETP inhibition for CHD prevention in this population. Objectives: In this study, we inferred the effect of CETP inhibition in individuals of European and East Asian ancestries using drug target Mendelian randomization. Methods: We leveraged genetic associations of CETP variants with major blood lipid fractions for individuals of European (n=1,320,016) and East Asian (n=146,492) ancestries. Colocalization was employed to identify potential cross-ancestry signals of CETP variants for plasma concentrations of low-density lipoprotein cholesterol (LDL-C) or high-density lipoprotein cholesterol (HDL-C). Drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition. Differences between ancestries were evaluated using interaction tests, applying a multiplicity corrected alpha of 1.9x10-3 based on the 26 considered traits. Results: There was strong support (posterior probability: 1.00) of a shared causal CETP variant affecting HDL-C in both populations, which was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP was associated with lower LDL-C, Lp[a], systolic blood pressure and pulse pressure in both groups, but the effects were more pronounced in European individuals (interaction p-values < 1.9x10-3). Lower CETP was protective against CHD, angina, intracerebral haemorrhage and heart failure in both ancestries, for example for CHD in East Asians (OR 0.89, 95%CI 0.84;0.94) compared to Europeans (OR 0.95, 95%CI 0.92;0.99, interaction p-value=0.05). Conclusions: In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.