Ultra-rare gene variants drive coronary artery disease risk in European ancestry

In this groundbreaking study, researchers uncover how ultra-rare genetic variants, especially in heart cells, play a critical role in raising the risk of coronary artery disease among individuals of European descent.

Study: Rare variant contribution to the heritability of coronary artery disease. Image Credit: Sergey Nivens / Shutterstock.com

In a recent study published in the journal Nature Communications, researchers investigate the contribution of rare variants in the heritability of coronary artery disease (CAD) using whole genome sequencing.

What causes CAD?

The development of CAD, one of the major causes of mortality worldwide, is largely determined by genetic risk factors. Previous studies conducted on European populations, for example, indicate that the heritability of CAD is about 60%.

Genome-wide association studies have also identified several genetic variants that account for a significant portion of the heritability of CAD. However, many of these variants are common, with minor allele frequencies greater than 1%, which does not explain a significant portion of the genetic risk of CAD. Recent studies have found that rare genetic variants, especially those found in non-coding regions, significantly contribute to the heritability of complex diseases such as CAD.

Whole genome sequencing has identified ultra-rare variants with less than 0.1% minor allele frequencies that have gene regulatory roles, especially in heart-related tissues. In fact, single-cell epigenomic studies have also indicated that variants associated with CAD are enriched in specific heart cells.

About the study

The present study aimed to determine the contributions of rare and ultra-rare genetic variants in the heritability of CAD using whole genome sequencing and explore their roles in gene-regulatory functions and protein-altering.

Whole genome sequence data were obtained from the TOPMed Freeze 9 dataset, which consists of over 160,000 samples and approximately 800 million single nucleotide variants. Only variants with at least 10 reads were included in the analysis.

Documented coronary interventions such as angioplasty or bypass surgery, as well as cases of myocardial infarction (MI) or death due to coronary heart disease, were used to identify cases of CAD. The controls included individuals without any documented angina, CAD, or death due to coronary heart disease.

To avoid bias, any related individuals were excluded from the analysis, and stringent quality control measures were applied to all the samples. A principal component analysis was used to infer genetic ancestry, focusing on data from 22,443 individuals of European ancestry that comprised over 28 million autosomal single nucleotide variants.

The heritability of CAD was estimated using genome-based restricted maximum likelihood with linkage disequilibrium and minor allele frequency stratification (GREML-LDMS) implemented in the software genome-wide complex trait analysis (GCTA).

The linkage disequilibrium scores were calculated for each single nucleotide variant. These values were then binned according to their minor allele frequencies and linkage disequilibrium. These results were then used to calculate a genetic relatedness matrix to estimate heritability.

Single nucleotide variants were further categorized based on evolutionary constraints determined through phyloP scores, cell-specific regulatory functions, and their predicted impact on proteins. The single nucleotide variants were also annotated based on their biological importance.

To identify the genetic variants that contributed significantly to CAD risk, single-nucleotide variant comparisons based on evolutionary constraints, protein-altering impact, and cell-regulatory functions were used.

Study findings

The heritability of CAD varied considerably based on the individual’s genetic ancestry and the frequency of the genetic variants, with significant contributions from ultra-rare variants. This analysis focused on individuals of European ancestry, as heritability estimates for CAD were inconsistent when the predictions were made based on self-inferred race and ethnicity as compared to genetically inferred ancestry.

The heritability of CAD among individuals of European ancestry was estimated to be 23.9%, which increased to 34.3% when the analyses were adjusted for disease prevalence. About 50% of this heritability was attributed to ultra-rare variants with a minor allele frequency of 0.1% or less with low linkage disequilibrium scores. These ultra-rare variants had a stronger effect on the risk of CAD than the common variants.

The heritability of CAD was estimated to be 25.5% among smaller groups of individuals of African ancestry. However, the contribution of ultra-rare variants to CAD heritability was lower, at 15%, among individuals of African ancestry than among individuals of European ancestry.

Protein-altering single nucleotide variants disproportionately contributed to the heritability of CAD. Furthermore, single nucleotide variants that affected regulatory elements in the coronary artery cells, such as smooth muscle and endothelial cells, were also significant contributors to the risk of CAD.

Conclusions

The study findings highlight the role of ultra-rare genetic variants in the heritability of CAD, especially among individuals of European ancestry. Single nucleotide variants with protein-altering functions or those located in gene regulatory regions significantly contributed towards CAD risk. In the future, more research is needed to examine the role of genetic variants in CAD risk among diverse populations and individuals of mixed group ancestry.