Hennah W, Thomson P, McQuillin A, Bass N, Loukola A, Anjorin A, Blackwood D, Curtis D, Deary I J, Harris S E, Isometsä E T, Lawrence J, Lönnqvist J, Muir W, Palotie A, Partonen T, Paunio T, Pylkkö E, Robinson M, Soronen P, Suominen K, Suvisaari J, Thirumalai S, St Clair D, Gurling H, Peltonen L, Porteous D
Medical Genetics Section, University of Edinburgh, Edinburgh EH4 2XU, Scotland.
Mol Psychiatry. 2009 Sep;14(9):865-73. doi: 10.1038/mp.2008.22. Epub 2008 Mar 4.
Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.
精神分裂症相关基因1（DISC1）与精神分裂症、分裂情感性障碍、双相情感障碍、重度抑郁症、自闭症和阿斯伯格综合征的发病风险相关，但除了最初的易位家族外，真正的致病变异尚未得到证实。在此，我们报告了一项针对欧洲精神分裂症和双相情感障碍队列中DISC1的协调性关联研究。我们确定了显著关联区域，证明了等位基因频率的异质性，并为变异之间的相互作用提供了初步证据。虽然在合并数据集中没有关联在置换分析中幸存下来，但在芬兰队列中，rs1538979位点与双相情感障碍存在显著的校正关联（未校正P = 0.00020；校正P = 0.016；优势比 = 2.73±95%置信区间（CI）1.42 - 5.27），在伦敦队列中，rs821577位点也存在显著关联（未校正P = 0.00070；校正P = 0.040；优势比 = 1.64±95% CI 1.23 - 2.19）。rs821577单核苷酸多态性（SNP）在合并的欧洲队列中显示出风险增加的证据（优势比 = 1.27±95% CI 1.07 - 1.51），尽管未检测到显著的校正关联（未校正P = 0.0058；校正P = 0.28）。在以两个风险等位基因为条件对欧洲数据集进行分析后，重新分析发现了第三个显著的SNP关联（未校正P = 0.00050；校正P = 0.025）。该SNP显示出相互作用的证据，其增加或降低风险取决于rs1538979或rs821577的存在与否。这些发现为DISC1在精神疾病中的作用提供了进一步支持，并证明了基因座异质性的存在，这使得临床相关的基因变异可能在合并队列的标准分析中未被发现。
