Hong L Elliot, Wonodi Ikwunga, Stine O Colin, Mitchell Braxton D, Thaker Gunvant K
Department of Psychiatry, Maryland Psychiatric Research Center, Baltimore, Maryland 21228, USA.
Biol Psychiatry. 2008 Jan 1;63(1):17-23. doi: 10.1016/j.biopsych.2007.05.011. Epub 2007 Jul 12.
Neuregulin 1 (NRG1) is one of the leading candidate genes in schizophrenia. Rodents with NRG1 knock-out showed significantly impaired prepulse inhibition (PPI) in the original report linking NRG1 to schizophrenia. A widely used surrogate measure of psychosis in animal models, PPI is considered a schizophrenia endophenotype. We hypothesized that if NRG1 influences PPI in rodents, then it should have a similar effect on PPI in humans.
We examined the potential neurophysiological effects of two nonsynonymous single nucleotide polymorphisms located on NRG1 (rs3924999 and rs10503929) on PPI. Genotyping was completed in 430 unrelated individuals, including 244 schizophrenia cases and 186 controls. PPI was available in a subgroup of 113 cases and 63 controls.
Rs3924999 genotype was significantly associated with PPI (p = .003): PPI was lowest in the subjects who were homozygous for the minor allele A/A carriers, intermediate in A/G carriers, and highest in homozygous major alleles G/G carriers. The associations persisted within cases (p = .02) and controls (p = .02) analyzed separately. An additive model suggested that rs3924999 alone contributes to 7.9% of the PPI variance. In contrast, rs10503929 genotype was not associated with PPI (p = .85). Schizophrenia patients had reduced PPI compared to control subjects (p = .04). Neither single nucleotide polymorphism was associated with schizophrenia (all p > .37). However, schizophrenia patients with abnormal PPI may be associated with rs3924999 (p = .05).
A missense mutation on rs3924999 of the neuregulin 1 gene may have a functional effect on prepulse inhibition in both schizophrenia and healthy control populations.
神经调节蛋白1（NRG1）是精神分裂症的主要候选基因之一。在最初将NRG1与精神分裂症联系起来的报告中，NRG1基因敲除的啮齿动物表现出明显受损的前脉冲抑制（PPI）。PPI是动物模型中广泛使用的一种精神病替代指标，被认为是精神分裂症的一种内表型。我们假设，如果NRG1影响啮齿动物的PPI，那么它对人类的PPI应该有类似的影响。
我们研究了位于NRG1上的两个非同义单核苷酸多态性（rs3924999和rs10503929）对PPI的潜在神经生理学影响。对430名无关个体进行了基因分型，其中包括244例精神分裂症患者和186名对照。在113例患者和63名对照的亚组中获得了PPI数据。
Rs3924999基因型与PPI显著相关（p = 0.003）：对于次要等位基因A/A携带者纯合子的受试者，PPI最低；A/G携带者处于中间水平；纯合主要等位基因G/G携带者最高。在分别分析的病例（p = 0.02）和对照（p = 0.02）中，这种关联持续存在。加性模型表明，仅rs3924999就导致了7.9%的PPI变异。相比之下，rs10503929基因型与PPI无关（p = 0.85）。与对照受试者相比，精神分裂症患者的PPI降低（p = 0.04）。两个单核苷酸多态性均与精神分裂症无关（所有p > 0.37）。然而，PPI异常的精神分裂症患者可能与rs3924999有关（p = 0.05）。
神经调节蛋白1基因rs3924999上的错义突变可能对精神分裂症患者和健康对照人群的前脉冲抑制有功能影响。
