Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination.

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

“…There is a similar 10-fold enrichment of deletions and duplications in ASD cohorts (11,12), and both CNVs have large effects on IQ (Z scores of 1.5 and 0.8, respectively) and Social Responsiveness Scale (SRS) (Z scores of 1 and 2, respectively) (10,(13)(14)(15). However, there are phenotypic differences between both CNVs: the 10-fold enrichment in schizophrenia cohorts (16,17) is only observed for duplications, and only deletions affect measures of language by 1.5 Z scores (18). Previous studies demonstrated "mirror" effects of both CNVs on head circumference and body mass index (13,19).…”

Recent Advances in the Genetics of Schizophrenia

“…As a result, many additional CNVs have now been reported to be associated with schizophrenia. These are described in detail below and summarized in Table 1, which includes those that reach significance in the largest case/control CNV analysis to date, on 41,321 cases and controls [31] and have been previously reported.…”

“…It contains the CHRNA7 gene encoding the A7 nicotinic acetylcholine receptor, previously linked to many psychiatric phenotypes including schizophrenia [51]. The 1q21.1 CNV was first reported by the International Schizophrenia Consortium to increase the risk when deleted [52] and later the reciprocal duplication was also found in excess [31, 53] in schizophrenia patients. Like the 16p11.2 CNV, reciprocal phenotypes have been described for the 1q21.1 CNV.…”

“…In addition, following the reports of this comorbidity, deletion screening of schizophrenia patients showed that some had the 22q deletion but were not diagnosed with VCFS because of their mild features [29, 30]. Most recently, in a large sample of 21,094 cases and 20,227 controls, this deletion was determined to increase the risk of carriers 68-fold and to be present in 0.3% of individuals diagnosed with schizophrenia [31]. The deleted region includes more than 50 genes including the highly cited catecholamine-degrading enzyme gene COMT .…”

Novel Translational Research Methodology and the Prospect to a Better Understanding of Neurodegenerative Disease

“…Stephan Ripke is an expert in statistical genetics at Harvard Medical School and Charité Universitaetsmedizin Berlin. His work and methodological input were vital for the recent progress in the characterization of genetic signatures of frequent psychiatric disorders including polygenetic effects and copy number variation [34-38], which might also be informative for a better understanding of the inherited liability for neurodegenerative disease. Neuroimaging has proven valid both for the early diagnosis of neurodegenerative disorders [1, 2], the noninvasive assessment of molecular and metabolic properties [39, 40], and also as a measure of therapeutic target engagement [9].…”