Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia

Abstract

Background: Numerous studies highlight the genetic underpinnings of mental disorders comorbidity, particularly in anxiety, depression, and schizophrenia. However, their shared genetic loci are not well understood. Our study employs Mendelian randomization (MR) and colocalization analyses, alongside multi-omics data, to uncover potential genetic targets for these conditions, thereby informing therapeutic and drug development strategies.

Methods: We utilized the Consortium for Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) analysis to investigate genetic correlations among anxiety, depression, and schizophrenia. Utilizing GTEx V8 eQTL and deCODE Genetics pQTL data, we performed a three-step summary-data-based Mendelian randomization (SMR) and protein-protein interaction analysis. This helped assess causal and comorbid loci for these disorders and determine if identified loci share coincidental variations with psychiatric diseases. Additionally, phenome-wide association studies, drug prediction, and molecular docking validated potential drug targets.

Results: We found genetic correlations between anxiety, depression, and schizophrenia, and under a meta-analysis of MR from multiple databases, the causal relationships among these disorders are supported. Based on this, three-step SMR and colocalization analyses identified ITIH3 and CCS as being related to the risk of developing depression, while CTSS and DNPH1 are related to the onset of schizophrenia. BTN3A1, PSMB4, and TIMP4 were identified as comorbidity loci for both disorders. Molecules that could not be determined through colocalization analysis were also presented. Drug prediction and molecular docking showed that some drugs and proteins have good binding affinity and available structural data.

Conclusions: Our study indicates genetic correlations and shared risk loci between anxiety, depression, and schizophrenia. These findings offer insights into the underlying mechanisms of their comorbidities and aid in drug development.

Keywords: Anxiety; Depression; Drug targets; Schizophrenia; Shared genetic architecture.

Fig. 1

Study design. SNP, single nucleotide polymorphism; SMR, summary-data-based mendelian randomization; PPI, Protein–Protein Interaction

Fig. 2

Summary of MR and LDSC analysis results between anxiety disorder, depression, and schizophrenia. a Results of MR Analysis of anxiety and other two diseases; b Results of MR Analysis of depression and other two diseases; c Results of MR Analysis of schizophrenia and other two diseases; d LDSC analysis using GWAS data from PGC database; e LDSC analysis using GWAS data from Finngen database.MR, Mendelian randomization; LDSC, linkage disequilibrium score regression

Fig. 3

Manhattan plots depicting the use of SMR to screen for QTLs in whole blood related to anxiety, depression, and schizophrenia. a Manhattan plots depicting eQTLs in whole blood related to anxiety; b Manhattan plots depicting pQTLs in whole blood related to anxiety; c Manhattan plots depicting eQTLs in whole blood related to depression; d Manhattan plots depicting pQTLs in whole blood related to depression; e Manhattan plots depicting eQTLs in whole blood related to schizophrenia; f Manhattan plots depicting pQTLs in whole blood related to schizophrenia. SMR, Summary-data-based Mendelian Randomization; eQTL, expression quantitative trait loci; pQTL, Protein Quantitative Trait Loci. Chr, Chromosome

Fig. 4

Core Site Analysis and Verification. a PPI analysis on the loci identified through SMR analysis for depression; b PPI analysis on the loci identified through SMR analysis for schizophrenia; c comorbidity sites between depression and schizophrenia; d Three-step SMR Analysis sites for depression; e Three-step SMR Analysis sites for schizophrenia. PPI, Protein–Protein Interaction; SMR, Summary-data-based Mendelian Randomization

Fig. 5

Circular dendrogram displaying the findings of PheWAS analysis. a Results of PheWAS for sites related to anxiety; b Results of PheWAS for sites related to depression; c Results of PheWAS for sites related to schizophrenia; d Results of PheWAS on comorbid-related loci for depression and schizophrenia. PheWAS, phenome-Wide Association Studies

Fig. 6

Docking results of available proteins small molecules. a CTSS docking Fostamatinib; b CTSS docking Petesicatib; c NT5C2 docking Pentoxifylline; d NT5C2 docking Cytarabine; e NT5C2 docking Didanosine; f NT5C2 docking Mercaptopurine; g NT5C2 docking Nelarabine; h PSMA4 docking Cotinine; i CYP21A2 docking Ketoconazole. (The PDB number of CTSS is 1GLO, the PDB number of NT5C2 is 2J2C, and the PDB number of CYP21A2 is 5VBU)