Sex chromosome trisomies (SCT) 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 cases, 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--Million Veteran Program, FinnGen, and UK Biobank--to identify individuals with 47,XXY, 47,XYY, and 47,XXX. We examined disease conditions associated with SCTs by performing phenome-wide association studies (PheWAS) using electronic health records (EHR) data for each cohort, followed by meta-analysis across cohorts. Association results are presented for each SCT and also stratified by presence or absence of a documented clinical diagnosis for 47,XXY. We identified 2,769 individuals with (47,XXY: 1,319; 47,XYY: 1,108; 47,XXX: 342), most of whom had no documented clinical diagnosis (47,XXY: 73.8%; 47,XYY: 98.6%; 47,XXX: 93.6%). The identified phenotypic associations with SCT spanned all PheWAS disease categories except neoplasms. Many associations are shared among three SCT subtypes, particularly for vascular diseases (e.g., chronic venous insufficiency (OR [95% CI] for 47,XXY 4.7 [3.9,5.8]; 47,XYY 5.6 [4.5,7.0]; 4 7,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]; 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]; 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 one or more X/Y homolog genes may underlie pathophysiology and comorbidities across SCTs.

Dr. Elswick Gentry reports grants (R01MH125938, R21MH126358, R01MH129356, P50AA022537), consulting fees (Rapid Forensic Cell Typing), and support for attending meetings (Lacy Family Funcs donated to VIPBG at VCU). Dr. Ganna reports role as a foundr of Real World Genetics Oy. Dr. Genovese reports grans through the Broad Institute (5R01HG006855, R01MH104964, R01MH123451). Dr. Hauger reports Million Veteran Program MVP022 Grant CX001727. Dr. Lapato reports the following grants: NIMH/NIH (K01 MH131847; PI: Lapato), NICHD/NIH (R21 HD113953; PI: Roberson-Nay), NIAAA/NIH (R21 AA029492; PI: Roberson-Nay), NIMH/NIH (R21 MH128562; PI: Roberson-Nay), NICHD/NIH (R01 NR020220; MPIs: Kinser and Bodnar-Deren), and Virginia Commonwealth University Affordable Course Content Award (PI: Lapato). Dr. Lynch, Dr. Teerlink, Dr. Lee, Dr. Chang, and Ms. Pridgen, report grants from Alnylam Pharmaceuticals, Inc., Astellas Pharma, Inc., AstraZeneca Pharmaceuticals LP, Biodesix, Inc, Celgene Corporation, Cerner Enviza, GSK PLC, IQVIA Inc., Janssen Pharmaceuticals, Inc., Novartis International AG, Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. Dr. Signh reports grants (NIH/NIMH R01MH125938, NIH/NIMH R01DA049867), an honorarium for teaching at the International Statistical Genetics Workshop from Institute for Behavioral Genetics at University of Colorado Boulder, and support for travel from Behavior Genetics Association and Society for Multivariate Experimental Psychology. Dr. Siplia reports grants from the FinnGen research consortia (https://www.finngen.fi/en/partners) and participation as a FinnGen data security analyst.

This research used data from the Million Veteran Program (MVP) [Office of Research and Development, Veterans Health Administration] and was supported by MVP022 award CX001727 (PI: Hauger).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The VA Central Institutional Review Board, the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa, and the UK Biobank Ethics and Governance Framework gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The data and code used to generate MVP results are accessible to researchers with MVP data access. Due to VA policy, MVP is currently only accessible to researchers with a funded MVP project (e.g., VA Merit Award, Career Development Award, NIH R01). See https://genhub.va.gov/file/view/897656 for additional information. For FinnGen, researchers can apply for health data from the Finnish Data Authority Findata (https://findata.fi/en/permits/) and individual-level genotype data available through the Fingenious portal (https://site.fingenious.fi/en/). These resources are hosted by the Finnish Biobank Cooperative FINBB (https://finbb.fi/en/). Access can only be provided for research projects within the scope of the Finnish Biobank Act, which includes health promotion, understanding disease mechanisms or developing medical products or treatment practices. Codes used to perform FinnGen PheWAS and across-biobank meta-analysis are available at https://github.com/dsgelab/Sex-Chromosome-Aneuploidy_PheWAS. The UK Biobank data utilized in this research is available to, bona fide researchers for health-related research in the public interest, through an application process accessible through the UK Biobank website, https://www.ukbiobank.ac.uk/. Codes used to perform UK Biobank PheWAS are available at https://github.com/POPGEM-Lab/UKB-SCT-PheWAS.