Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus

Abstract

Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditoryevoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the ␣7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score ‫؍‬ 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the ␣7-nicotinic receptor. Despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the ␣7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

“…14 Although CYP1A2 by itself has never been implicated in pathogenesis of schizophrenia, the neighboring loci (15q13-15) have all been implicated. [20][21][22][23] CYP1A2 (15q21) is located in the vicinity of nicotinic receptors CHRNA3, CHRNA5 and CHRNB4, localized at 15q24. CYP1A2 mRNA has been detected in the rat brain (cortex, cerebellum, brain stem, thalamus, hippocampus and striatum 24 ).…”

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

“…For example, the QT elongation on electrocardiogram was used to discover the genes underlying the long QT syndrome, characterized by syncope, ventricle arrhythmias, and sudden death (Keating and Sanguinetti, 2001). In the field of psychiatry, disturbances of P50 auditory evoked response and smooth pursuit eye movements are among the best established endophenotypes present in schizophrenic patients and their unaffected relatives, and linkage studies have already identified the loci involved in chromosome 15q (Freedman et al, 1997) and 6p (Arolt et al, 1996), respectively. In OCD, stratification by 5-HT level could decrease genetic heterogeneity and increase power to identify susceptibility genes in association and linkage studies.…”

α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

“…Moreover, an association has been demonstrated between the homozygous 113 bp allele on the D15S1360 polymorphism of the CNRNA7 gene and smoking risk in schizophrenia [63]. Taken together, these results suggest that the CHRNA7 gene is likely susceptible to the deficits of P50 sensory gating in schizophrenia [10, 23, 44, 49, 50, 53, 58, 63-67]. Interestingly, a 2 bp deletion in exon 6 of CHRFAM7A, which disrupts the hybrid gene for the CHRNA7 gene, was associated with episodic memory performance in schizophrenia, suggesting that the CHRFAM7A/CHRNA7 locus plays a role in modulating episodic memory function [68].…”