Genome-Wide Linkage Scan Identifies Two Novel Genetic Loci for Coronary Artery Disease: In GeneQuest Families

Abstract

Coronary artery disease (CAD) is the leading cause of death worldwide. Recent genome-wide association studies (GWAS) identified >50 common variants associated with CAD or its complication myocardial infarction (MI), but collectively they account for <20% of heritability, generating a phenomena of “missing heritability”. Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL) analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL = 5.49) and 3q29 (NPL = 6.84). We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL = 3.18–4.07). These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD.

Identification of Risk Pathways and Functional Modules for Coronary Artery Disease Based on Genome-Wide SNP Data

“…More similar studies have also been performed in different populations, leading to the excavation of more CAD-related single nucleotide polymorphisms (SNPs) [4], [5]. As a result, population-based studies with thousands of patients and healthy controls included have identified more than 50 CAD-associated genetic loci in total [6], [7], [8], [9].…”

Genome-Wide Linkage Analysis of Large Multiple Multigenerational Families Identifies Novel Genetic Loci for Coronary Artery Disease

“…As shown in Table 2, the 3q29 and 9q22.33 CAD loci were identified by both GWLS with 24 large families (GeneQuest II) and by a similar analysis with 428 nuclear families in the GeneQuest population 40 . Our results also demonstrate that GWLA has a comparable power to GWAS.…”

“…Since then, over ten GWLAs, including our own studies, have identified additional genetic loci for CAD or MI, including 1p34–36,1q25, 2q14.3, 2q36–37.3, 2q13, 3q13, 5q31, 7p14, 8p22, 13q12–13,14q32.3, 15q26.3, 16p13, and 17p11.2–17q21 28 – 39 . Recently, we have completed a genome-wide linkage scan in a well characterized U.S GeneQuest cohort with 428 nuclear families and identified six novel CAD loci on chromosomes 3p25.1, 3p29, 9q22.3, 9p34.11, 17p12, and 21q22.3 40 . In contrast to aforementioned GWASs, the number of genetic loci identified by GWLA was much smaller and independent, suggesting that many linkage loci remain to be identified in new CAD or MI families 40 .…”

Analysis of causal effect of APOA5 variants on premature coronary artery disease

“…The details of this diagnostic criteria and ascertainment of GeneQuest participants have been described by us previously (Guo et al, 2017, Gao et al, 2014, Shen et al, 2014). In brief, the presence or absence of CAD was evaluated according to a coronary angiography with a >70% stenosis, history of revascularization procedures, such as percutaneous coronary angioplasty (PCA) or coronary artery bypass (CABG), and previous diagnoses of MI as described (Guo et al, 2017, Gao et al, 2014, Shen et al, 2014). Patients with hypercholesterolemia, insulin-dependent diabetes, childhood hypertension, congenital heart disease, cardiomyopathy, valvular disease, and renal or hepatic disease were excluded from this study.…”