确定焦虑症状的新基因组位点以及与精神疾病的广泛遗传重叠。

IF 5 3区医学 Q1 CLINICAL NEUROLOGY

Psychiatry and Clinical Neurosciences Pub Date : 2024-12-01 Epub Date: 2024-09-20 DOI:10.1111/pcn.13742

Markos Tesfaye, Piotr Jaholkowski, Alexey A Shadrin, Dennis van der Meer, Guy F L Hindley, Børge Holen, Nadine Parker, Pravesh Parekh, Viktoria Birkenæs, Zillur Rahman, Shahram Bahrami, Gleda Kutrolli, Oleksandr Frei, Srdjan Djurovic, Anders M Dale, Olav B Smeland, Kevin S O'Connell, Ole A Andreassen

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引用次数: 0

摘要

目的：焦虑症很普遍，焦虑症状（ANX）与许多精神疾病共存。我们旨在确定与 ANX 相关的基因组位点，描述其遗传结构以及与精神疾病的遗传重叠：我们纳入了一项关于ANX（英国生物库和百万退伍军人计划的荟萃分析，n = 301 732）、精神分裂症（SCZ）、双相情感障碍（BIP）、重度抑郁症（MD）、注意力缺陷/多动障碍（ADHD）和自闭症谱系障碍（ASD）的全基因组关联研究，并在挪威母亲、父亲和儿童队列（n = 95 841）中验证了研究结果。我们采用了二元因果混合模型和局部协方差关联分析来描述遗传结构，包括表型之间的重叠。我们还进行了条件假发现率分析和连带假发现率分析，以进一步确定与焦虑相关并与精神疾病共享的基因位点：结果：焦虑是多基因遗传，有 1290 万个遗传变异，并与精神疾病（410 万-1140 万个变异）广泛重叠，焦虑与精神疾病之间主要存在正遗传相关性。通过对精神疾病的条件分析，我们发现了119个新的焦虑基因位点，以及焦虑与MD n = 47 $ \left(n=47\right) $$ 、BIP n = 33 $ \left(n=33\right) $$ 、SCZ n = 71 $ \left(n=71\right) $$ 、ADHD n = 20 $ \left(n=20\right) $$ 和ASD n = 5 $ \left(n=5\right) $$ 之间共享的基因位点。与注释到共享基因位点的基因相比，注释到焦虑基因位点的基因在包括细胞粘附和神经纤维缠结在内的更广泛的生物通路中表现出富集性：焦虑是一种高度多基因表型，与精神疾病有广泛的遗传重叠。共同的遗传结构可能是焦虑症广泛的跨疾病并发症的基础，已确定的分子基础可能会导致潜在的药物靶点。

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Identification of novel genomic loci for anxiety symptoms and extensive genetic overlap with psychiatric disorders.

Aims: Anxiety disorders are prevalent and anxiety symptoms (ANX) co-occur with many psychiatric disorders. We aimed to identify genomic loci associated with ANX, characterize its genetic architecture, and genetic overlap with psychiatric disorders.

Methods: We included a genome-wide association study of ANX (meta-analysis of UK Biobank and Million Veterans Program, n = 301,732), schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), and validated the findings in the Norwegian Mother, Father, and Child Cohort (n = 95,841). We employed the bivariate causal mixture model and local analysis of covariant association to characterize the genetic architecture including overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of loci associated with anxiety and shared with psychiatric disorders.

Results: Anxiety was polygenic with 12.9k genetic variants and overlapped extensively with psychiatric disorders (4.1k-11.4k variants) with predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 119 novel loci for anxiety by conditioning on the psychiatric disorders, and loci shared between anxiety and MD $(n = 47)$ , BIP $(n = 33)$ , SCZ $(n = 71)$ , ADHD $(n = 20)$ , and ASD $(n = 5)$ . Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways including cell adhesion and neurofibrillary tangle compared with genes annotated to the shared loci.

Conclusions: Anxiety is highly polygenic phenotype with extensive genetic overlap with psychiatric disorders, and we identified novel loci for anxiety implicating new molecular pathways. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified molecular underpinnings may lead to potential drug targets.

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来源期刊

Psychiatry and Clinical Neurosciences 医学-精神病学

CiteScore

7.40

自引率

4.20%

发文量

181

审稿时长

6-12 weeks

期刊介绍： PCN (Psychiatry and Clinical Neurosciences) Publication Frequency: Published 12 online issues a year by JSPN Content Categories: Review Articles Regular Articles Letters to the Editor Peer Review Process: All manuscripts undergo peer review by anonymous reviewers, an Editorial Board Member, and the Editor Publication Criteria: Manuscripts are accepted based on quality, originality, and significance to the readership Authors must confirm that the manuscript has not been published or submitted elsewhere and has been approved by each author