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 auditory-evoked 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 alpha 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 alpha 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 alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.

Figure 1

Segregation of alleles of D15S1360 and P50 ratio in a portion of K1548. A indicates abnormal and N indicates normal, based on previously determined distributions of the P50 ratio for schizophrenics and normals (42). The ♦ represents a schizophrenic. The pedigree has been altered in several ways to protect subject confidentiality. Auditory-evoked responses to paired stimuli (arrows) demonstrate normal and abnormal P50 ratios in clinically unaffected siblings (subjects A and C) and an abnormal P50 ratio in a schizophrenic sibling (subject B). A computer algorithm (43) identified the P50 waves in the vertex electroencephalography (marks below the tracings) and measured their amplitudes relative to the preceding negative peaks (marks above the tracings). Simultaneous electrooculographic recordings illustrate that the P50 wave was not generated by eye movement artifact.

Figure 2

Distribution of P50 ratios in the nine pedigrees. Values ≤0.40 were coded unaffected and values ≥0.50 were coded affected, based on previous studies of unrelated normals and schizophrenics (42).

Figure 3

(A) Multipoint parametric lod score analysis for P50 ratio abnormality with markers at 15q. (B) Multipoint nonparametric linkage analysis for P50 ratio abnormality with markers at 15q. Results are presented for the most likely map locations for D15S1360 and L76630; the total length of the abscissa is 45 centimorgans.