Evidence map›Paper›PMID 40840450›Full record

ArticleAmerican journal of human genetics2025

Phenome-wide association study of male and female sex chromosome trisomies in 1.5 million participants of MVP, FinnGen, and UK Biobank.

Shanlee M Davis, Aoxing Liu, Craig C Teerlink, Dana M Lapato, Bryan Gorman, Giulio Genovese, Madhurbain Singh, Mary P Reeve, Amanda E Gentry, Kati M Donner and 14 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Review
  3. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

24 authors.

Shanlee M DavisDepartment of Pediatrics, School of Medicine, University of Colorado School of Medicine, Aurora, CO, USA; eXtraOrdinarY Kids Clinic, Children's Hospital Colorado, Aurora, CO, USA.
Aoxing LiuAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Craig C TeerlinkVA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, USA; Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Dana M LapatoDepartment of Human & Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Bryan GormanVA Boston Healthcare System, Boston, MA, USA.
Giulio GenoveseProgram in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Madhurbain SinghDepartment of Human & Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Mary P ReeveInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Amanda E GentryDepartment of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Kati M DonnerInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Timo P SipiläInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Awaisa GhazalInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Meghana S PagadalaResearch Service, VA San Diego Healthcare System, San Diego, CA, USA; Medical Scientist Training Program, University of California, San Diego, La Jolla, CA, USA; Biomedical Science Program, University of California, San Diego, La Jolla, CA, USA.
Matthew S PanizzonCenter for Behavior Genetics of Aging, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Eva E LancasterDepartment of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
FinnGen
Chris ChatzinakosDepartment of Psychiatry and Behavioral Sciences, Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
Andrea GannaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Tim B BigdeliDepartment of Psychiatry and Behavioral Sciences, Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY, USA; Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
Mark J DalyAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Julie A LynchVA Informatics and Computing Infrastructure (VINCI), VA Salt Lake City Health Care System, Salt Lake City, UT, USA; Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
Judith RossNemours Children's Hospital DE, Wilmington, DE, USA; Department of Pediatrics, School of Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Roseann E PetersonDepartment of Psychiatry and Behavioral Sciences, Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY, USA. Electronic address: sctphewas@gmail.com.
Richard L HaugerCenter of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA; Center for Behavior Genetics of Aging, School of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: rhauger@health.ucsd.edu.

Funding

Genetic architecture of transdiagnostic psychosis symptom dimensionsK01MH131847 · NIMH · VIRGINIA COMMONWEALTH UNIVERSITY · PI Dana Lapato · 2023 to 2026
$632k
NIMH NIH HHS K01 MH131847
6 · The paper itself

Abstract

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.

Indexed as

Sex Chromosome AberrationsTrisomyAdultAgedBiological Specimen BanksCohort StudiesFemaleGenome-Wide Association StudyHumansKlinefelter SyndromeMaleMeta-Analysis as TopicMiddle AgedPhenotypeSex ChromosomesUK BiobankKlinefelterPheWASsex chromosome trisomyvascular disease

Identifiers

PMID40840450
PMCPMC12461006

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.