Facal Fernando, Costas Javier
Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Galicia, Spain; Servizo de Psiquiatría, Complexo Hospitalario Universitario de Santiago de Compostela, Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Galicia, Spain.
Instituto de Investigación Sanitaria (IDIS) de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saúde (SERGAS), Santiago de Compostela, Galicia, Spain.
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jan 10;136:111183. doi: 10.1016/j.pnpbp.2024.111183. Epub 2024 Oct 28.
While schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) genetically correlate, the pleiotropy underlying response/resistance to drugs used in these disorders has not been investigated. The aim of this study is to analyze the genetic relationship between treatment-resistant schizophrenia (TRS), response to lithium in BD (respLi) and response to antidepressants in MDD (respAD) using the conditional/conjunctional false discovery rate (cond/conjFDR) methodology, based on the hypothesis that shared mechanisms related to a common psychopathology factor underlie these phenotypes. A cross-trait polygenic enrichment for TRS conditioned on associations with respLi was observed. The conjFDR analysis identified rs11631065 (chr15:66654304) as a shared locus between them. One of the genes at this locus is MAP2K1, previously reported as associated with TRS after conditioning on body mass index genome-wide association study (GWAS). The set of genes at TRS-respLi conjFDR < 0.95 showed enrichment in response to psychotropic drugs in severe mental disorders from GWAS Catalog as well as in neurodevelopment and synaptic pathways. In conclusion, our study constitutes the first evidence of a transdiagnostic genetic signal associated with response to different pharmacological treatments in psychotic and affective disorders. It is necessary to confirm these results when larger GWAS of these phenotypes are available.
虽然精神分裂症（SCZ）、双相情感障碍（BD）和重度抑郁症（MDD）在基因上存在关联，但尚未对这些疾病中药物反应/耐药性背后的多效性进行研究。本研究的目的是基于共同精神病理学因素相关的共享机制是这些表型的基础这一假设，使用条件/联合错误发现率（cond/conjFDR）方法分析难治性精神分裂症（TRS）、BD对锂的反应（respLi）和MDD对抗抑郁药的反应（respAD）之间的遗传关系。观察到以与respLi的关联为条件的TRS的跨性状多基因富集。联合FDR分析确定rs11631065（chr15:66654304）是它们之间的一个共享位点。该位点的一个基因是MAP2K1，在基于全基因组关联研究（GWAS）的体重指数进行条件分析后，先前报道其与TRS相关。TRS-respLi联合FDR < 0.95的基因集在GWAS目录中严重精神障碍对精神药物的反应以及神经发育和突触途径中显示出富集。总之，我们的研究构成了与精神病性和情感性障碍中不同药物治疗反应相关的跨诊断遗传信号的首个证据。当有这些表型的更大规模GWAS时，有必要确认这些结果。
