Body mass index, smoking behavior, and depression mediated the effects of schizophrenia on chronic obstructive pulmonary disease: trans-ethnic Mendelian-randomization analysis

Abstract

Background: Previous studies have highlighted the association between schizophrenia (SCZ) and chronic obstructive pulmonary disease (COPD), yet the causal relationship remains unestablished.

Methods: Under the genome-wide significance threshold (P<5×10-⁸), data from individuals of European (EUR) and East Asian (EAS) ancestries with SCZ were selected for analysis. Univariable Mendelian randomization (MR) explored the causal relationship between SCZ and COPD. Linkage disequilibrium score (LDSC) regression was used to calculate genetic correlation, while multivariable and mediation MR further investigated the roles of six confounding factors and their mediating effects. The primary method utilized was inverse-variance weighted (IVW), complemented by a series of sensitivity analyses and false discovery rate (FDR) correction.

Results: LDSC analysis revealed a significant genetic correlation between SCZ and COPD within EUR ancestry (r_g = 0.141, P = 6.16×10-⁷), with no such correlation found in EAS ancestry. IVW indicated a significant causal relationship between SCZ and COPD in EUR ancestry (OR = 1.042, 95% CI 1.013-1.071, P = 0.003, P_FDR = 0.015). Additionally, replication datasets provide evidence of consistent causal associations(P < 0.05 & P_FDR < 0.05). Multivariable and mediation MR analyses identified body mass index (BMI)(Mediation effect: 50.57%, P = 0.02), age of smoking initiation (Mediation effect: 27.42%, P = 0.02), and major depressive disorder (MDD) (Mediation effect: 60.45%, P = 6.98×10-⁵) as partial mediators of this causal relationship. No causal associations were observed in EAS (OR = 0.971, 95% CI 0.875-1.073, P = 0.571, P_FDR = 0.761) ancestry. No causal associations were found in the reverse analysis across the four ancestries (P > 0.05 & P_FDR > 0.05).

Conclusions: This study confirmed a causal relationship between SCZ and the risk of COPD in EUR ancestry, with BMI, smoking, and MDD serving as key mediators. Future research on a larger scale is necessary to validate the generalizability of these findings across other ancestries.

Keywords: Mendelian randomization; causality; chronic obstructive pulmonary disease; mediation analysis; schizophrenia.

Figure 1

Study design. SCZ, Schizophrenia; COPD, chronic obstructive pulmonary disease; BMI, body mass index; GSCAN, GWAS and Sequencing Consortium of Alcohol and Nicotine use; GIANT, Genetic Investigation of Anthropometric Traits; PGC, Psychiatric Genomics Consortium; CPD, cigarettes per day; ASI, age of smoking initiation; ADPW, Alcoholic drinks per week; TDI, Townsend deprivation index; GBMI, Global Biobank Meta-analysis Initiative; EUR, European; EAS, East Asian; MDD, Major depression disorder; MR-PRESSO, MR Pleiotropy Residual Sum and Outlier; IVW, inverse-variance-weighted; RAPS, robust adjusted profile score; CML, constrained maximum likelihood; dIVW, debiased inverse-variance weighted; SNP, single nucleotide polymorphism; IV, instrumental variable; MR, Mendelian randomization; UVMR, univariable MR; MVMR, multivariable MR; BWMR, Bayesian weighted Mendelian randomization.

Figure 2

Summary of univariable Mendelian randomization analysis. SCZ, Schizophrenia; COPD, chronic obstructive pulmonary disease; GBMI, Global Biobank Meta-analysis Initiative; EUR, European; EAS, East Asian; IVW, inverse-variance-weighted; RAPS, robust adjusted profile score; CML, constrained maximum likelihood; dIVW, debiased inverse-variance weighted; SNP, single nucleotide polymorphism; IV, instrumental variable; MR, Mendelian randomization; OR, Odds Ratio; CI, Confidence Interval; BWMR, Bayesian weighted Mendelian randomization.

Figure 3

Complete exclusion of outliers by RadialMR-assisted MR-PRESSO in the EUR. (A) SCZ→COPD(GBMI), (B) SCZ→COPD(FinnGen). SCZ, Schizophrenia; COPD, chronic obstructive pulmonary disease; GBMI, Global Biobank Meta-analysis Initiative; EUR, European; MR-PRESSO, MR Pleiotropy Residual Sum and Outlier.

Figure 4

Results after thorough exclusion of outliers by RadialMR in the EUR pedigree. SCZ, Schizophrenia; COPD, chronic obstructive pulmonary disease; GBMI, Global Biobank Meta-analysis Initiative; EUR, European; IVW, inverse-variance-weighted; RAPS, robust adjusted profile score; CML, constrained maximum likelihood; dIVW, debiased inverse-variance weighted; SNP, single nucleotide polymorphism; MR, Mendelian randomization; OR, Odds Ratio; CI, Confidence Interval; BWMR, Bayesian weighted Mendelian randomization.