解码遗传学/安进公司Kari Stefansson研究小组报道了罕见的功能丧失变异在HECTD2和AKAP11中会增加双相情感障碍的风险。相关论文发表在2025年3月25日出版的《自然—遗传学》杂志上。

为了利用罕见的功能丧失（LOF）变异所包含的信息，有望为潜在的生物学提供信息，研究人员对来自冰岛（4197例，超过20万对照）和英国生物银行（1881例，426622对照）的双相情感障碍LOF变异的全基因组测序数据进行了变异负担分析。课题组发现HECTD2与双相情感障碍相关，并在双相外显子组数据集中证实了这一点。双相外显子组荟萃分析也显示，AKAP11的LOF变异与双相情感障碍有关。这两种与双相情感障碍的关联都是新的，但AKAP11先前与精神病和精神分裂症有关。AKAP11和heg2的产物与GSK3β相互作用，GSK3β是一种被锂抑制的蛋白质，是治疗双相情感障碍最有效的情绪稳定剂。

据悉，双相情感障碍是一种高度遗传性的精神疾病；双相情感障碍的全基因组关联研究已经发现了60多个包含常见变异的风险位点。

附：英文原文

Title: Rare loss-of-function variants in HECTD2 and AKAP11 confer risk of bipolar disorder

Author: Thorgeirsson, Thorgeir E., Tragante, Vinicius, Sveinbjornsson, Gardar, Jonsdottir, Gudrun A., Walters, G. Bragi, Ivarsdottir, Erna V., Arnadottir, Gudny A., Sturluson, Arni, Jensson, Brynjar O., Fridriksdottir, Run, Skuladottir, Astros Th., Einarsson, Gudmundur, Bjornsdottir, Gyda, Gunnarsson, Arni F., Gisladottir, Rosa S., Sigurdsson, Asgeir, Oddsson, Asmundur, Jonsson, Hakon, Magnusson, Olafur Th., Helgason, Hannes, Norddahl, Gudmundur, Thorleifsson, Gudmar, Haraldsson, Magnus, Sigurdsson, Engilbert, Holm, Hilma, Masson, Gisli, Gudbjartsson, Daniel F., Stefansson, Hreinn, Sulem, Patrick, Stefansson, Kari

Issue&Volume: 2025-03-25

Abstract: Bipolar disorder is a highly heritable psychiatric disorder; genome-wide association studies of bipolar disorder have yielded over 60 risk loci harboring common variants. To harness the information contained in rare loss-of-function (LOF) variants, holding promise for informing on the underlying biology, we performed a variant burden analysis for bipolar disorder using gene-based aggregation of LOF variants in whole-genome sequencing data from Iceland (4,197 cases, more than 200,000 controls) and the UK Biobank (1,881 cases, 426,622 controls). We found that HECTD2 was associated with bipolar disorder and confirmed it using the Bipolar Exome dataset. Meta-analysis with Bipolar Exome also revealed that LOF variants in AKAP11 were associated with bipolar disorder. Both associations with bipolar disorder are new, but AKAP11 has previously been associated with psychosis and schizophrenia. The products of AKAP11 and HECTD2 interact with GSK3β, a protein inhibited by lithium, the most effective mood stabilizer available to treat bipolar disorder.

DOI: 10.1038/s41588-025-02141-1

Source: https://www.nature.com/articles/s41588-025-02141-1