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. 2025 Mar 3;24(1):11.
doi: 10.1186/s12991-025-00551-3.

Genetic overlap between schizophrenia and constipation: insights from a genome-wide association study in a European population

Qinghua Luo #  1   2 , Mingwei An #  3 , Yunxiang Wu  3 , Jiawen Wang  1 , Yuanting Mao  2   3 , Leichang Zhang  4   5 , Chen Wang  6
Affiliations

Genetic overlap between schizophrenia and constipation: insights from a genome-wide association study in a European population

Qinghua Luo et al. Ann Gen Psychiatry. .

Abstract

Background: Patients with schizophrenia (SCZ) experience constipation at significantly higher rates compared with the general population. This relationship suggests a potential genetic overlap between these two conditions.

Methods: We analyzed genome-wide association study (GWAS) data for both SCZ and constipation using a five-part approach. The first and second parts assessed the overall and local genetic correlations using methods such as linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics (HESS). The third part investigated the causal association between the two traits using Mendelian randomization (MR). The fourth part employed conditional/conjunctional false discovery rate (cond/conjFDR) to analyze the genetic overlap with different traits based on the statistical theory. Finally, an LDSC-specifically expressed gene (LDSC-SEG) analysis was conducted to explore the tissue-level associations.

Results: Our analyses revealed both overall and specific genetic correlations between SCZ and constipation at the genomic level. The MR analysis suggests a positive causal relationship between SCZ and constipation. The ConjFDR analysis confirms the genetic overlap between the two conditions and identifies two genetic risk loci (rs7583622 and rs842766) and seven mapped genes (GPR75-ASB3, ASB3, CHAC2, ERLEC1, GPR75, PSME4, and ACYP2). Further investigation into the functions of these genes could provide valuable insights. Interestingly, disease-related tissue analysis revealed associations between SCZ and constipation in eight brain regions (substantia nigra, anterior cingulate cortex, hypothalamus, cortex, hippocampus, cortex, amygdala, and spinal cord).

Conclusion: This study provides the first genetic evidence for the comorbidity of SCZ and constipation, enhancing our understanding of the pathophysiology of both conditions.

Keywords: Constipation; Genetic Overlap; Genetic structure; Gut-brain axis; Schizophrenia.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. The data used for analysis were obtained from published studies and public databases. The GWAS database is a database of publicly available datasets, where each study has been approved by local institutional review boards and ethics committees. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
HESS analysis of SCZ and constipation. The top and middle sections of each subgraph represent local genetic correlations and covariances, respectively, and the colored bars represent loci with significant local genetic correlations and covariances. The bottom portion represents the local snp heritability of an individual trait, and the colored bars represent loci with significant local snp heritability. SCZ, schizophrenia
Fig. 2
Fig. 2
The MR analysis results of SCZ and constipation.SCZ, schizophrenia
Fig. 3
Fig. 3
(A) Forest plot for the leave-one-out analysis of SCZ on constipation. (B) Forest plot for the leave-one-out analysis of constipation on SCZ.SCZ, schizophrenia
Fig. 4
Fig. 4
Conditional quantile-quantile plot. The dashed line indicates the expected line under the null hypothesis, and the deflection to the left indicates the degree of pleiotropic enrichment. SCZ, schizophrenia
Fig. 5
Fig. 5
ConjFDR Manhattan plot. The shared risk loci between SCZ and constipation were marked. The statistically significant causality is defined to be conjFDR < 0.05. SCZ, schizophrenia
Fig. 6
Fig. 6
Mapping genes and their co-expression genes were analyzed via GeneMANIA
Fig. 7
Fig. 7
Tissues enrichment results of SCZ (A) and constipation (B) using gene expression data of 53 tissues from GTEx. SCZ, schizophrenia
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