美国西奈山伊坎医学院Niamh Mullins小组的一项最新研究显示，精细定位基因组位点细化双相情感障碍风险基因。这一研究成果于2025年6月25日发表在国际顶尖学术期刊《自然—神经科学》上。

课题组对这些基因座应用了一套统计和功能精细映射方法，并对17个可能导致双相情感障碍的SNP进行了优先排序。课题组人员将这些SNP定位到基因上，并通过整合变异注释、脑细胞型表观基因组注释、大脑数量性状位点和双相情感障碍罕见变异外显子组测序结果来研究它们可能的功能后果。越来越多的证据支持参与神经传递和神经发育的基因，包括SCN2A、TRANK1、DCLK3、INSYN2B、SYNE1、THSD7A、CACNA1B、TUBBP5、FKBP2、RASGRP1、FURIN、FES、MED24和THRA等在双相情感障碍中的作用。这些代表了有希望的候选功能实验，以了解生物学机制和治疗潜力。此外，该研究组证明了精细图谱效应大小可以提高双相情感障碍多基因风险评分在不同人群中的表现，并提出了一个高通量精细图谱管道。

据介绍，双相情感障碍是一种病因复杂的遗传性精神疾病。虽然已发表的最大的全基因组关联研究确定了64个双相情感障碍风险位点，但这些位点内的遗传SNP和基因仍然未知。

附：英文原文

Title: Fine-mapping genomic loci refines bipolar disorder risk genes

Author: Koromina, Maria, Ravi, Ashvin, Panagiotaropoulou, Georgia, Schilder, Brian M., Humphrey, Jack, Braun, Alice, Bidgeli, Tim, Chatzinakos, Chris, Coombes, Brandon J., Kim, Jaeyoung, Liu, Xiaoxi, Terao, Chikashi, OConnell, Kevin S., Adams, Mark J., Adolfsson, Rolf, Alda, Martin, Alfredsson, Lars, Andlauer, Till F. M., Andreassen, Ole A., Antoniou, Anastasia, Baune, Bernhard T., Bengesser, Susanne, Biernacka, Joanna, Boehnke, Michael, Bosch, Rosa, Cairns, Murray J., Carr, Vaughan J., Casas, Miquel, Catts, Stanley, Cichon, Sven, Corvin, Aiden, Craddock, Nicholas, Dafnas, Konstantinos, Dalkner, Nina, Dannlowski, Udo, Degenhardt, Franziska, Di Florio, Arianna, Dikeos, Dimitris, Fellendorf, Frederike Tabea, Ferentinos, Panagiotis, Forstner, Andreas J., Forty, Liz, Frye, Mark, Fullerton, Janice M., Gawlik, Micha, Gizer, Ian R., Gordon-Smith, Katherine, Green, Melissa J., Grigoroiu-Serbanescu, Maria, Guzman-Parra, Jos, Hahn, Tim, Henskens, Frans, Hillert, Jan, Jablensky, Assen V., Jones, Lisa, Jones, Ian, Jonsson, Lina, Kelsoe, John R., Kircher, Tilo, Kirov, George

Issue&Volume: 2025-06-25

Abstract: Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline.

DOI: 10.1038/s41593-025-01998-z

Source: https://www.nature.com/articles/s41593-025-01998-z