No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis

Abstract

In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.

Figure 1. Chromosome-wide association results.

The statistical model assumes no inactivation and no SNP*sex interaction. Shown are logarithmized random effects p-values of all 184,673 quality controlled SNPs in order of physical position in mega base pairs (mbp).

Figure 2. Estimated power.

The power to detect an effect was estimated in dependence of the odds ratio (OR) and the effect allele frequency (EAF) using software Quanto (version 1.2.4 from May 2009). Parameters used for simulation: Binary (disease) phenotype, significance level α = 5·10⁻⁸, disease prevalence k_P = 0.1, log-additive genetic model, no gene-environment interaction. (A) Effective N_cases = 27,640, 1.5817 effective controls per effective case (corresponding to 43,718 effective controls), (B) Female N_cases = 12,160, 2.3968 female controls per female case (corresponding to 29,145 female controls).