Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1

Abstract

Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1.

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Associations ofmicroRNAsingle nucleotide polymorphisms and disease risk and pathophysiology

“…Single nucleotide polymorphisms (SNPs) located in the gene‐encoding miRNAs may affect the expression and biogenesis or biological activity of miRNAs. Thus, these SNPs can contribute to patient susceptibility to various diseases , such as cancers , autoimmune diseases , cardiovascular diseases , schizophrenia (Sz) , and central nervous system (CNS) disorders . Many reports have showed that specific miRNA SNPs are pathogenic, such as the SNPs of miRNA‐137 , miRNA‐499 , miRNA‐146a , miRNA‐196a2 and others.…”

Translational Genetic Modelling of 3D Craniofacial Dysmorphology: Elaborating the Facial Phenotype of Neurodevelopmental Disorders Through the “Prism” of Schizophrenia

“…The NRG1 gene has been associated replicably with risk for psychotic illness and with structural and functional neuroimaging abnormalities in psychosis [ 40 , 43 , 44 ]. Thus, members of the NRG1 gene family have been modified in mutant mice to result in a variety of psychosis-related phenotypes [ 43 , 45 , 46 ].…”