Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium
Authors: Hahn Julie , Fu Yi-Ping , Brown Michael R. , Bis Joshua C. , de Vries Paul S. , Feitosa Mary F. , Yanek Lisa R. , Weiss Stefan , Giulianini Franco , Smith Albert Vernon , Guo Xiuqing , Bartz Traci M. , Becker Diane M. , Becker Lewis C. , Boerwinkle Eric , Brody Jennifer A. , Chen Yii-Der Ida , Franco Oscar H. , Grove Megan , Harris Tamara B. , Hofman Albert , Hwang Shih-Jen , Kral Brian G. , Launer Lenore J. , Markus Marcello R. P. , Rice Kenneth M. , Rich Stephen S. , Ridker Paul M. , Rivadeneira Fernando , Rotter Jerome I. , Sotoodehnia Nona , Taylor Kent D. , Uitterlinden André G. , Völker Uwe , Völzke Henry , Yao Jie , Chasman Daniel I. , Dörr Marcus , Gudnason Vilmundur , Mathias Rasika A. , Post Wendy , Psaty Bruce M. , Dehghan Abbas , O’Donnell Christopher J. , Morrison Alanna C. 
Published: November 2020

Background

Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

Methods and results

Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10−7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

Conclusion

This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.