挪威奥斯陆大学Ole A. Andreassen、美国西奈山伊坎医学院Niamh Mullins等研究人员合作通过基因组关联研究揭示躁郁症的生物学基础。该项研究成果于2021年5月17日在线发表在《自然—遗传学》杂志上。

研究人员对41,917例躁郁症病例和371,549例欧洲血统对照进行了全基因组关联研究，从而确定了64个相关的基因组位点。躁郁症风险等位基因富含突触信号通路中的基因和脑表达的基因，尤其是那些在额叶前额皮质和海马神经元中具有高表达特异性的基因。在编码抗精神病药、钙通道阻滞剂、抗癫痫药和麻醉药靶标的基因中，研究人员发现了明显的信号富集。

整合表达定量性状基因座数据发现躁郁症相关的15个基因，这些基因编码了可成药的靶标，例如HTR6、MCHR1、DCLK3和FURIN。对躁郁症亚型的分析表明，I型和II型之间存在高但不完善的遗传相关性，并确定了其他相关位点。总之，这些结果加深了人们对躁郁症生物学病因的理解，确定了新的治疗方法，并为功能性后续研究确定了基因的优先级。

据介绍，躁郁症是一种病因复杂、可遗传的精神疾病。

附：英文原文

Title: Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author: Niamh Mullins, Andreas J. Forstner, Kevin S. OConnell, Brandon Coombes, Jonathan R. I. Coleman, Zhen Qiao, Thomas D. Als, Tim B. Bigdeli, Sigrid Brte, Julien Bryois, Alexander W. Charney, Ole Kristian Drange, Michael J. Gandal, Saskia P. Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M. Schilder, Laura G. Sloofman, Stacy Steinberg, Vassily Trubetskoy, Bendik S. Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Esben Agerbo, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Anastasia Antoniou, Swapnil Awasthi, Ji Hyun Baek, Marie Bkvad-Hansen, Nicholas Bass, Michael Bauer, Eva C. Beins, Sarah E. Bergen, Armin Birner, Carsten Bcker Pedersen, Erlend Ben, Marco P. Boks, Rosa Bosch, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Toni-Kim Clarke, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham

Issue&Volume: 2021-05-17

Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. 

DOI: 10.1038/s41588-021-00857-4

Source: https://www.nature.com/articles/s41588-021-00857-4