Analysis of Intellectual Disability Copy Number Variants for Association With Schizophrenia

Abstract

Importance At least 11 rare copy number variants (CNVs) have been shown to be major risk factors for schizophrenia (SZ). These CNVs also increase the risk for other neurodevelopmental disorders, such as intellectual disability. It is possible that additional intellectual disability–associated CNVs increase the risk for SZ but have not yet been implicated in SZ because of previous studies being underpowered. Objective To examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci. Design, Setting, and Participants We used single-nucleotide polymorphism (SNP) array data to evaluate a set of 51 CNVs implicated in intellectual disability (excluding the known SZ loci) in a large data set of patients with SZ and healthy persons serving as controls recruited in a variety of settings. We analyzed a new sample of 6934 individuals with SZ and 8751 controls and combined those data with previously published large data sets for a total of 20 403 cases of SZ and 26 628 controls. Main Outcomes and Measures Burden analysis of CNVs implicated in intellectual disability (excluding known SZ CNVs) for association with SZ. Association of individual intellectual disability CNV loci with SZ. Results Of data on the 20 403 cases (6151 [30.15%] female) and 26 628 controls (14 252 [53.52%] female), 51 intellectual disability CNVs were analyzed. Collectively, intellectual disability CNVs were significantly enriched for SZ (P = 1.0 × 10−6; odds ratio [OR], 1.9 [95% CI, 1.46-2.49]). Of the 51 CNVs tested, 19 (37%) were more common in SZ cases; only 4 (8%) were more common in controls (no observations were made for the remaining 28 [55%] loci). One novel locus, deletion at 16p12.1, was significantly associated with SZ after correction for multiple testing (rate in SZ, 33 [0.16%]; rate in controls, 12 [0.05%]; corrected P = .017; OR, 3.3; 95% CI, 1.61-7.05), and 2 loci reached nominal levels of significance (deletions at 2q11.2: 6 [0.03%] vs 1 [0.004%]; OR, 9.3; 95% CI, 1.03-447.76; corrected P > .99; and duplications at 10q11.21q11.23: 5 [0.2%] vs 0 [0.03%]; OR, infinity; 95% CI, 1.26-infinity; corrected P = .71). Our new data set also provided independent support for the 11 SZ risk loci previously reported to be associated with the disorder and for the protective effect of 22q11.2 duplication. Conclusions and Relevance A large proportion of CNV loci implicated in intellectual disability are risk factors for SZ, but the available sample size precludes statistical confirmation for additional individual loci.

Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry

“…There is now replicated evidence that duplications at 22q11.2 are substantially less common in schizophrenia cases than in the general population, but reciprocal deletions are an established strong risk factor for schizophrenia (Rees et al, 2014(Rees et al, , 2016. Our findings suggest a possible underlying neurobiological basis for these divergent behavioral phenotypes.…”

“…In an analysis of Ͼ47,000 individuals, the 22q-dup was significantly less common in schizophrenia cases than in the general population (0.014% compared with 0.085%, OR ϭ 0.17), suggesting the first putative protective mutation for schizophrenia (Rees et al, 2014). This finding of lower schizophrenia incidence in 22q-dup carriers compared with noncarriers has now been replicated in independent studies (Li et al, 2016;Rees et al, 2016; CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium, Psychosis Endophenotypes International Consortium, 2017).…”

“…Quality assessment of MRI. Structural T1-weighted MRI brain scans were analyzed in an unbiased, whole-brain approach using well-validated analysis and quality control protocols developed for the ENIGMA consortium (Enhancing Neuroimaging Genetics through Meta-Analysis) (Thompson et al, 2014), which have previously been applied in large-scale studies of major depression (Schmaal et al, 2016), bipolar disorder , and schizophrenia (van Erp et al, 2016). We used the ENIGMA quality assessment pipeline (Thompson et al, 2017) to determine scan quality.…”

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

“…So far, numerous SNPs have been reported to be associated with complex diseases, largely supported by linkage disequilibrium in large case-control paired cohorts of up to hundreds of thousands of individuals (Manolio 2009). However, several SNPs and their overlapping CNVs were reported to be both associated with the same disease or trait, such as schizophrenia (rs1009153 and rs4778334 in 15q11.2 deletion (Zhao et al 2013), rs165774 in 22q11.2 deletion and 22q11.2 duplication (Higashiyama et al 2016; Rees et al 2016)), obesity/body mass index (rs12446632 in 16p12.3 deletion (Locke et al 2015; Yang et al 2013a)), and breast cancer (rs17370615 and rs6001376 in deletions of APOBEC3 gene (Long et al 2013; Marouf et al 2016)) (Table S6). This might cause the overestimation or misannotation of association signals of the SNPs in the same regions.…”

DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

“…Genome-wide association studies (GWAS) have identified over a hundred common single nucleotide polymorphisms (SNPs) robustly associated with these disorders, most for SCZ, but all with small effect sizes [5][6][7]. Individually rare copy number variants from case-control studies and exome sequencing-derived missense variants with large effects have also been reported [8][9][10][11][12]. However, even within families, individuals with these variants show variability in clinical phenotype [13][14][15][16].…”