Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q
Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q
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DOI：
10.1038/sj.mp.4001847
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发表时间：
2006-08-01
影响因子：
11
通讯作者：
Nestadt, G.
中科院分区：
文献类型：
--
作者：
Shugart, Y. Y.;Samuels, J.;Nestadt, G.
强迫症（OCD）是全球第十大致残性疾病。双胞胎和家庭的研究暗示这种疾病的遗传病因，虽然具体的基因尚未确定。在这里，我们提出了第一个大规模的无模型的连锁分析的扩展和核心家庭使用“广泛”（明确和可能的诊断）和“狭窄”（明确的）定义的强迫症。我们对219个家庭进行了基因组扫描分析，这些家庭是作为强迫症协作遗传学研究的一部分收集的。染色体3q 27 -28（P = 0.0003）、6 q（P = 0.003）、7 p（P = 0.001）、1 q（P = 0.003）和15 q（P = 0.006）上的多点分析揭示了提示连锁信号。使用“广义”强迫症定义，我们观察到最强有力的证据，染色体3q 27 -28上的连锁。最大总体Kong和考克斯LODall评分（2.67）发生在D3 S1262和D3 S2398，这两个信号基于模拟的P值分别为0.0003和0.0004，尽管对于这两个信号，基于模拟的全基因组显著性水平为0.055。协变量连锁分析表明，1号染色体上的基因可能在增加强迫症早期发作的风险中起作用。我们目前正在对这五个区域进行精细定位，并给出提示性信号，特别关注3q 27 -28。考虑到强迫症可能的病因异质性，通过复制研究、大规模以家族为基础的连锁研究和新的统计方法的应用，可能会增强与强迫症相关的基因定位。
Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both 'broad' (definite and probable diagnoses) and 'narrow' (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P = 0.0003), 6q (P = 0.003), 7p (P = 0.001), 1q (P = 0.003), and 15q (P = 0.006). Using the 'broad' OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods.