Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.
Identification of shared risk loci and pathways for bipolar disorder and schizophrenia.
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DOI：
10.1371/journal.pone.0171595
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Nöthen MM
中科院分区：
文献类型：
--
作者：
Forstner AJ;Hecker J;Hofmann A;Maaser A;Reinbold CS;Mühleisen TW;Leber M;Strohmaier J;Degenhardt F;Treutlein J;Mattheisen M;Schumacher J;Streit F;Meier S;Herms S;Hoffmann P;Lacour A;Witt SH;Reif A;Müller-Myhsok B;Lucae S;Maier W;Schwarz M;Vedder H;Kammerer-Ciernioch J;Pfennig A;Bauer M;Hautzinger M;Moebus S;Schenk LM;Fischer SB;Sivalingam S;Czerski PM;Hauser J;Lissowska J;Szeszenia-Dabrowska N;Brennan P;McKay JD;Wright A;Mitchell PB;Fullerton JM;Schofield PR;Montgomery GW;Medland SE;Gordon SD;Martin NG;Krasnov V;Chuchalin A;Babadjanova G;Pantelejeva G;Abramova LI;Tiganov AS;Polonikov A;Khusnutdinova E;Alda M;Cruceanu C;Rouleau GA;Turecki G;Laprise C;Rivas F;Mayoral F;Kogevinas M;Grigoroiu-Serbanescu M;Becker T;Schulze TG;Rietschel M;Cichon S;Fier H;Nöthen MM
双相情感障碍（BD）是一种高度遗传的神经精神疾病，其特征是反复发作的躁狂和抑郁。BD显示与其他精神疾病，特别是精神分裂症（SCZ）的大量临床和遗传重叠。这种病因重叠的基因基本上仍然未知。精神病学基因组学联盟最近的SCZ全基因组关联研究（GWAS）确定了128个独立的全基因组显著单核苷酸多态性（SNP）。本研究通过在一个大型BD GWAS数据集（9747例患者，14278例对照）中进行相关性检验，调查这些SCZ相关SNP是否也有助于BD的发展。在重新插补和校正样本重叠后，107个研究的SCZ SNP中有22个显示与BD存在名义相关性。共享SCZ-BD SNP的数量显著高于预期（p = 1.46x10 - 8）。这提供了进一步的证据，SCZ相关基因座有助于BD的发展。两个SNP在Bonferroni校正后仍然显著。最强相关的SNP位于TRANK 1附近，TRANK 1是已报道的BD的全基因组显著风险基因。所有共享SCZ-BD SNP的通路分析揭示了25个名义上富集的基因集，其在潜在基因方面显示部分重叠。富集的基因组包括钙和谷氨酸信号，背角神经元中的神经病理性疼痛信号，和钙调蛋白结合。目前的数据为BD和SCZ的共同风险位点和疾病相关途径提供了进一步的见解。这可能为这两种主要精神疾病的治疗和预防提出新的研究方向。
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.