Transferability of European-derived cardiometabolic polygenic risk scores in the South Asians and their interplay with family history

Abstract

Background & Aims: We aimed to investigate the effect of polygenic risk scores (PRSs) derived from individuals of European (EUR) ancestry on common diseases among individuals of South Asian (SAS) ancestry in the UK Biobank (UKB). Additionally, we studied the interaction between PRS and family history (FH) in the same population. Methods: To calculate the PRS, we used a previously published panel of SNPs derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. We applied the PRS using summary statistics from genome-wide association studies (GWAS) for cardiometabolic and lifestyle diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D). Each PRS was adjusted according to an individual's predicted genetic ancestry to derive an adjusted PRS (aPRS). We calculated the percentiles based on aPRS and divided them according to the percentiles into three categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates. Results: The risk of developing severe obesity for individuals of SAS ancestry was almost threefold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 3.67 (95% CI = 2.47-5.48, P < 0.01). While the risk of severe obesity was lower in the low-aPRS group (OR = 0.19, CI = 0.05-0.52, P < 0.01). Comparable results were found in the EUR data, where the low-PRS group had an OR of 0.26 (95% CI= 0.24-0.3, P < 0.01) and the high-PRS group had an OR of 3.2 (95% CI = 3.1-3.3, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS exhibit further higher risk to these diseases, thereby implying a greater genetic predisposition to these conditions. Conclusion: Our findings suggest that using CAD, obesity, and T2D GWAS summary statistics predominantly from the EUR population have sufficient power to identify SAS individuals with higher genetic risk. With future GWAS recruiting more SAS participants and tailoring the PRSs towards SAS ancestry, we believe that the predictive power of PRS would improve.

Competing Interest Statement

DRB is the founder and CEO of Wellytics Technologies Pvt Ltd. No potential conflicts (financial, professional, or personal) for the other authors relevant to the manuscript.

Funding Statement

No funding was obtained for this study

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics approval for the UK Biobank (UKB) study was obtained from the North West Multicentre for Research Ethics Committee (MREC). The UKB ethics statement is available at https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics. All UKB participants provided informed consent at recruitment.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

Genome-wide genotyping data, exome-sequencing data, and phenotypic data from the UK Biobank are available upon successful project application (http://www.ukbiobank.ac.uk/about-biobank-uk/). Restrictions apply to the availability of these data, which were used under license for the current study (Project ID: 52446).

http://www.ukbiobank.ac.uk/about-biobank-uk/

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