lancet-header

Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.

Sex Chromosome Aneuploidies are Underdiagnosed and Associated with Increased Risk of Mental Disorders

14 Pages Posted: 18 Jul 2022

See all articles by Xabier Calle Sanchez

Xabier Calle Sanchez

University of Copenhagen - Institute for Biological Psychiatry

Simone Montalbano

University of Copenhagen - Institute for Biological Psychiatry

Morteza Vaez

University of Copenhagen - Institute for Biological Psychiatry

Morten Dybdahl Krebs

University of Copenhagen - Institute for Biological Psychiatry

Jonas Bygbjerg-Grauholm

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)

Preben B. Mortensen

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)

Anders D. Børglum

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)

David M. Hougaard

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)

Merete Nordentoft

Mental Health Centre Copenhagen - Danish Research Institute for Suicide Prevention; Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH)

Daniel H. Geschwind

University of California, Los Angeles (UCLA) - Semel Institute for Neuroscience and Human Behavior

Alfonso Buil

University of Copenhagen - Institute for Biological Psychiatry

Andrew J. Schork

University of Copenhagen - Institute for Biological Psychiatry

Wesley K. Thompson

University of California, San Diego (UCSD)

Armin Raznahan

National Institute of Mental Health

Dorte Helenius

University of Copenhagen - Institute for Biological Psychiatry

Thomas Werge

University of Copenhagen - Institute for Biological Psychiatry

Andrés Ingason

University of Copenhagen - Institute for Biological Psychiatry

More...

Abstract

Background: Elevated rates of mental illness have been reported in clinical studies of sex chromosome aneuploidies (SCAs) but accurate population-based estimates of SCA prevalence, clinical ascertainment rate, and associated risk of psychiatric disorders are lacking.

Methods: In this study we provide population-valid prevalence estimates of the most common SCA karyotypes (45X, 47XXX, 47XXY and 47XYY) and gonadal sex-matched hazard ratios (HR) for attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia spectrum disorder (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD). Our study leverages the iPSYCH2015 casecohort dataset including all 93,608 persons born in Denmark between 1981-2008 and diagnosed with any of the above listed disorders by the end of 2015 and a random cohort of 50,615 individuals from the same study population.

Findings: Overall SCA prevalence was 0.0015, slightly lower than reported in a previous population-based study (0.0021, trend across all four SCA; P=0.046). All four SCAs were associated with increased risk of any psychiatric disorder to a similar level (HR = 2.2-4.3) as estimated for several pathogenic copy number variants (CNVs) in a similar population-based setting. Increased risks of ADHD (HR = 2.0-6.2), ASD (HR = 2.7-8.5) and SCZ (HR = 1.8-4.6) were also associated with all four SCAs, while increased risks of MDD and BPD were associated with 47XXY and 47XYY (HR = 1.9 & 2.7), and 47XXX (HR = 4.3), respectively. Clinical SCA ascertainment rate was high (84%) for 45X but much lower (14-18%) for 47XXX, 47XXY and 47XYY, and did not differ with respect to diagnosis of a psychiatric disorder.

Interpretation: Increased SCA-associated risk of psychiatric disorders, combined with low clinical SCA ascertainment rates, compromises adequate provision of necessary healthcare and counselling to affected individuals and their families.

Funding Information: This work was supported by grants from the Lundbeck Foundation (R165–2013–15320, R155–2014–1724, and R248–2017–2003) and the NIH (R01 MH124789-01).

Declaration of Interests: The authors declare no potential conflict of interests.

Ethics Approval Statement: The iPSYCH Initiative was approved by the Danish Scientific-Ethical Committee.

Keywords: SCA, Sex chromosome aneuploidies, Klinefelter syndrome, Turner syndrome, Jacob's syndrome, Triple X syndrome, Psychiatric, Schizophrenia, Autism, ADHD, depression, Bipolar disorder

Suggested Citation

Calle Sanchez, Xabier and Montalbano, Simone and Vaez, Morteza and Krebs, Morten Dybdahl and Bygbjerg-Grauholm, Jonas and Mortensen, Preben B. and Børglum, Anders D. and Hougaard, David M. and Nordentoft, Merete and Geschwind, Daniel H. and Buil, Alfonso and Schork, Andrew J. and Thompson, Wesley K. and Raznahan, Armin and Helenius, Dorte and Werge, Thomas and Ingason, Andrés, Sex Chromosome Aneuploidies are Underdiagnosed and Associated with Increased Risk of Mental Disorders. Available at SSRN: https://ssrn.com/abstract=4165610 or http://dx.doi.org/10.2139/ssrn.4165610

Xabier Calle Sanchez

University of Copenhagen - Institute for Biological Psychiatry ( email )

Simone Montalbano

University of Copenhagen - Institute for Biological Psychiatry ( email )

Morteza Vaez

University of Copenhagen - Institute for Biological Psychiatry ( email )

Morten Dybdahl Krebs

University of Copenhagen - Institute for Biological Psychiatry ( email )

Jonas Bygbjerg-Grauholm

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) ( email )

Preben B. Mortensen

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) ( email )

Anders D. Børglum

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) ( email )

David M. Hougaard

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) ( email )

Merete Nordentoft

Mental Health Centre Copenhagen - Danish Research Institute for Suicide Prevention ( email )

Copenhagen
Denmark

Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) ( email )

Daniel H. Geschwind

University of California, Los Angeles (UCLA) - Semel Institute for Neuroscience and Human Behavior ( email )

760 Westwood Plaza
Los Angeles, CA 90095
United States

Alfonso Buil

University of Copenhagen - Institute for Biological Psychiatry ( email )

Andrew J. Schork

University of Copenhagen - Institute for Biological Psychiatry ( email )

Wesley K. Thompson

University of California, San Diego (UCSD) ( email )

9500 Gilman Drive
La Jolla, CA 92093
United States

Armin Raznahan

National Institute of Mental Health

6001 Executive Boulevard, Rm. 7117, MSC 9629
Bethesda, MA 20892
United States

Dorte Helenius

University of Copenhagen - Institute for Biological Psychiatry ( email )

Thomas Werge

University of Copenhagen - Institute for Biological Psychiatry ( email )

Andrés Ingason (Contact Author)

University of Copenhagen - Institute for Biological Psychiatry ( email )

Click here to go to TheLancet.com

Paper statistics

Downloads
108
Abstract Views
494
PlumX Metrics