Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians

• Published in: Journal of the American College of Cardiology Vol. 76; no. 6; pp. 703 - 714
• Main Authors: Wang, Minxian, Menon, Ramesh, Mishra, Sanghamitra, Patel, Aniruddh P., Chaffin, Mark, Tanneeru, Deepak, Deshmukh, Manjari, Mathew, Oshin, Apte, Sanika, Devanboo, Christina S., Sundaram, Sumathi, Lakshmipathy, Praveena, Murugan, Sakthivel, Sharma, Krishna Kumar, Rajendran, Karthikeyan, Santhosh, Sam, Thachathodiyl, Rajesh, Ahamed, Hisham, Balegadde, Aniketh Vijay, Alexander, Thomas, Swaminathan, Krishnan, Gupta, Rajeev, Mullasari, Ajit S., Sigamani, Alben, Kanchi, Muralidhar, Peterson, Andrew S., Butterworth, Adam S., Danesh, John, Di Angelantonio, Emanuele, Naheed, Aliya, Inouye, Michael, Chowdhury, Rajiv, Vedam, Ramprasad L., Kathiresan, Sekar, Gupta, Ravi, Khera, Amit V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.08.2020
• Subjects: Adult; Aged; Bangladesh; Cardiovascular; Case-Control Studies; coronary artery disease; Coronary Artery Disease - genetics; Female; Genome-Wide Association Study; genomic medicine; Humans; India; Male; Middle Aged; Multifactorial Inheritance; polygenic score; South Asian; Bangladesh; India; coronary artery disease; genomic medicine; PCs; OR/SD; CI; CAD; South Asian; GPS; polygenic score; AUC; area under the receiver-operator curve; genome-wide polygenic score(s); confidence interval; principal components; odds ratios per standard deviation
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2020.06.024

Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population. This analysis used summary statistics from a prior genome-wide association study to derive a new GPSCAD for South Asians. This GPSCAD was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPSCAD reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPSCAD reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India. The GPSCAD, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPSCAD distribution—ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each). The new GPSCAD has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment. [Display omitted]