Approved Research

Comparing variant distributions and Polygenic Risk Score between the UK Biobank and South Asian cohorts

Lay summary

As part of our project codenamed PhenoGen, we are collecting deep phenotypic and genomic data on individuals from Central and South India. We plan to jointly analyze this cohort with the UKBB cohort to understand the variant distributions between these two cohorts and to identify novel disease-specific genetic variants that can provide new insights into disease biology.  One-fourth of the global population is of South Asian ancestry, but the representation of South Asian genomes in global genomic studies remains sparse, with a major focus being on Caucasian individuals. By expanding the South Asian cohort substantially using the PhenoGen cohort (phase 1: 10K, phase 2: 100K), we aim to get a deeper understanding of how genomic variants in the South Asians impact various diseases of interest. We also propose to build risk predictors for NAFLD/NASH and CAD with better applicability to South Asians.

NAFLD/NASH and CAD have high prevalence in India and risk prediction and new therapeutics for both areas are of great societal interest.  NAFLD/NASH is the leading cause of liver-related mortality with an ever increasing prevalence rate and no approved pharmacotherapy till date. Similarly, the incidence, prevalence, and mortality from premature CAD in Indians and other South Asians is reportedly ~50-400 times higher as compared to any other ethnic group. Both NAFLD/NASH and CAD are known to have significant genetic underpinnings, and also have a high heritable component. With the PhenoGen project, we hope to expand our understanding of the genetic architecture of both these diseases by deepening the knowledge of the molecular mechanisms, pathophysiological processes and the interplay between genetic factors for the identification of novel therapeutic targets. Our initial focus is on these two areas, but we hope to look at other disease areas in due course of time.

Given that disease risk stems from a combination of rare and common genomic variants, we propose to analyze the UKBB cohort and the PhenoGen cohorts jointly to identify rare and common variant loci of interest to the above two disease areas that could provide better ways to predict risk as well as yield new drug targets. In the process, we would also like to do a broader variant distribution analysis across the two cohorts. We expect the project to start in Jan 2023 and continue for 2 years.