Genome-wide association studies on coronary artery disease: A systematic review and implications for populations of different ancestries

Abstract

Background: Cardiovascular diseases are some of the leading causes of death worldwide, with coronary artery disease leading as one of the primary causes of mortality in both the developing and developed worlds. Despite its prevalence, there is a disproportionately small number of studies conducted in populations of non-European ancestry, with the limited sample sizes of such studies further restricting the power and generalizability of respective findings. This research aimed at understanding the differences in the genetic architecture of coronary artery disease (CAD) in populations of diverse ancestries in order to contribute towards the understanding of the pathophysiology of coronary artery disease.

Methods: We performed a systematic review on the 6th of October, 2022 summarizing genome-wide association studies on coronary artery disease, while employing the GWAS Catalog as an independent database to support the search. We developed a framework to assess the methodological quality of each study. We extracted and grouped associated single nucleotide polymorphisms and genes according to ancestry groups of participants.

Results: We identified 3100 studies, of which, 36 relevant studies were included in this research. Three of the studies that were included were not listed in the GWAS Catalog, highlighting the value of conducting an independent search alongside established databases in order to ensure the full research landscape has been captured. 743,919 CAD case participants from 25 different countries were analysed, with 61% of the studies identified in this research conducted in populations of European ancestry. No studies investigated populations of Africans living in continental Africa or admixed American ancestry groups besides African-Americans, while limited sample sizes were included of population groups besides Europeans and East Asians. This observed disproportionate population representation highlights the gaps in the literature, which limits our ability to understand coronary artery disease as a global disease. 71 genetic loci were identified to be associated with coronary artery disease in more than one article, with ancestry-specific genetic loci identified in each respective population group which were not detected in studies of other ancestries.

Conclusions: Although the replication and validation of these variants are still warranted, these finding are indicative of the value of including diverse ancestry populations in GWAS reference panels, as a more comprehensive understanding of the genetic architecture and pathophysiology of CAD can be achieved.

Fig 1. Preferred reporting items for systematic reviews and meta-analyses flowchart for the systematic review of genome-wide association studies of coronary artery disease.

Fig 2. Identified and included studies for this systematic review compared to the number of coronary artery disease studies listed in the GWAS Catalog.

Fig 3. Percentage distribution of identified ancestries of participants from genome-wide association studies on coronary artery disease included in this systematic review.

European (EUR); East Asian (EAS); African-American (AFR-AMR); South Asian (SAS); a combination of ancestries including those identified as African-American, Hispanic or Middle Eastern (Other).

Fig 4. Ancestry-specific genes affected by SNPs identified in a systematic review of genome-wide association studies on coronary artery disease.

African-American (AFR-AMR), European (EUR); East Asian (EAS), South Asian (SAS).