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Analysis Estimates Psychiatric Disorder Risk from Specific Copy Number Variants in Danish Cohort

NEW YORK — Certain copy number variants are more prevalent among the general population and confer a lower risk for psychiatric disorders than previously thought, according to a new population-based analysis.

De novo CNVs have been tied to increased risk of a number of psychiatric disorders, including autism spectrum disorder, intellectual disability, and later-onset psychotic disorders. In a new analysis, researchers from Copenhagen University Hospital drew upon the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 2012 database that includes more than 57,000 Danish individuals with psychiatric disorders and population-based controls to examine the prevalence of copy number variants at six genomic loci and whether they affected risk of disease.

As they reported in JAMA Psychiatry on Wednesday, the researchers found that the CNVs are generally associated with a higher risk of ASD or attention-deficit/hyperactivity disorder, but a lower risk of schizophrenia than previously reported. Further, they uncovered that the pathogenicity of some CNVs were modulated by sex.

"This finding on genomic risk variants at the level of a population may be important for healthcare planning and clinical decision making, and thus the advancement of precision healthcare," senior author Thomas Werge from Copenhagen University Hospital and colleagues wrote in their paper.

The iPSYCH cohort includes all 57,377 individuals born in Denmark between May 1981 and December 2005 who have been diagnosed with ADHD, ASD, bipolar disorder, major depressive disorder, or schizophrenia, as well as 30,000 population controls from the same birth cohort. Following CNV analysis, the researchers identified 520 deletions and 660 duplications affecting the six genomic loci they focused on: 1q21.1, 15q11.2, 15q13.3, 16p11.2, 17p12, and 17q12.

Compared to what has been reported based on the UK Biobank and large meta-analyses of neurodevelopmental disorders, the Copenhagen-led team noted a higher prevalence for some CNVs. At the same time, they estimated the disease penetrance of the CNVs to be generally decreased.

Still, in line with previous work, deletions at 1q21.1 and 15q13.3 were associated with an increased risk across most diagnoses and had higher hazard ratios than duplications at those sites. Additionally, the 16p11.2 duplication increased the risk of ASD, ADHD, and epilepsy. Deletions at 17p12, meanwhile, were consistently associated with a decreased risk of a neuropsychiatric disorder, a finding the researchers said warranted further follow up.

Deletions at 1q21.1 were linked in particular to a nearly sixfold increased risk of major depressive disorder and a 17-fold increase in risk of bipolar disorder, though only among men. At the same time, 16p11.2 deletions increased ASD risk among women, while a duplication at this locus increased ASD risk among men. The researchers called this finding "particularly interesting given the considerable difference in the baseline hazard for ASD between sexes."

CNVs at these six loci were also more common in some somatic disorders. For instance, the researchers noted that 15q13.3 deletion carriers were more likely to have thyroiditis, while CNVs at other sites were linked to immune-related disorders like juvenile arthritis.

Further, the researchers noted a trend toward reduced fertility among female carriers of the 16p11.2 deletion and among male carriers of the 1q21.1 and15q11.2 duplications, though they cautioned that the iPSYCH cohort is still young.

The analyses suggested to the researchers that "precision healthcare needs to be tailored to the specific CNV, and to the age and gender of the affected individual."

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