Meyers Jacquelyn L, Zhang Jian, Manz Niklas, Rangaswamy Madhavi, Kamarajan Chella, Wetherill Leah, Chorlian David B, Kang Sun J, Bauer Lance, Hesselbrock Victor, Kramer John, Kuperman Samuel, Nurnberger John I, Tischfield Jay, Wang Jen Chyong, Edenberg Howard J, Goate Alison, Foroud Tatiana, Porjesz Bernice
Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
Int J Psychophysiol. 2017 May;115:74-85. doi: 10.1016/j.ijpsycho.2016.12.008. Epub 2016 Dec 28.
Differences in fast beta (20-28Hz) electroencephalogram (EEG) oscillatory activity distinguish some individuals with psychiatric and substance use disorders, suggesting that it may be a useful endophenotype for studying the genetics of disorders characterized by neural hyper-excitability. Despite the high heritability estimates provided by twin and family studies, there have been relatively few genetic studies of beta EEG, and to date only one genetic association finding has replicated (i.e., GABRA2).
In a sample of 1564 individuals from 117 families of European Ancestry (EA) drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Genome-Wide Association Study (GWAS) on resting-state fronto-central fast beta EEG power, adjusting regression models for family relatedness, age, sex, and ancestry. To further characterize genetic findings, we examined the functional and behavioral significance of GWAS findings.
Three intronic variants located within DSE (dermatan sulfate epimerase) on 6q22 were associated with fast beta EEG at a genome wide significant level (p<5×10). The most significant SNP was rs2252790 (p<2.6×10; MAF=0.36; β=0.135). rs2252790 is an eQTL for ROS1 expressed most robustly in the temporal cortex (p=1.2×10) and for DSE/TSPYL4 expressed most robustly in the hippocampus (p=7.3×10; β=0.29). Previous studies have indicated that DSE is involved in a network of genes integral to membrane organization; gene-based tests indicated that several variants within this network (i.e., DSE, ZEB2, RND3, MCTP1, and CTBP2) were also associated with beta EEG (empirical p<0.05), and of these genes, ZEB2 and CTBP2 were associated with DSM-V Alcohol Use Disorder (AUD; empirical p<0.05).'
In this sample of EA families enriched for AUDs, fast beta EEG is associated with variants within DSE on 6q22; the most significant SNP influences the mRNA expression of DSE and ROS1 in hippocampus and temporal cortex, brain regions important for beta EEG activity. Gene-based tests suggest evidence of association with related genes, ZEB2, RND3, MCTP1, CTBP2, and beta EEG. Converging data from GWAS, gene expression, and gene-networks presented in this study provide support for the role of genetic variants within DSE and related genes in neural hyperexcitability, and has highlighted two potential candidate genes for AUD and/or related neurological conditions: ZEB2 and CTBP2. However, results must be replicated in large, independent samples.
快速β波（20 - 28Hz）脑电图（EEG）振荡活动的差异可区分一些患有精神疾病和物质使用障碍的个体，这表明它可能是研究以神经兴奋性过高为特征的疾病遗传学的有用内表型。尽管双胞胎和家族研究提供了较高的遗传度估计，但关于β波EEG的遗传研究相对较少，迄今为止只有一项遗传关联发现得到了重复验证（即GABRA2）。
在从酒精中毒遗传学合作研究（COGA）中抽取的117个欧洲血统（EA）家庭的1564名个体样本中，我们对静息状态下额中央快速β波EEG功率进行了全基因组关联研究（GWAS），并针对家族相关性、年龄、性别和血统调整了回归模型。为了进一步表征遗传发现，我们研究了GWAS发现的功能和行为意义。
位于6q22上硫酸皮肤素表异构酶（DSE）内的三个内含子变体在全基因组显著水平（p < 5×10）与快速β波EEG相关。最显著的单核苷酸多态性（SNP）是rs2252790（p < 2.6×10；小等位基因频率[MAF]=0.36；β = 0.135）。rs2252790是ROS1的一个表达数量性状基因座（eQTL），在颞叶皮质中表达最强（p = 1.2×10），也是DSE/TSPYL4的eQTL，在海马体中表达最强（p = 7.3×10；β = 0.29）。先前的研究表明，DSE参与了一个对膜组织至关重要的基因网络；基于基因的测试表明，该网络内的几个变体（即DSE、ZEB2、RND3、MCTP1和CTBP2）也与β波EEG相关（经验性p < 0.05），在这些基因中，ZEB2和CTBP2与《精神疾病诊断与统计手册》第五版（DSM - V）酒精使用障碍（AUD）相关（经验性p < 0.05）。
在这个富含AUD的EA家庭样本中，快速β波EEG与6q22上DSE内的变体相关；最显著的SNP影响海马体和颞叶皮质中DSE和ROS1的mRNA表达，这两个脑区对β波EEG活动很重要。基于基因的测试表明与相关基因ZEB2、RND3、MCTP1、CTBP2和β波EEG存在关联证据。本研究中来自GWAS、基因表达和基因网络的汇聚数据为DSE和相关基因内的遗传变体在神经兴奋性过高中的作用提供了支持，并突出了两个AUD和/或相关神经疾病的潜在候选基因：ZEB2和CTBP2。然而，结果必须在大型独立样本中进行重复验证。
