1] Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, MRC Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Edinburgh, UK.
Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
Mol Psychiatry. 2014 Jun;19(6):668-75. doi: 10.1038/mp.2013.68. Epub 2013 Jun 4.
A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
一个平衡的 t(1;11)易位，截断了精神分裂症 1 号基因（DISC1），在一个苏格兰大家庭中，对精神分裂症和复发性重度抑郁症（rMDD）表现出全基因组显著连锁，但全基因组和外显子测序的关联研究并未支持 DISC1 在精神疾病中的作用。为了更详细地研究 DISC1，我们对 653 例病例和 889 例对照进行了 DISC1 基因座 528kb 的测序。我们报告了 2718 个经过验证的单核苷酸多态性（SNP），其中 2010 个 SNP 的次要等位基因频率<1%。只有 38%的这些变体存在于 1000 基因组计划的欧洲子集中。这表明许多 DISC1 SNP 仍未被发现，基本上是私有的。仅在患者中发现的罕见编码变异位于可能的功能蛋白结构域中。rs16856199 与 rMDD 之间观察到显著的全区域关联（P=0.026，未调整 P=6.3×10(-5)，OR=3.48）。在额外的复发性重度抑郁症样本中未得到复制（复制 P=0.11）。原始和复制数据集的综合分析支持了原始关联（P=0.0058，OR=1.46）。这种变体与疾病的遗传分离在从初级保健机构转介来的 rMDD 个体的家族中是有限的。对编码和非编码变体的负担分析与诊断以及情绪和认知测量呈名义关联。总之，这些观察结果可能适用于其他主要精神疾病的候选基因，因此可能为未来研究的设计提供指导。
