Analysis of Intellectual Disability Copy Number Variants for Association With Schizophrenia.
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.



To examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci.



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.



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.



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.



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.
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Elliott
E
Rees
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Kimberley
K
Kendall
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Antonio F
AF
Pardiñas
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Sophie E
SE
Legge
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Andrew
A
Pocklington
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Valentina
V
Escott-Price
Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, England.
James H
JH
MacCabe
SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England; Discovery Neuroscience Research, Eli Lilly and Company Ltd, Lilly Research Laboratories, Surrey, England.
David A
DA
Collier
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Peter
P
Holmans
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
Michael C
MC
O'Donovan
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales; Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales.
Michael J
MJ
Owen
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
James T R
JTR
Walters
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales.
George
G
Kirov
D000328:Adult; D016022:Case-Control Studies; D003024:Clozapine / Q000627:therapeutic use; D015331:Cohort Studies; D015897:Comorbidity; D056915:DNA Copy Number Variations / Q000235:genetics*; D004351:Drug Resistance; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012016:Reference Values; D012306:Risk; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D006113:United Kingdom
D003024:Clozapine