Tesfaye Markos, Jaholkowski Piotr, Shadrin Alexey A, van der Meer Dennis, Hindley Guy F L, Holen Børge, Parker Nadine, Parekh Pravesh, Birkenæs Viktoria, Rahman Zillur, Bahrami Shahram, Kutrolli Gleda, Frei Oleksandr, Djurovic Srdjan, Dale Anders M, Smeland Olav B, O'Connell Kevin S, Andreassen Ole A
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Clinical Science, University of Bergen, Bergen, Norway.
medRxiv. 2024 Apr 8:2023.09.01.23294920. doi: 10.1101/2023.09.01.23294920.
Anxiety disorders are prevalent and anxiety symptoms co-occur with many psychiatric disorders. We aimed to identify genomic risk loci associated with anxiety, characterize its genetic architecture, and genetic overlap with psychiatric disorders.
We used the GWAS of anxiety symptoms, schizophrenia, bipolar disorder, major depression, and attention deficit hyperactivity disorder (ADHD). We employed MiXeR and LAVA to characterize the genetic architecture and genetic overlap between the phenotypes. Conditional and conjunctional false discovery rate analyses were performed to boost the identification of genomic loci associated with anxiety and those shared with psychiatric disorders. Gene annotation and gene set analyses were conducted using OpenTargets and FUMA, respectively.
Anxiety was polygenic with 12.9k estimated genetic risk variants and overlapped extensively with psychiatric disorders (4.1-11.4k variants). MiXeR and LAVA revealed predominantly positive genetic correlations between anxiety and psychiatric disorders. We identified 114 novel loci for anxiety by conditioning on the psychiatric disorders. We also identified loci shared between anxiety and major depression ( = 47), bipolar disorder ( = 33), schizophrenia ( = 71), and ADHD ( = 20). Genes annotated to anxiety loci exhibit enrichment for a broader range of biological pathways and differential tissue expression in more diverse tissues than those annotated to the shared loci.
Anxiety is a highly polygenic phenotype with extensive genetic overlap with psychiatric disorders. These genetic overlaps enabled the identification of novel loci for anxiety. The shared genetic architecture may underlie the extensive cross-disorder comorbidity of anxiety, and the identified genetic loci implicate molecular pathways that may lead to potential drug targets.
焦虑症很常见，且焦虑症状与许多精神疾病同时出现。我们旨在确定与焦虑相关的基因组风险位点，描述其遗传结构，以及与精神疾病的遗传重叠情况。
我们使用了焦虑症状、精神分裂症、双相情感障碍、重度抑郁症和注意力缺陷多动障碍（ADHD）的全基因组关联研究（GWAS）。我们采用MiXeR和LAVA来描述表型之间的遗传结构和遗传重叠。进行了条件性和联合错误发现率分析，以加强对与焦虑相关的基因组位点以及与精神疾病共享的位点的识别。分别使用OpenTargets和FUMA进行基因注释和基因集分析。
焦虑是多基因的，估计有12900个遗传风险变异，并且与精神疾病广泛重叠（4100 - 11400个变异）。MiXeR和LAVA显示焦虑与精神疾病之间主要存在正遗传相关性。通过以精神疾病为条件，我们确定了114个新的焦虑位点。我们还确定了焦虑与重度抑郁症（ = 47）、双相情感障碍（ = 33）、精神分裂症（ = 71）和ADHD（ = 20）之间共享的位点。与焦虑位点注释的基因相比，与共享位点注释的基因在更广泛的生物途径中表现出富集，并且在更多样化的组织中具有差异组织表达。
焦虑是一种高度多基因的表型，与精神疾病有广泛的遗传重叠。这些遗传重叠使得能够识别新的焦虑位点。共享的遗传结构可能是焦虑广泛的跨疾病共病的基础，并且所确定的遗传位点涉及可能导致潜在药物靶点的分子途径。
