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HECTD2和AKAP11中罕见的功能丧失变异会增加双相情感障碍的风险。

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

作者信息

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

机构信息

deCODE genetics/Amgen, Reykjavik, Iceland.

School of Humanities, University of Iceland, Reykjavik, Iceland.

出版信息

Nat Genet. 2025 Apr;57(4):851-855. doi: 10.1038/s41588-025-02141-1. Epub 2025 Mar 25.

DOI:10.1038/s41588-025-02141-1
PMID:40133559
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11985335/
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.

摘要

双相情感障碍是一种高度可遗传的精神疾病；双相情感障碍的全基因组关联研究已经产生了60多个包含常见变异的风险位点。为了利用罕见功能丧失（LOF）变异中包含的信息，这些变异有望揭示潜在生物学机制，我们使用冰岛全基因组测序数据（4197例病例，超过200,000名对照）和英国生物银行（1881例病例，426,622名对照）中基于基因的LOF变异聚集，对双相情感障碍进行了变异负担分析。我们发现HECTD2与双相情感障碍相关，并使用双相外显子数据集进行了验证。与双相外显子数据集的荟萃分析还显示，AKAP11中的LOF变异与双相情感障碍相关。这两种与双相情感障碍的关联都是新发现，但AKAP11此前已与精神病和精神分裂症相关。AKAP11和HECTD2的产物与GSK3β相互作用，GSK3β是一种受锂抑制的蛋白质，锂是治疗双相情感障碍最有效的情绪稳定剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f5a/11985335/1ee4f55c646c/41588_2025_2141_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f5a/11985335/fe185038623e/41588_2025_2141_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f5a/11985335/1ee4f55c646c/41588_2025_2141_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f5a/11985335/fe185038623e/41588_2025_2141_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f5a/11985335/1ee4f55c646c/41588_2025_2141_Fig2_HTML.jpg

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Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.罕见的蛋白截断变异导致的精神分裂症风险在不同的人类群体中是保守的。
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The sequences of 150,119 genomes in the UK Biobank.英国生物库中 150119 个基因组的序列。
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Rare coding variants in ten genes confer substantial risk for schizophrenia.十个基因中的罕见编码变异赋予精神分裂症的显著风险。
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