Tesfaye Markos, Shadrin Alexey, Parker Nadine, Jaholkowski Piotr, Parekh Pravesh, Kutrolli Gleda, Birkenæs Viktoria, Bakken Nora R, Ask Helga, 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 Nov 20:2024.11.19.24317523. doi: 10.1101/2024.11.19.24317523.
IMPORTANCE-: There is extensive comorbidity between anxiety disorders (ANX) and major depression (MD). Most studies on the genetics of ANX do not exclude comorbid cases of MD, and , therefore confounding genetic association analyses. Disorder-specific analysis of genomic data may reveal more precise biological pathways and causal relationships.
OBJECTIVE-: To investigate the genetic relationship between disorder-specific ANX and MD compared to samples with comorbidity, including their causal relationship.
DESIGN SETTING AND PARTICIPANTS-: Data from UK Biobank was used to perform genome-wide association studies (GWAS) of ANX-only and MD-only, and generate disorder-specific polygenic risk scores (PRS). The Norwegian Mother, Father, and Child Cohort (MoBa) was used to test the associations of PRS with diagnosis and symptoms. MD and ANX GWAS data including comorbidities (MD-co and ANX-co) were used as comparators. Genetic correlation was assessed using LDSC, and Mendelian randomization was employed to infer causal relationships.
GWAS of ICD-10 diagnoses of ANX, MD, or both. Genetic correlations between pairs of ANX and MD phenotypes. PRS associations with diagnoses of ANX, MD, and their comorbid states, and anxiety or depressive symptoms.
RESULTS-: The GWAS of ANX-only (9,980 cases and 179,442 controls) and MD-only (15,301 cases and 179,038 controls) showed a lower genetic correlation (0.53) than the one between ANX-co and MD-co (0.90). ANX-only showed a causal relationship with MD-only (P=1.5e-02), but not , while comorbid cases showed a significant bidirectional causal relationship (P=2.9e-12, P =9.3e-06). The PRS-MD-only were differentially associated with MD-only compared to ANX-only cases (β= -0.08; 95%CI: -0.11, -0.03); however, this differential association was not observed for the PRS-MD-co. A similar pattern of differential association with anxiety and depressive symptoms was observed for PRS-ANX-only, but not for PRS-MD-co.
CONCLUSIONS AND RELEVANCE-: The genetics and underlying biology of ANX and MD are more distinct when comorbid cases are excluded from analyses and reveals that ANX may be causal for MD. This confounding of genetic relationships as a result of comorbidity is likely to apply to other psychiatric disorders. Disorder-specific genetic studies may help uncover more relevant biological mechanisms and guide more targeted clinical interventions.
焦虑症（ANX）和重度抑郁症（MD）之间存在广泛的共病现象。大多数关于焦虑症遗传学的研究并未排除合并重度抑郁症的病例，因此混淆了基因关联分析。对基因组数据进行特定疾病分析可能会揭示更精确的生物学途径和因果关系。
与合并症样本相比，研究特定疾病的焦虑症和重度抑郁症之间的遗传关系，包括它们的因果关系。
设计、背景和参与者：利用英国生物银行的数据对仅患有焦虑症和仅患有重度抑郁症的样本进行全基因组关联研究（GWAS），并生成特定疾病的多基因风险评分（PRS）。使用挪威母婴队列研究（MoBa）来检验PRS与诊断及症状之间的关联。将包括合并症（MD-co和ANX-co）的重度抑郁症和焦虑症GWAS数据用作对照。使用LDSC评估遗传相关性，并采用孟德尔随机化来推断因果关系。
对国际疾病分类第十版（ICD-10）中焦虑症、重度抑郁症或两者的诊断进行GWAS。焦虑症和重度抑郁症表型对之间的遗传相关性。PRS与焦虑症、重度抑郁症及其合并状态的诊断以及焦虑或抑郁症状之间的关联。
仅患有焦虑症（9980例病例和179442例对照）和仅患有重度抑郁症（15301例病例和179038例对照）的GWAS显示，其遗传相关性（0.53）低于合并焦虑症和合并重度抑郁症样本之间的遗传相关性（0.90）。仅患有焦虑症的样本与仅患有重度抑郁症的样本之间存在因果关系（P=1.5×10⁻²），但反之不然，而合并症样本显示出显著的双向因果关系（P=2.9×10⁻¹²，P =9.3×10⁻⁶）。与仅患有焦虑症的病例相比，仅患有重度抑郁症的PRS与仅患有重度抑郁症的样本存在差异关联（β= -0.08；95%置信区间：-0.11，-0.03）；然而，对于合并重度抑郁症的PRS，未观察到这种差异关联。对于仅患有焦虑症的PRS，观察到与焦虑和抑郁症状存在类似的差异关联模式，但对于合并重度抑郁症的PRS则未观察到。
当分析中排除合并症病例时，焦虑症和重度抑郁症的遗传学及潜在生物学特性更为不同，并揭示出焦虑症可能是重度抑郁症的病因。这种因合并症导致的遗传关系混淆可能适用于其他精神疾病。特定疾病的基因研究可能有助于揭示更相关的生物学机制，并指导更有针对性的临床干预。
