Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants

Abstract

Importance: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.

Objective: To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.

Design, setting, and participants: This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.

Exposures: Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.

Main outcomes and measures: Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.

Results: A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.

Conclusions and relevance: This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

Figure 1.. Population-Based Recurrent Copy Number Variant (rCNV) Prevalence in iPSYCH2015 and Comparison With UK Biobank (UKB)

A, Population-based prevalence in iPSYCH2015 of deletions and duplications at 18 rCNV loci. Dotted line indicates deletion-duplication prevalence parity. The 8 loci with significant deletion-duplication prevalence disparity (false discovery rate [FDR] P < .05) are indicated on the plot. Population-based rCNV prevalence of deletions (B) and duplications (C) in iPSYCH2015 (full color, top) are compared with that reported for the UKB (semitransparent color, bottom), with loci ordered from top to bottom by decreasing sum loss-of-function observed/expected upper-bound fraction score (eTable 1 in Supplement 1). In the UKB study, 22q11.2b (turquoise) was not included as an independent locus and the prevalence of PWAS deletion was less than 1 in 100 000. Error bars indicate the SE of the weighted population-based prevalence in iPSYCH2015 and observed prevalence in UKB, respectively. For detailed results, see eTable 7 in Supplement 1. ^aFDR P < .001. ^bFDR P < .05. ^cFDR P < .01.

Figure 2.. Recurrent Copy Number Variant (rCNV)–Associated Risk of Psychiatric Disorders in the iPSYCH2105 Case Cohort

rCNV-associated hazard ratios (HRs) and 95% CIs were derived from Cox proportional hazards (CPH) models using inverse probability of sampling weights and are indicated for deletions and duplications by red and blue, respectively. Loci are ordered on the y-axis by decreasing sum loss-of-function observed/expected upper-bound fraction score. Locus names include information on associated common breakpoints and/or prominent encompassed genes and indication of curated loss (L) and/or gain (G) disease (eTable 1 in Supplement 1). Comparisons involving less than 2 case carriers, or where the CPH model failed a test of proportionality of hazards, were excluded. NA indicates not assessed.

Figure 3.. Contrasts in Associated Risk Between Main Psychiatric Outcomes Across Recurrent Copy Number Variants (rCNVs)

Hazard ratios (HRs) with error bars indicating SE for rCNV deletions (circles) and duplications (triangles) are plotted in a pairwise comparison for attention-deficit/hyperactivity disorder (ADHD) vs autism spectrum disorder (ASD), schizophrenia spectrum disorder (SSD) vs ASD, and SSD vs ADHD. The dashed line indicates risk parity. On each pairwise comparison plot, we have highlighted those rCNVs showing significant evidence of an rCNV-by-diagnosis interaction in generalized estimating equations predicting case status for 2 diagnoses at a time (false discovery rate [FDR] P < .05), with colors corresponding to the rCNV locus in Figure 1.

Figure 4.. Contrasts in Associated Risk by Dosage Change Across Recurrent Copy Number Variant (rCNV) Loci

Hazard ratios (HRs) with error bars indicating SE for deletions and duplications are plotted on the x-axis and y-axis, respectively, for attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia spectrum disorder (SSD). The 16 loci with available HR estimates for both deletions and duplications for at least 1 diagnosis are indicated by different colors corresponding to previous figures. The dashed line indicates risk parity. We found no evidence of a locus-by-dosage interaction increasing prediction of case status in an overall test across all loci and diagnoses between a generalized estimating equation model with the interaction term and a nested model without the interaction term (likelihood ratio test, P = .16).

Figure 5.. Recurrent Copy Number Variant (rCNV)–Associated Risk as a Function of Locus Properties and rCNV Prevalence

Hazard ratios (HR) with error bars indicating SE for deletions and duplications associated with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia spectrum disorder (SSD) are plotted against (A) locus size and (B) sum loss-of-function observed/expected upper-bound fraction (LOEUF) score (eTable 1 in Supplement 1 and eTable 12 in Supplement 2). PWAS duplication was excluded because of outlying locus and effect size. The plots include fitted trend lines. The overall trend for both locus features across all 3 psychiatric outcomes was assessed in a single generalized estimating equation model including all rCNV carriers, and significant positive associations were found for both locus size (P = .003) and sum LOEUF score (P = .003).