Associations Between Mosaic Loss of Sex Chromosomes and Incident Hospitalization for Atrial Fibrillation in the United Kingdom

Abstract

Background: Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear.

Methods and results: We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190 613 men and 224 853 women with genotyping data from the UK Biobank. Among these participants, there were 37 037 men with mLOY and 13 978 women with mLOX detected using the Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization was conducted to estimate causal associations. Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR, 1.06 [95% CI, 1.03-1.11]). The associations were apparent in both never smokers (HR, 1.07 [95% CI, 1.01-1.14]) and ever smokers (HR, 1.05 [95% CI, 1.01-1.11]) as well as men aged >60 and ≤60 years. Mendelian randomization analyses supported causal associations between mLOY and atrial fibrillation (HR_MR-PRESSO, 1.15 [95% CI, 1.13-1.18]). Among postmenopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR, 0.90 [95% CI, 0.83-0.98]). However, associations with mLOY and mLOX were not found for other heart diseases.

Conclusions: Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

Keywords: atrial fibrillation; heart disease; incident relative risk; mosaic loss of sex chromosomes; prospective cohort study.

Figure 1. Analytical flowchart.

GWAS indicates genome‐wide association study; mLOX, mosaic loss of chromosome X; and mLOY, mosaic loss of chromosome Y.

Figure 2. Mosaic loss of chromosome Y (mLOY) in prediagnostic leukocytes and risk of newly diagnosed atrial fibrillation, stratified by mosaic cell fractions (mCFs) with mLOY.

We analyzed participants with complete genotyping and covariate data. Multivariable Cox regression models were used to estimate hazard ratios and 95% CIs of newly diagnosed (incident) atrial fibrillation in relation to mLOY (detectable vs not detectable) among men. We adjusted for potential confounders, including study assessment center, age at recruitment, self‐reported race and ethnicity, 10 principal components for genetic ancestry, educational attainment (ie, qualifications), smoking status, body mass index, material deprivation, alcohol, diabetes status, glycated hemoglobin (mmol/mol), and hypertension status based on average systolic and diastolic blood pressure at baseline, total white blood cell count at enrollment, and any cancer diagnosis at enrollment. Analytic subgroup sample sizes with complete data: no detectable mLOY (comparison group): 10245 cases/153367 men; 0

Figure 3. Mendelian randomization (MR) analyses to assess the potential causal associations between prediagnostic leukocyte mosaic loss of chromosome Y and risk of newly diagnosed atrial fibrillation in the UK Biobank.

IVW indicates inverse variance weighted; MR‐PRESSO, MR pleiotropy residual sum and outlier; and MR‐RAPS, MR robust adjusted profile score.