Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.
Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.
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DOI：
10.1038/mp.2017.115
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发表时间：
2018-05
影响因子：
11
通讯作者：
McCombie WR
中科院分区：
文献类型：
--
作者：
Teng S;Thomson PA;McCarthy S;Kramer M;Muller S;Lihm J;Morris S;Soares DC;Hennah W;Harris S;Camargo LM;Malkov V;McIntosh AM;Millar JK;Blackwood DH;Evans KL;Deary IJ;Porteous DJ;McCombie WR
精神分裂症（SCZ）、双相情感障碍（BD）和复发性重度抑郁症（rMDD）是常见的精神疾病。所有这些都与较低的认知能力有关，并显示出遗传重叠的证据和认知功能和神经质多效性的实质性证据。DISC1蛋白直接与参与大脑发育和信号传导的大量蛋白质（DISC1 Interactome）相互作用。DISC1表达的调节改变了一组限制性基因（DISC1调节组）的表达，这些基因也与脑生物学和疾病有关。在这里，我们报告了654名精神病患者和889名认知表型对照受试者的59个DISC1相互作用基因组基因和154个调节基因组基因的靶向测序，我们以前曾报道过DISC1基因座完整测序的性状相关证据。对罕见和单胎变异的精神障碍、认知变量和人格特征进行了预测为有害的负荷分析。DISC1相互作用组和调节组在测试的表型中显示出差异关联。在对所有性状进行家系误差校正后（FWERacross），Regulome中单细胞破坏性变异的负担增加与SCZ相关（FWERacross P=0.0339）。DISC1相互作用基因组中的单细胞破坏性变异的负担与11岁时的低认知能力相关（FWERAcross P=0.0043）。这些结果确定了DISC1及其核心相互作用体对精神分裂症候选基因的调节改变，作为精神分裂症风险的替代途径，与智力残疾相关的罕见拷贝数变异的新兴效应一致。
Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.
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影响因子：
4.5
作者：
Katsel, Pavel;Tan, Weilun;Abazyan, Bagrat;Davis, Kenneth L.;Ross, Christopher;Pletnikov, Mikhail V.;Haroutunian, Vahram
通讯作者：
Haroutunian, Vahram
影响因子：
11
作者：
通讯作者：
--
影响因子：
6.6
作者：
Johnstone, Mandy;Thomson, Pippa A.;Porteous, David J.
通讯作者：
Porteous, David J.
影响因子：
11
作者：
Camargo, L. M.;Collura, V.;Brandon, N. J.
通讯作者：
Brandon, N. J.
影响因子：
4.8
作者：
Javier Suarez-Rama, Jose;Arrojo, Manuel;Costas, Javier
通讯作者：
Costas, Javier