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Novel CNV contribution to schizophrenia from a genome wide study of 41,321 subjects

Genomic copy number variants (CNVs) have been strongly implicated in the etiology schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the very low frequencies of risk alleles, all occurring in less than 1% of patients. We sought to address this obstacle through a collaborative effort unprecedented in psychiatry in which we applied a centralized analysis pipeline to a large SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden is observed in SCZ patients (OR=1.11, P=5.7e-15), and persists after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV Burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-05). While only previously implicated loci surpass strict genome-wide testing correction, we identify “novel” CNVs (BH-FDR < 0.05) that confer both protective and risk effects on SCZ and are predominantly mediated by non-allelic homologous recombination (NAHR). Our combined data find genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00010001074 Mulitple CNV platforms 1
Publications Citations
PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data.
Genome Res 17: 2007 1665-1674
Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia.
Science 320: 2008 539-543
Strong association of de novo copy number mutations with sporadic schizophrenia.
Nat Genet 40: 2008 880-885
Rare chromosomal deletions and duplications increase risk of schizophrenia.
Nature 455: 2008 237-241
Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs.
Nat Genet 40: 2008 1253-1260
Disruption of the neurexin 1 gene is associated with schizophrenia.
Hum Mol Genet 18: 2009 988-996
Microduplications of 16p11.2 are associated with schizophrenia.
Nat Genet 41: 2009 1223-1227
Functional impact of global rare copy number variation in autism spectrum disorders.
Nature 466: 2010 368-372
Microdeletions of 3q29 confer high risk for schizophrenia.
Am J Hum Genet 87: 2010 229-236
Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function.
PLoS Genet 6: 2010 e1001097
Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.
Nature 471: 2011 499-503
Testing for an unusual distribution of rare variants.
PLoS Genet 7: 2011 e1001322
Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism.
Proc Natl Acad Sci U S A 108: 2011 17076-17081
Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions.
J Med Genet 48: 2011 840-850
De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.
Mol Psychiatry 17: 2012 142-153
High frequencies of de novo CNVs in bipolar disorder and schizophrenia.
Neuron 72: 2011 951-963
CNVs: harbingers of a rare variant revolution in psychiatric genetics.
Cell 148: 2012 1223-1241
KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.
Nature 485: 2012 363-367
Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood.
Genet Couns 23: 2012 135-148
Individual differences in amygdala-medial prefrontal anatomy link negative affect, impaired social functioning, and polygenic depression risk.
J Neurosci 32: 2012 18087-18100
Evidence that duplications of 22q11.2 protect against schizophrenia.
Mol Psychiatry 19: 2014 37-40
Distal Xq28 microdeletions: clarification of the spectrum of contiguous gene deletions involving ABCD1, BCAP31, and SLC6A8 with a new case and review of the literature.
Am J Med Genet A 164A: 2014 2613-2617
Biological insights from 108 schizophrenia-associated genetic loci.
Nature 511: 2014 421-427
Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review.
BMC Med Genet 16: 2015 12
Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia.
Neuron 86: 2015 1203-1214
Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.
Nat Genet 49: 2017 27-35