No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis.
Loley C., Alver M., Assimes TL., Bjonnes A., Goel A., Gustafsson S., Hernesniemi J., Hopewell JC., Kanoni S., Kleber ME., Lau KW., Lu Y., Lyytikäinen LP., Nelson CP., Nikpay M., Qu L., Salfati E., Scholz M., Tukiainen T., Willenborg C., Won HH., Zeng L., Zhang W., Anand SS., Beutner F., Bottinger EP., Clarke R., Dedoussis G., Do R., Esko T., Eskola M., Farrall M., Gauguier D., Giedraitis V., Granger CB., Hall AS., Hamsten A., Hazen SL., Huang J., Kähönen M., Kyriakou T., Laaksonen R., Lind L., Lindgren C., Magnusson PK., Marouli E., Mihailov E., Morris AP., Nikus K., Pedersen N., Rallidis L., Salomaa V., Shah SH., Stewart AF., Thompson JR., Zalloua PA., Chambers JC., Collins R., Ingelsson E., Iribarren C., Karhunen PJ., Kooner JS., Lehtimäki T., Loos RJ., März W., McPherson R., Metspalu A., Reilly MP., Ripatti S., Sanghera DK., Thiery J., Watkins H., Deloukas P., Kathiresan S., Samani NJ., Schunkert H., Erdmann J., König IR.
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.