Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo M C, Reimherr F, Wender P, Yaw J, Young D A, Breese C R, Adams C, Patterson D, Adler L E, Kruglyak L, Leonard S, Byerley W
Department of Psychiatry, University of Colorado School of Medicine, Denver, USA.
Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):587-92. doi: 10.1073/pnas.94.2.587.
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.
在九个有多名精神分裂症患者的家族中，对一种调节听觉刺激反应的神经元机制缺陷的遗传情况进行了研究。这种缺陷表现为对成对刺激中的第二个刺激，P50听觉诱发反应的正常抑制作用减弱，它与精神分裂症中的注意力障碍有关。P50抑制作用减弱不仅发生在大多数精神分裂症患者中，也发生在他们的许多非精神分裂症亲属中，其分布情况与该疾病的遗传易感性一致。对人类和动物模型的神经生物学研究表明，α7烟碱型胆碱能受体功能降低可能是这种生理缺陷的基础。在本研究中，假设为常染色体显性遗传进行全基因组连锁分析，结果显示该缺陷与位于15q13 - 14染色体上的二核苷酸多态性（α7烟碱型受体所在位点）连锁[最大优势对数（lod）分数 = 5.3，重组率为零]。尽管许多精神分裂症患者大量吸烟，但之前人们并不认为烟碱型受体与精神分裂症有关。因此，这些连锁数据提供了独特的新证据，表明α7烟碱型受体基因可能是该疾病病理生理方面遗传的原因。
