{"title":"Using human genetics to understand the epidemiological association between neuroticism and lung cancer.","authors":"Dongsheng Wu, Yongcheng Liu, Shuqiao Liu, Xiaohu Hao, Xin Li, Quan Zheng, Tengyong Wang, Yuchen Huang, Shiyou Wei, Jian Zhou, Lunxu Liu","doi":"10.21037/tlcr-24-950","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Neuroticism, a personality trait characterized by emotional instability, has been linked to an increased risk of lung cancer (LC). However, the genetic underpinnings of this association remain poorly understood. This study aimed to comprehensively dissect the genetic link underlying neuroticism and LC.</p><p><strong>Methods: </strong>We used genome-wide association study (GWAS) data to investigate the intricate genetic relationship between neuroticism and LC, along with specific histological subtypes: lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small-cell LC (SCLC). Our analytical framework encompassed global and local genetic correlation, cross-trait meta-analysis, transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) analysis.</p><p><strong>Results: </strong>Notable genetic correlations were found between neuroticism and overall LC (r<sub>g</sub>=0.15, P=2.24×10<sup>-5</sup>), with stronger associations observed for LUSC (r<sub>g</sub>=0.21, P=3.39×10<sup>-6</sup>) and SCLC (r<sub>g</sub>=0.16, P=2.50×10<sup>-3</sup>). Partitioning the genome revealed additional genetic correlations in specific local genomic regions (including chr6q27 and chr6q16.2-q16.3) and functional categories (such as H3K27ac and H3K9ac). The cross-trait meta-analysis revealed 24 genetic loci that influenced both traits, including four novel ones. Looking into the gene-tissue level, TWAS identified 35 genes associated with both neuroticism and LC across multiple tissues, particularly in the nervous, respiratory, cardiovascular, and endocrine systems. MR analysis indicated a potential causal effect of neuroticism on overall LC [odds ratio (OR) =1.48, P=5.53×10<sup>-4</sup>] and LUSC (OR =1.52, P=8.00×10<sup>-3</sup>), but not on LUAD or SCLC. No reverse causality was observed.</p><p><strong>Conclusions: </strong>This study reveals a genetic link between neuroticism and LC, offering new insights into LC risk assessment and potential prevention strategies for individuals with high neuroticism levels.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 4","pages":"1104-1117"},"PeriodicalIF":4.0000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082198/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational lung cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21037/tlcr-24-950","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/15 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Neuroticism, a personality trait characterized by emotional instability, has been linked to an increased risk of lung cancer (LC). However, the genetic underpinnings of this association remain poorly understood. This study aimed to comprehensively dissect the genetic link underlying neuroticism and LC.
Methods: We used genome-wide association study (GWAS) data to investigate the intricate genetic relationship between neuroticism and LC, along with specific histological subtypes: lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small-cell LC (SCLC). Our analytical framework encompassed global and local genetic correlation, cross-trait meta-analysis, transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) analysis.
Results: Notable genetic correlations were found between neuroticism and overall LC (rg=0.15, P=2.24×10-5), with stronger associations observed for LUSC (rg=0.21, P=3.39×10-6) and SCLC (rg=0.16, P=2.50×10-3). Partitioning the genome revealed additional genetic correlations in specific local genomic regions (including chr6q27 and chr6q16.2-q16.3) and functional categories (such as H3K27ac and H3K9ac). The cross-trait meta-analysis revealed 24 genetic loci that influenced both traits, including four novel ones. Looking into the gene-tissue level, TWAS identified 35 genes associated with both neuroticism and LC across multiple tissues, particularly in the nervous, respiratory, cardiovascular, and endocrine systems. MR analysis indicated a potential causal effect of neuroticism on overall LC [odds ratio (OR) =1.48, P=5.53×10-4] and LUSC (OR =1.52, P=8.00×10-3), but not on LUAD or SCLC. No reverse causality was observed.
Conclusions: This study reveals a genetic link between neuroticism and LC, offering new insights into LC risk assessment and potential prevention strategies for individuals with high neuroticism levels.
期刊介绍：
Translational Lung Cancer Research(TLCR, Transl Lung Cancer Res, Print ISSN 2218-6751; Online ISSN 2226-4477) is an international, peer-reviewed, open-access journal, which was founded in March 2012. TLCR is indexed by PubMed/PubMed Central and the Chemical Abstracts Service (CAS) Databases. It is published quarterly the first year, and published bimonthly since February 2013. It provides practical up-to-date information on prevention, early detection, diagnosis, and treatment of lung cancer. Specific areas of its interest include, but not limited to, multimodality therapy, markers, imaging, tumor biology, pathology, chemoprevention, and technical advances related to lung cancer.
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