挪威奥斯陆大学Kevin S. O’Connell等研究人员合作发现，基因组学为双相情感障碍提供生物学和表型的见解。该研究于2025年1月22日在线发表于国际一流学术期刊《自然》。

研究人员分析了来自欧洲、东亚、非洲裔美国人和拉丁裔血统的参与者数据（158036例双相情感障碍病例，280万对照组），并结合了临床、社区和自我报告样本。在多血统的元分析中，研究人员鉴定出了298个全基因组显著位点，是先前发现的四倍，并在东亚人群中发现了一个血统特异性的关联。通过整合细致定位和其他变异到基因映射的方法，研究人员识别出了36个在双相情感障碍病因中的可信基因。通过细致定位优先考虑的基因在双相情感障碍病例中富集了超稀有的致病错义和蛋白质截断变异，结果突显了常见变异和稀有变异信号的趋同。

研究人员报告了双相情感障碍的遗传结构差异，这些差异取决于患者的筛查来源以及双相情感障碍亚型（I型或II型）。多项分析表明，特定细胞类型在双相情感障碍的发病机制中发挥作用，包括GABA能抑制性中间神经元和中型棘突神经元。这些分析共同提供了对双相情感障碍遗传结构和生物学基础的进一步见解。

据悉，双相情感障碍是全球疾病负担的主要原因之一。尽管其遗传性较高（60-80%），但大多数潜在的遗传决定因素仍未明确。

附：英文原文

Title: Genomics yields biological and phenotypic insights into bipolar disorder

Author: OConnell, Kevin S., Koromina, Maria, van der Veen, Tracey, Boltz, Toni, David, Friederike S., Yang, Jessica Mei Kay, Lin, Keng-Han, Wang, Xin, Coleman, Jonathan R. I., Mitchell, Brittany L., McGrouther, Caroline C., Rangan, Aaditya V., Lind, Penelope A., Koch, Elise, Harder, Arvid, Parker, Nadine, Bendl, Jaroslav, Adorjan, Kristina, Agerbo, Esben, Albani, Diego, Alemany, Silvia, Alliey-Rodriguez, Ney, Als, Thomas D., Andlauer, Till F. M., Antoniou, Anastasia, Ask, Helga, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bigdeli, Tim B., Pedersen, Carsten Bcker, Boks, Marco P., Brte, Sigrid, Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cabana-Domnguez, Judit, Cairns, Murray J., Carpiniello, Bernardo, Casas, Miquel, Cervantes, Pablo, Chatzinakos, Chris, Chen, Hsi-Chung, Clarence, Tereza, Clarke, Toni-Kim, Claus, Isabelle, Coombes, Brandon, Corfield, Elizabeth C., Cruceanu, Cristiana

Issue&Volume: 2025-01-22

Abstract: Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n=158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

DOI: 10.1038/s41586-024-08468-9

Source: https://www.nature.com/articles/s41586-024-08468-9