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Original Investigation |

Analysis of Intellectual Disability Copy Number Variants for Association With Schizophrenia

Elliott Rees, PhD1; Kimberley Kendall, MBBCh1; Antonio F. Pardiñas, PhD1; Sophie E. Legge, PhD1; Andrew Pocklington, PhD1; Valentina Escott-Price, PhD1; James H. MacCabe, PhD, MRCPsych2; David A. Collier, PhD3,4; Peter Holmans, PhD1; Michael C. O’Donovan, PhD, FRCPsych1; Michael J. Owen, PhD, FRCPsych1,5; James T. R. Walters, MRCPsych, PhD1; George Kirov, PhD, MRCPsych1
[+] Author Affiliations
1Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales
2Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, England
3SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, England
4Discovery Neuroscience Research, Eli Lilly and Company Ltd, Lilly Research Laboratories, Surrey, England
5Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales
JAMA Psychiatry. 2016;73(9):963-969. doi:10.1001/jamapsychiatry.2016.1831.
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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.

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Analysis of Intellectual Disability Copy Number Variants (CNVs) Power Calculation

Power calculations for CNV loci under a dominant model are based on 20 403 cases and 26 628 controls, an α level of .05, and the relative risks for schizophrenia (SZ) and general population frequencies reported in eTable 2 in the Supplement. The solid line indicates 80% power given a sample size of 20 403 cases and 26 628 controls with an α level of .05. The dashed line indicates 80% power given a sample size of 100 000 cases and 100 000 controls with an α level of .05. We excluded loci that were not observed in a patient with SZ or a control. del indicates deletion; dup, duplication.

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