Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
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DOI：
10.1016/s0140-6736(12)62129-1
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发表时间：
2013-04-20
期刊：
影响因子：
168.9
通讯作者：
Devlin, Bernie
中科院分区：
文献类型：
--
作者：
Smoller, Jordan W.;Craddock, Nicholas;Kendler, Kenneth;Lee, Phil Hyoun;Neale, Benjamin M.;Nurnberger, John I.;Ripke, Stephan;Santangelo, Susan;Sullivan, Patrick F.;Purcell, Shaun;Anney, Richard;Buitelaar, Jan;Fanous, Ayman;Faraone, Stephen V.;Hoogendijk, Witte;Lesch, Klaus-Peter;Levinson, Douglas F.;Perlis, Roy H.;Rietschel, Marcella;Riley, Brien;Sonuga-Barke, Edmund;Schachar, Russell;Schulze, Thomas G.;Thapar, Anita;Neale, Michael;Bender, Patrick;Cichon, Sven;Daly, Mark J.;Kelsoe, John;Lehner, Thomas;O'Donovan, Mick;Gejman, Pablo;Sebat, Jonathan;Sklar, Pamela;Devlin, Bernie
来自家庭和双胞胎研究的发现表明，基因对精神疾病的影响并不是在所有情况下都映射到目前的诊断类别。我们的目的是确定在精神病学基因组学联盟的五种疾病之间共享的遗传效应的特定变异：自闭症谱系障碍、注意缺陷多动障碍、双相情感障碍、重度抑郁症和精神分裂症。我们分析了这五种疾病的全基因组单核苷酸多态性（SNP）数据，这些数据来自33 332例病例和27 888例欧洲血统的对照。为了描述等位基因对每种疾病的影响，我们采用了带有模型选择的多项逻辑回归程序，以确定基因型和表型之间关系的最佳拟合模型。我们检查了先前发现的双相情感障碍和精神分裂症的全基因组显著位点的交叉障碍效应，并使用多基因风险评分分析来检查来自更广泛的常见变异的这种影响。我们进行了通路分析，以确定五种疾病遗传重叠的生物学关联。我们使用表达数量性状位点（eQTL）数据的富集分析来评估在死后脑组织样本中，具有交叉紊乱关联的snp是否富集了调节性snp。在初步分析中，4个位点的snp超过了全基因组意义的截止点（p<5×10−8）：染色体3p21和10q24上的区域，以及两个l型电压门控钙通道亚基CACNA1C和CACNB2内的snp。模型选择分析支持这些基因座对几种疾病的影响。先前与双相情感障碍或精神分裂症相关的基因座具有可变的诊断特异性。多基因风险评分显示出跨疾病的关联，尤其是在成人发病的疾病之间。通路分析支持钙通道信号基因在所有五种疾病中的作用。最后，在脑eQTL标记中富集了具有交叉障碍关联证据的snp。我们的研究结果表明，特定的snp与一系列儿童发病或成人发病的精神疾病有关。特别是，钙通道活性基因的变异似乎对精神病理有多效性影响。这些结果为超越精神病学的描述性症候群，朝着根据病因建立病种学的目标提供了相关证据。国家心理健康研究所。
Findings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. We analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33 332 cases and 27 888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples. SNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers. Our findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause. National Institute of Mental Health.