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Sex chromosome trisomies (SCTs) are the most common whole-chromosome aneuploidy in humans. Yet, our understanding of the prevalence and associated health outcomes is largely driven by observational studies of clinically diagnosed individuals, resulting in a disproportionate focus on 47,XXY and associated hypogonadism. We analyzed microarray intensity data of sex chromosomes for 1.5 million individuals enrolled in three large cohorts-the Million Veteran Program, FinnGen, and UK Biobank-to identify individuals with 47,XXY, 47,XYY, and 47,XXX. We examined disease conditions associated with each SCT by performing phenome-wide association studies using electronic health records for each cohort, followed by meta-analysis across cohorts. We identified 2,769 individuals with SCTs (47,XXY: 1,319; 47,XYY: 1,108; and 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; and 47,XXX: 93.6%). The identified phenotypic associations with SCT spanned all examined disease categories except neoplasms. Many associations are shared among three SCT subtypes, particularly for vascular diseases (e.g., chronic venous insufficiency [odds ratio (OR) (95% confidence interval [CI]) for 47,XXY: 4.7 (3.9,5.8), 47,XYY: 5.6 (4.5,7.0), and 47,XXX: 4.6 (2.7,7.6)]; venous thromboembolism [47,XXY: 4.6 (3.7-5.6), 47,XYY: 4.1 (3.3-5.0), and 47,XXX: 8.1 (4.2-15.4)]; and glaucoma [47,XXY: 2.5 (2.1-2.9), 47,XYY: 2.4 (2.0-2.8), and 47,XXX: 2.3 (1.4-3.5)]). A third sex chromosome confers an increased risk for systemic comorbidities, even if the SCT is not documented. SCT phenotypes largely overlap, suggesting that one or more X/Y homolog genes, possibly in the pseudoautosomal region, may underlie pathophysiology and comorbidities across SCTs.