Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas, USA.
Am J Med Genet B Neuropsychiatr Genet. 2011 Jan;156B(1):44-58. doi: 10.1002/ajmg.b.31136. Epub 2010 Nov 2.
Event-related brain oscillations (EROs) represent highly heritable neuroelectrical correlates of human perception and cognitive performance that exhibit marked deficits in patients with various psychiatric disorders. We report the results of the first genome-wide association study (GWAS) of an ERO endophenotype-frontal theta ERO evoked by visual oddball targets during P300 response in 1,064 unrelated individuals drawn from a study of alcohol dependence. Forty-two SNPs of the Illumina HumanHap 1 M microarray were selected from the theta ERO GWAS for replication in family-based samples (N = 1,095), with four markers revealing nominally significant association. The most significant marker from the two-stage study is rs4907240 located within ARID protein 5A gene (ARID5A) on chromosome 2q11 (unadjusted, Fisher's combined P = 3.68 × 10⁻⁶). However, the most intriguing association to emerge is with rs7916403 in serotonin receptor gene HTR7 on chromosome 10q23 (combined P = 1.53 × 10⁻⁴), implicating the serotonergic system in the neurophysiological underpinnings of theta EROs. Moreover, promising SNPs were tested for association with diagnoses of alcohol dependence (DSM-IV), revealing a significant relationship with the HTR7 polymorphism among GWAS case-controls (P = 0.008). Significant recessive genetic effects were also detected for alcohol dependence in both case-control and family-based samples (P = 0.031 and 0.042, respectively), with the HTR7 risk allele corresponding to theta ERO reductions among homozygotes. These results suggest a role of the serotonergic system in the biological basis of alcohol dependence and underscore the utility of analyzing brain oscillations as a powerful approach to understanding complex genetic psychiatric disorders.
事件相关脑电波（EROs）是人类感知和认知表现的高度遗传神经电相关物，在各种精神障碍患者中表现出明显的缺陷。我们报告了第一个与视觉Oddball 靶标诱发的 P300 反应中的额theta ERO 相关的 ERO 内表型的全基因组关联研究（GWAS）的结果，该研究涉及从酒精依赖研究中抽取的 1064 名无关个体。从 theta ERO GWAS 中选择了 Illumina HumanHap 1 M 微阵列的 42 个 SNP，用于在基于家族的样本（N = 1095）中进行复制，其中四个标记显示出名义上的显著关联。来自两阶段研究的最显著标记是位于 2q11 染色体上的 ARID 蛋白 5A 基因（ARID5A）内的 rs4907240（未经调整，Fisher 联合 P = 3.68 × 10⁻⁶）。然而，出现的最有趣的关联是与 10q23 染色体上的血清素受体基因 HTR7 中的 rs7916403 相关（联合 P = 1.53 × 10⁻⁴），表明 5-羟色胺能系统在 theta EROs 的神经生理基础中起作用。此外，还测试了有前途的 SNP 与酒精依赖（DSM-IV）的诊断相关，发现 GWAS 病例对照中 HTR7 多态性与酒精依赖显著相关（P = 0.008）。在病例对照和基于家族的样本中，也检测到酒精依赖的显著隐性遗传效应（分别为 P = 0.031 和 0.042），HTR7 风险等位基因对应于纯合子中 theta ERO 的减少。这些结果表明 5-羟色胺能系统在酒精依赖的生物学基础中起作用，并强调了分析脑电波作为理解复杂遗传精神障碍的有力方法的实用性。
