X-linked genetic associations in sporadic thoracic aortic dissection.

Pubmed ID: 38688863

Pubmed Central ID: PMC11315632

Journal: American journal of medical genetics. Part A

Publication Date: Sept. 1, 2024

MeSH Terms: Humans, Male, Female, Aged, Case-Control Studies, Cohort Studies, Gene Frequency, Genetic Predisposition to Disease, Middle Aged, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Association Studies, Aortic Aneurysm, Thoracic, Chromosomes, Human, X, Dissection, Thoracic Aorta, Genes, X-Linked

Grants: RC2 HL102419, HHSN268201700004I, HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700002I, HHSN268201700002C, HHSN268201700005C, HHSN268201700001C, HHSN268201700003C, HHSN268201700004C, R01 HL062594, R01 DK118631, R03 HD098552, P50 HL083794, R01 HL109942, IK2 BX005759, P01 HL110869

Authors: Boerwinkle E, Grove ML, Chen H, Guo D, Milewicz DM, Prakash SK, Musfee FI, Jun G, Mitchell LE, Adkar SS, Choi RB, Klarin D

Cite As: Musfee FI, Jun G, Mitchell LE, Chen H, Guo D, Prakash SK, Adkar SS, Grove ML, Choi RB, Klarin D, Million Veteran Program, Boerwinkle E, Milewicz DM. X-linked genetic associations in sporadic thoracic aortic dissection. Am J Med Genet A 2024 Sep;194(9):e63644. Epub 2024 Apr 30.

Studies:

Abstract

The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF &lt;0.01)-was associated with sporadic TAD in three cohorts of European descent (Discovery: 364 cases, 874 controls; Replication: 516 cases, 440,131 controls, and ARIC [Atherosclerosis Risk in Communities study]: 753 cases, 2247 controls). For analysis of common variants, we applied a sex-stratified logistic regression model followed by a meta-analysis of sex-specific odds ratios. Furthermore, we conducted a meta-analysis of overlapping common variants between the Discovery and Replication cohorts. For analysis of rare variants, we used a sex-stratified optimized sequence kernel association test model. Common variants results showed no statistically significant findings in the Discovery cohort. An intergenic common variant near SPANXN1 was statistically significant in the Replication cohort (p = 1.81 × 10<sup>-8</sup>). The highest signal from the meta-analysis of the Discovery and Replication cohorts was a ZNF182 intronic common variant (p = 3.5 × 10<sup>-6</sup>). In rare variants results, RTL9 reached statistical significance (p = 5.15 × 10<sup>-5</sup>). Although most of our results were statistically insignificant, our analysis is the most comprehensive X-chromosome association analysis of sporadic TAD to date.