Imaging Genetics Center at the Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, Neuroscience Research Building 225E 635 Charles Young Drive, Los Angeles, CA, 90095-1769, USA.
Brain Imaging Behav. 2013 Jun;7(2):102-15. doi: 10.1007/s11682-012-9199-7.
Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson's disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 706) and the Queensland Twin Imaging Study (QTIM; N = 639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (P MA = 4.79 × 10(-8)). This commonly-carried genetic variant accounted for 2.68 % and 0.84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster's involvement in lentiform nucleus volume differences in human populations.
豆状核体积和形态的缺陷与许多受遗传影响的疾病有关，包括帕金森病、精神分裂症和 ADHD。在这里，我们进行了全基因组搜索，以发现与人群中豆状核体积差异相关的常见遗传变异。我们评估了两个大型基因样本的大脑结构 MRI 扫描：阿尔茨海默病神经影像学倡议（ADNI；N=706）和昆士兰双胞胎成像研究（QTIM；N=639）。使用固定效应模型对每个队列的关联统计数据进行合并荟萃分析，以提高功效并减少假阳性发现的发生率。我们在黄素单加氧酶（FMO）基因簇内和周围发现了一些关联。最显著相关的 SNP，rs1795240，位于 FMO3 基因中；荟萃分析后，它显示与豆状核体积有全基因组显著关联（P MA = 4.79×10(-8)）。这个常见的遗传变异在 ADNI 和 QTIM 样本中分别解释了 2.68%和 0.84%的性状变异性，尽管 QTIM 样本的平均年龄要小 50 岁。通路富集分析表明，该基因对细胞色素 P450 通路有显著贡献，该通路参与代谢许多治疗疼痛、癫痫、躁狂、抑郁、焦虑和精神病的药物。我们确定的遗传变异为 FMO 基因簇参与人群中豆状核体积差异提供了复制的、全基因组显著的证据。
