Disruption of the neurexin 1 gene is associated with schizophrenia

Abstract

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia.

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility

“…We identified shared risk alleles in both schizophrenia samples at SNPs rs9309200 and rs1915220 at NRXN1 (OMIM: 600565). Disruption of NRXN1 has been reported as a risk factor for both schizophrenia [21][22][23] and autism. 24,25 Axonal neurexins form transynaptic complexes with neuroligins on dendrites and are required for the formation of synaptic contacts and for efficient neurotransmission, including maintaining normal postsynaptic NMDA receptor function.…”

Adult Neurogenesis and Psychiatric Disorders

“…Furthermore, significant numbers of dentate gyrus granule cells were histologically and electrophysiologically immature, more than would be predicted based on proliferation rates and the tempo of normal development, and these mice showed severe impairments in working memory . Neurexins (NRXNs) and neuroligins (NLGNs) are families of synaptic proteins, which are known to be risk factors for schizophrenia (Novak et al 2009;Rujescu et al 2009;Ikeda et al 2010;Gauthier et al 2011;Mozhui et al 2011;Sun et al 2011;Yue et al 2011). These proteins are synaptic cell-adhesion molecules involved in various neuronal processes, including differentiation, maturation, stabilization, and plasticity of both inhibitory and excitatory synapses (Bang and Owczarek 2013).…”

The Emerging Link Between Autoimmune Disorders and Neuropsychiatric Disease

“…In some instances, neuropsychiatric disorders such as autism and schizophrenia are postulated to result from genetic mutations in these neuronal cell-adhesion systems. 27,28 Recent discoveries now indicate that acquired autoimmune syndromes also target trans -synaptic signals. Leucine-rich glioma-inactivated 1 (LGI1) is a secreted protein that interacts with presynaptic ADAM23 and postsynaptic ADAM22 to create a trans -synaptic protein complex, which also includes potassium channels and AMPA-type glutamate receptors.…”