Forstner Andreas J, Hecker Julian, Hofmann Andrea, Maaser Anna, Reinbold Céline S, Mühleisen Thomas W, Leber Markus, Strohmaier Jana, Degenhardt Franziska, Treutlein Jens, Mattheisen Manuel, Schumacher Johannes, Streit Fabian, Meier Sandra, Herms Stefan, Hoffmann Per, Lacour André, Witt Stephanie H, Reif Andreas, Müller-Myhsok Bertram, Lucae Susanne, Maier Wolfgang, Schwarz Markus, Vedder Helmut, Kammerer-Ciernioch Jutta, Pfennig Andrea, Bauer Michael, Hautzinger Martin, Moebus Susanne, Schenk Lorena M, Fischer Sascha B, Sivalingam Sugirthan, Czerski Piotr M, Hauser Joanna, Lissowska Jolanta, Szeszenia-Dabrowska Neonila, Brennan Paul, McKay James D, Wright Adam, Mitchell Philip B, Fullerton Janice M, Schofield Peter R, Montgomery Grant W, Medland Sarah E, Gordon Scott D, Martin Nicholas G, Krasnov Valery, Chuchalin Alexander, Babadjanova Gulja, Pantelejeva Galina, Abramova Lilia I, Tiganov Alexander S, Polonikov Alexey, Khusnutdinova Elza, Alda Martin, Cruceanu Cristiana, Rouleau Guy A, Turecki Gustavo, Laprise Catherine, Rivas Fabio, Mayoral Fermin, Kogevinas Manolis, Grigoroiu-Serbanescu Maria, Becker Tim, Schulze Thomas G, Rietschel Marcella, Cichon Sven, Fier Heide, Nöthen Markus M
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
PLoS One. 2017 Feb 6;12(2):e0171595. doi: 10.1371/journal.pone.0171595. eCollection 2017.
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.
双相情感障碍（BD）是一种具有高度遗传性的神经精神疾病，其特征为躁狂和抑郁反复发作。BD与其他精神疾病，特别是精神分裂症（SCZ），在临床和遗传方面存在大量重叠。导致这种病因重叠的基因在很大程度上仍不为人知。精神病基因组学联盟最近进行的一项精神分裂症全基因组关联研究（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双相情感障碍GWAS数据集（9747例患者，14278例对照）中进行关联测试，调查了这些与精神分裂症相关的SNP是否也对双相情感障碍的发病有影响。在对样本重叠进行重新估算和校正后，所研究的107个精神分裂症SNP中有22个显示出与双相情感障碍的名义关联。精神分裂症与双相情感障碍共享的SNP数量显著高于预期（p = 1.46x10-8）。这进一步证明与精神分裂症相关的基因座对双相情感障碍的发病有影响。经过Bonferroni校正后，有两个SNP仍然显著。关联最强的SNP位于TRANK1附近，TRANK被报道是双相情感障碍全基因组显著的风险基因。对所有共享的精神分裂症与双相情感障碍SNP进行通路分析，发现了25个名义上富集的基因集，这些基因集在基础基因方面存在部分重叠。富集的基因集包括钙信号和谷氨酸信号、背角神经元中的神经性疼痛信号以及钙调蛋白结合。本研究数据为双相情感障碍和精神分裂症的共享风险基因座及疾病相关通路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示新的研究方向。
