Evidence of missense mutations on the neuregulin 1 gene affecting function of prepulse inhibition
Evidence of missense mutations on the neuregulin 1 gene affecting function of prepulse inhibition
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DOI：
10.1016/j.biopsych.2007.05.011
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发表时间：
2008-01-01
影响因子：
10.6
通讯作者：
Thaker, Gunvant K.
中科院分区：
文献类型：
--
作者：
Hong, L. Elliot;Wonodi, Ikwunga;Thaker, Gunvant K.
背景：神经调节蛋白I（NRG 1）是精神分裂症的主要候选基因之一。在将NRG 1与精神分裂症联系起来的原始报告中，NRG 1基因敲除的啮齿动物显示出显著受损的前脉冲抑制（PPI）。PPI被认为是精神分裂症的一种表型，是动物模型中广泛使用的精神病的替代指标。我们假设，如果NRG 1影响啮齿动物的PPI，那么它应该对人类的PPI有类似的作用。方法：我们研究了位于NRG 1上的两个非同义单核苷酸多态性（rs3924999和rs 10503929）对PPI的潜在神经生理作用。在430名无关个体中完成了基因分型，包括244名精神分裂症患者和186名对照。PPI可在一个亚组的113例和63 controls.Results：Rs3924999基因型与PPI显着相关（p = 0.003）：PPI是最低的受试者谁是纯合子的次要等位基因A/A载体，中间的A/G载体，和最高的纯合子主要等位基因G/G载体。分别分析的病例组（p =.02）和对照组（p =.02）之间的相关性持续存在。加性模型表明，rs3924999单独贡献了PPI方差的7.9%。相比之下，rs 10503929基因型与PPI无关（p = 0.85）。与对照组相比，精神分裂症患者的PPI降低（p = 0.04）。单核苷酸多态性与精神分裂症无相关性（均p > 37）。然而，精神分裂症患者PPI异常可能与rs3924999（p =.05）。结论：神经调节蛋白1基因rs3924999的错义突变可能对精神分裂症和健康对照人群的前脉冲抑制有功能影响。
Background: Neuregulin I (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 enclophenotype.We hypothesized that if NRG1 influences PPI in rodents,then it should have a similar effect on PPI in humans.Methods: 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.Results: 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 nucleoticle polymorphism was associated with schizophrenia (all p > 37). However, schizophrenia patients with abnormal PPI may be associated with rs3924999 (p =.05).Conclusions: 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.