Enhanced polygenic risk score incorporating gene–environment interaction suggests the association of major depressive disorder with cardiac and lung function

• Published in: Briefings in bioinformatics Vol. 25; no. 2
• Main Authors: Pan, Chuyu, Cheng, Bolun, Qin, Xiaoyue, Cheng, Shiqiang, Liu, Li, Yang, Xuena, Meng, Peilin, Zhang, Na, He, Dan, Cai, Qingqing, Wei, Wenming, Hui, Jingni, Wen, Yan, Jia, Yumeng, Liu, Huan, Zhang, Feng
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 22.01.2024; Oxford Publishing Limited (England)
• Subjects: Cardiovascular diseases; Case Study; Depressive Disorder, Major - complications; Depressive Disorder, Major - genetics; Drinking behavior; Environmental factors; Gene-Environment Interaction; Genetic Risk Score; Genomes; Health risks; Humans; Lung; Lungs; Mental depression; Nucleotides; Regression analysis; Respiratory diseases; Respiratory function; Risk; Single-nucleotide polymorphism; Smoking; Smoking - adverse effects; cardiac function; polygenic and gene–environment interaction risk score (PGIRS); lung function; depression
• ISSN: 1467-5463; 1477-4054; 1477-4054
• DOI: 10.1093/bib/bbae070

Abstract Background Depression has been linked to an increased risk of cardiovascular and respiratory diseases; however, its impact on cardiac and lung function remains unclear, especially when accounting for potential gene–environment interactions. Methods We developed a novel polygenic and gene–environment interaction risk score (PGIRS) integrating the major genetic effect and gene–environment interaction effect of depression-associated loci. The single nucleotide polymorphisms (SNPs) demonstrating major genetic effect or environmental interaction effect were obtained from genome-wide SNP association and SNP-environment interaction analyses of depression. We then calculated the depression PGIRS for non-depressed individuals, using smoking and alcohol consumption as environmental factors. Using linear regression analysis, we assessed the associations of PGIRS and conventional polygenic risk score (PRS) with lung function (N = 42 886) and cardiac function (N = 1791) in the subjects with or without exposing to smoking and alcohol drinking. Results We detected significant associations of depression PGIRS with cardiac and lung function, contrary to conventional depression PRS. Among smokers, forced vital capacity exhibited a negative association with PGIRS (β = −0.037, FDR = 1.00 × 10−8), contrasting with no significant association with PRS (β = −0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (β = 0.088, FDR = 0.010), whereas no such association was found with PRS (β = 0.040, FDR = 0.265). Notably, in individuals who both smoked and drank, forced expiratory volume in 1-second demonstrated a negative association with PGIRS (β = −0.042, FDR = 6.30 × 10−9), but not with PRS (β = −0.003, FDR = 0.857). Conclusions Our findings underscore the profound impact of depression on cardiac and lung function, highlighting the enhanced efficacy of considering gene–environment interactions in PRS-based studies.