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Sex Chromosome Aneuploidies are Underdiagnosed and Associated with Increased Risk of Mental Disorders
14 Pages Posted: 18 Jul 2022
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: Suggested Citation