Copy number variation at the 22q11.2 locus influences prevalence, severity, and psychiatric impact of sleep disturbance

Abstract

Background: Sleep disturbance is common, impairing, and may affect symptomatology in developmental neuropsychiatric disorders. Here, we take a genetics-first approach to study the complex role of sleep in psychopathology. Specifically, we examine severity of sleep disturbance in individuals with a reciprocal copy number variant (CNV) at the 22q11.2 locus and determine sleep's effect on psychiatric symptoms. CNVs (deletion or duplication) at this locus confer some of the greatest known risks of neuropsychiatric disorders; recent studies suggest the 22q11.2 deletion negatively impacts sleep, but sleep disruption associated with 22q11.2 duplication has not been investigated.

Methods: We compared subjective sleep disturbance and its relationship to psychiatric symptoms cross-sectionally and longitudinally over 1 year in 107 22q11.2 deletion (22qDel) carriers (14.56±8.0 years; 50% male), 42 22q11.2 duplication (22qDup) carriers (16.26±13.1 years; 54.8% male), and 88 age- and sex-matched controls (14.65±7.4 years; 47.1% male). Linear mixed models were used to compare sleep disturbance, assessed via the Structured Interview for Psychosis-Risk Syndromes (SIPS), across groups. Next, CNV carriers were categorized as good or poor sleepers to investigate sleep effects on multiple neurobehavioral traits: psychosis-risk symptoms (SIPS), autism-related behaviors (Repetitive Behavior Scale (RBS) and Social Responsiveness Scale (SRS)), real-world executive function (Behavior Rating Inventory of Executive Function (BRIEF)), and emotional/behavioral problems (Child Behavior Checklist (CBCL)). Linear mixed models tested the effect of sleep category and a group-by-sleep interaction on each measure, cross-sectionally and longitudinally.

Results: 22qDel and 22qDup carriers both reported poorer sleep than controls, but did not differ from each other. Cross-sectionally and longitudinally, poor sleepers scored higher on positive symptoms, anxious/depressed, somatic complaints, thought problems, and aggressive behavior, as well as RBS and SRS total scores. There were significant group-by-sleep interactions for positive symptoms and the majority of CBCL subdomains, in which the difference between good and poor sleepers was larger in 22qDel compared to 22qDup.

Conclusions: Our findings indicate that CNVs at the 22q11.2 locus impact sleep which, in turn, influences psychopathology. Sleep disturbances can differentially impact psychopathology, depending on 22q11.2 gene dosage. Our findings serve as a starting point for exploring a genetic basis for sleep disturbance in developmental neuropsychiatric disorders.

Keywords: 22q11.2 locus; Autism spectrum disorder; Behavioral problems; Copy number variation; Developmental neuropsychiatric disorders; Executive function; Psychosis; Psychosis-risk symptoms; Schizophrenia; Sleep.

Fig. 1

Quantitative measure of sleep disturbance across groups. Sleep disturbance, assessed via the SIPS, is significantly worse in CNV carriers compared to controls cross-sectionally (q<0.001) and longitudinally (q<0.001). However, there is no significant difference in sleep quality between CNV groups (q>0.940). Large dots represent the group mean and 95% confidence interval at each timepoint

Fig. 2

Clinical measures in good and poor sleepers at each timepoint within 22q11.2 CNV groups. In both cross-sectional and longitudinal analyses across CNV groups, poor sleepers score higher (i.e., more pathological) on positive symptoms (cross-sectional: q=<0.001, longitudinal: q<0.001), total repetitive behaviors (cross-sectional: q= 0.005, longitudinal: q=0.018), and social responsiveness (cross-sectional: q= 0.026, longitudinal: q=0.015 ). The effect of sleep on BRIEF global composite score failed to survive FDR correction (cross-sectional: p= 0.0, longitudinal: p=0.0). Large dots represent the group mean and 95% confidence interval for good and poor sleepers at each timepoint

Fig. 3

Baseline CNV group-by-sleep interactions. There were significant group-by-sleep interactions at baseline for positive psychosis-risk symptoms (q=0.041), and CBCL-measured withdrawn/depressed (q=0.020), somatic complaints (q=0.007), social problems (q=0.017), thought problems (q=0.012), attention problems (q=0.009), rule-breaking (q=0.006), and aggressive behaviors subscales (q=0.004). Large dots represent the group mean and 95% confidence interval for good and poor sleepers in each subject group

Fig. 4

CBCL subdomain scores in good and poor sleepers at each timepoint within 22q11.2 CNV groups. At baseline, there was a significant main effect of sleep category on all CBCL subdomains (q<0.017). Across timepoints, there was a significant main effect of sleep category on anxious/depressed (q=0.005), somatic complaints (q=0.038), thought problems (q<0.001), and aggressive behavior (q=0.002) subscales. There was a trend towards a significant effect of sleep category on attention problems (q=0.061). Large dots represent the group mean and 95% confidence interval for good and poor sleepers at each timepoint