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Original Investigation
November 24, 2021

Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders

Author Affiliations
  • 1Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark
  • 2The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen and Aarhus, Denmark
  • 3Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark
  • 4National Centre for Register-based Research, Aarhus University, Aarhus, Denmark
  • 5Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark
  • 6Big Data Centre for Environment and Health, Aarhus University, Aarhus, Denmark
  • 7Department of Biomedicine and iSEQ-Centre for Integrative Sequencing, Aarhus University, Denmark
  • 8Center for Genomics and Personalized Medicine, Aarhus University, Denmark
  • 9Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
  • 10Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  • 11Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
  • 12Department of Neurology, University of California, Los Angeles
  • 13Department of Human Genetics, University of California, Los Angeles
  • 14Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at UCLA, University of California, Los Angeles
  • 15Center for Human Development, University of California, San Diego
  • 16Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine at UCLA, University of California Los Angeles
  • 17Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland
  • 18Herbert Wertheim School of Public Health and Human Longevity, University of California, San Diego, La Jolla, California
  • 19Lundbeck Foundation Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark
JAMA Psychiatry. 2022;79(1):59-69. doi:10.1001/jamapsychiatry.2021.3392
Key Points

Question  What are the population-based prevalence and risk of psychiatric disorders associated with pathogenic copy number variations (CNVs) and how do they compare?

Findings  In a cohort study including 86 189 individuals, increased CNV-associated risk of autism, attention-deficit/hyperactivity disorder, schizophrenia, and major depressive disorder, as well as bipolar disorder in men for deletion at 1q21.1, was observed. Population-based penetrance estimates were generally lower than those from prior studies; time-dependent analyses identified variegated disease trajectories across genomic loci, whereas deletions and duplications within each locus had similar trajectory patterns.

Meaning  The findings of this study suggest that population-based analysis substantially revises prevalence and penetrance estimates for pathogenic CNVs; precision health care needs to be tailored to the specific CNV, and to the age and gender of the affected individual.


Importance  Although the association between several recurrent genomic copy number variants (CNVs) and mental disorders has been studied for more than a decade, unbiased, population-based estimates of the prevalence, disease risks and trajectories, fertility, and mortality to contrast chromosomal abnormalities and advance precision health care are lacking.

Objective  To generate unbiased, population-based estimates of prevalence, disease risks and trajectories, fertility, and mortality of CNVs implicated in neuropsychiatric disorders.

Design, Setting, and Participants  In a population-based case-cohort study, using the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 2012 database, individuals born between May 1, 1981, and December 31, 2005, and followed up until December 31, 2012, were analyzed. All individuals (n = 57 377) with attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia (SCZ), autism spectrum disorder (ASD), or bipolar disorder (BPD) were included, as well as 30 000 individuals randomly drawn from the database. Data analysis was conducted from July 1, 2017, to September 7, 2021.

Exposures  Copy number variants at 6 genomic loci (1q21.1, 15q11.2, 15q13.3, 16p11.2, 17p12, and 17q12).

Main Outcomes and Measures  Population-unbiased hazard ratio (HR) and survival estimates of CNV associations with the 5 ascertained psychiatric disorders, epilepsy, intellectual disability, selected somatic disorders, fertility, and mortality.

Results  Participants’ age ranged from 1 to 32 years (mean, 12.0 [IQR, 6.9] years) during follow-up, and 38 662 were male (52.3%). Copy number variants broadly associated with an increased risk of autism spectrum disorder and ADHD, whereas risk estimates of SCZ for most CNVs were lower than previously reported. Comparison with previous studies suggests that the lower risk estimates are associated with a higher CNV prevalence in the general population than in control samples of most case-control studies. Significant risk of major depressive disorder (HR, 5.8; 95% CI, 1.5-22.2) and sex-specific risk of bipolar disorder (HR, 17; 95% CI, 1.5-189.3, in men only) were noted for the 1q21.1 deletion. Although CNVs at 1q21.1 and 15q13.3 were associated with increased risk across most diagnoses, the 17p12 deletion consistently conferred less risk of psychiatric disorders (HR 0.4-0.8), although none of the estimates differed significantly from the general population. Trajectory analyses noted that, although diagnostic risk profiles differed across loci, they were similar for deletions and duplications within each locus. Sex-stratified analyses suggest that pathogenicity of many CNVs may be modulated by sex.

Conclusions and Relevance  The findings of this study suggest that the iPSYCH population case cohort reveals broad disease risk for some of the studied CNVs and narrower risk for others, in addition to sex differential liability. This finding on genomic risk variants at the level of a population may be important for health care planning and clinical decision making, and thus the advancement of precision health care.

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