Author + information
- Received March 17, 2020
- Revision received June 5, 2020
- Accepted June 8, 2020
- Published online August 3, 2020.
- Minxian Wang, PhDa,
- Ramesh Menon, PhDb,
- Sanghamitra Mishra, PhDb,
- Aniruddh P. Patel, MDa,c,d,
- Mark Chaffin, MSca,
- Deepak Tanneeru, MTechb,
- Manjari Deshmukh, MScb,
- Oshin Mathew, MScb,
- Sanika Apte, MScb,
- Christina S. Devanboo, MScb,
- Sumathi Sundaram, BScb,
- Praveena Lakshmipathy, MScb,
- Sakthivel Murugan, PhDb,
- Krishna Kumar Sharma, PhDe,
- Karthikeyan Rajendran, BPTf,
- Sam Santhosh, BTech, MBAb,
- Rajesh Thachathodiyl, MBBS, MDg,
- Hisham Ahamed, MDg,
- Aniketh Vijay Balegadde, MBBS, MDg,
- Thomas Alexander, MDh,
- Krishnan Swaminathan, MDh,
- Rajeev Gupta, MD, PhDe,
- Ajit S. Mullasari, MBBS, MDi,
- Alben Sigamani, MBBS, MDf,
- Muralidhar Kanchi, MBBS, MD, MBAf,
- Andrew S. Peterson, PhDj,
- Adam S. Butterworth, PhDk,l,
- John Danesh, Dphilk,l,m,n,o,p,
- Emanuele Di Angelantonio, MD, PhDk,l,
- Aliya Naheed, MBBS, MPH, PhDq,
- Michael Inouye, PhDr,s,t,u,v,
- Rajiv Chowdhury, MPH, PhDk,w,
- Ramprasad L. Vedam, PhDb,
- Sekar Kathiresan, MDd,x,
- Ravi Gupta, PhDb and
- Amit V. Khera, MD, MSca,c,d,∗ (, )@amitvkhera
- aCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- bMedGenome Labs Ltd., Bengaluru, India
- cCenter for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts
- dCardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
- eEternal Heart Care Centre, Jaipur, India
- fNarayana Health, Bengaluru, India
- gAmrita Institute Medical Sciences, Kochi, India
- hKovai Medical Center and Hospital Research Foundation, Coimbatore, India
- iMadras Medical Mission, Chennai, India
- jMedGenome Inc., Foster City, California
- kBritish Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- lNational Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom
- mBritish Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom
- nNational Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom
- oHealth Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom
- pDepartment of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom
- qInternational Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh
- rCambridge Baker Systems Genomics Initiative, Melbourne, Victoria, Australia, and Cambridge, United Kingdom
- sBaker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- tDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- uDepartment of Clinical Pathology and School of BioSciences, University of Melbourne, Parkville, Victoria, Australia
- vThe Alan Turing Institute, London, United Kingdom
- wCentre for Non-Communicable Disease Research, Dhaka, Bangladesh
- xVerve Therapeutics, Cambridge, Massachusetts
- ↵∗Address for correspondence:
Dr. Amit V. Khera, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 6.256, Boston, Massachusetts 02114.
Background 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.
Objectives This analysis used summary statistics from a prior genome-wide association study to derive a new GPSCAD for South Asians.
Methods 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.
Results 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).
Conclusions The new GPSCAD has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.
Dr. Patel is supported by grant T32HL007208 from the National Heart, Lung, and Blood Institute. Dr. Kathiresan is supported by the Ofer and Shelly Nemirovsky Research Scholar Award from Massachusetts General Hospital and the National Human Genome Research Institute under award number 5UM1HG008895; is an employee of Verve Therapeutics; holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics; has served on scientific Advisory Boards for Regeneron Genetics Center and Corvidia Therapeutics; has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, Pfizer, and Medscape; and has patents related to a method of identifying and treating a person having a pre-disposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). Dr. Khera is supported by a Merkin Institute Fellowship from the Broad Institute of MIT and Harvard award number 1K08HG010155 from the National Human Genome Research Institute, a Hassenfeld Scholar Award from Massachusetts General Hospital, and a sponsored research agreement from IBM Research; has served as a consultant to or received honoraria from Color Genomics, Illumina, Novartis, Maze Therapeutics, and Navitor Pharmaceuticals; has received grant support from the Novartis Institute for Biomedical Research; and has a patent related to a genetic risk predictor (20190017119). Drs. Menon, Mishra, Tanneeru, Deshmukh, Mathew, Apte, Devanboo, Sundaram, Lakshmipathy, Murugan, Santhosh, Vedam, and Gupta are employees of MedGenome (Bangalore, India). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received March 17, 2020.
- Revision received June 5, 2020.
- Accepted June 8, 2020.
- 2020 American College of Cardiology Foundation
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