Neuroticism Increases the Risk of Stroke: Mendelian Randomization Study

HomeStrokeVol. 52, No. 11Neuroticism Increases the Risk of Stroke: Mendelian Randomization Study Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBNeuroticism Increases the Risk of Stroke: Mendelian Randomization Study Yaozhong Liu, MD, Peng Cheng, MD, Na Liu, MD, Biao Li, MD, Yingxu Ma, MD, Wanyun Zuo, MD and Qiming Liu, MD Yaozhong LiuYaozhong Liu https://orcid.org/0000-0001-6187-6055 Department of Cardiovascular Medicine (Y.L., N.L., B.L., Y.M., W.Z., Q.L.), Second Xiangya Hospital, Central South University, Hunan Province, China. , Peng ChengPeng Cheng Department of Psychiatry (P.C.), Second Xiangya Hospital, Central South University, Hunan Province, China. , Na LiuNa Liu Department of Cardiovascular Medicine (Y.L., N.L., B.L., Y.M., W.Z., Q.L.), Second Xiangya Hospital, Central South University, Hunan Province, China. , Biao LiBiao Li Department of Cardiovascular Medicine (Y.L., N.L., B.L., Y.M., W.Z., Q.L.), Second Xiangya Hospital, Central South University, Hunan Province, China. , Yingxu MaYingxu Ma Department of Cardiovascular Medicine (Y.L., N.L., B.L., Y.M., W.Z., Q.L.), Second Xiangya Hospital, Central South University, Hunan Province, China. , Wanyun ZuoWanyun Zuo Department of Cardiovascular Medicine (Y.L., N.L., B.L., Y.M., W.Z., Q.L.), Second Xiangya Hospital, Central South University, Hunan Province, China. and Qiming LiuQiming Liu Correspondence to: Qiming Liu, MD, Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Rd, Changsha, Hunan 410011, P.R.China. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5213-2668 Department of Cardiovascular Medicine (Y.L., N.L., B.L., Y.M., W.Z., Q.L.), Second Xiangya Hospital, Central South University, Hunan Province, China. Originally published29 Sep 2021https://doi.org/10.1161/STROKEAHA.121.036131Stroke. 2021;52:e742–e743Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 29, 2021: Ahead of Print AbstractDownload figureDownload PowerPointNeuroticism describes a tendency to experience anxiety, depression, and other negative feelings. Whether it increases the risk of stroke is unclear. We assessed the causal relationship between neuroticism and stroke by applying 2-sample Mendelian randomization (MR). Analyses were performed for any stroke; any ischemic stroke; and 3 ischemic stroke subtypes, including large artery stroke, small vessel stroke, and cardioembolic stroke. The summarized genetic results (n=150 765–446 696) were obtained from the International Stroke Genetics Consortium.1The genome-wide association study (GWAS) of neuroticism contained ≥366 276 UKB participants.2 We selected single-nucleotide polymorphisms associated with the weighted neuroticism sum-score at genome-wide significance (P<5×10−8). These single-nucleotide polymorphisms were clumped to ascertain independence. If a single-nucleotide polymorphism instrument was unavailable in the outcome data set, its proxy was identified.All analyses were performed using the TwoSampleMR package. Codes to replicate the results are available from the corresponding author upon reasonable request. The study design was approved by the Institutional Committee on Human Research at the Second Xiangya Hospital. This study relied on publicly available summary statistics from large-scale GWAS. Ethical approval and patient's written informed consent have been obtained for all original studies.In the conventional MR analysis (inverse-variance weighted method), and after correcting for multiple testing (P<0.01 [0.05/5]), 1-SD increase in genetic liability to neuroticism was associated with increased risks of large artery stroke (odds ratio [OR], 1.87 [95% CI, 1.27–2.78]; P=0.002) and small vessel stroke (OR, 1.59 [95% CI, 1.15–2.20]; P=0.005). At a significant threshold of P=0.05, neuroticism also increased the risks of any stroke (OR, 1.20 [95% CI, 1.03–1.40]; P=0.017), and any ischemic stroke (OR, 1.24 [95% CI, 1.05–1.46]; P=0.012). The Egger-intercept test indicated no directional pleiotropy. Sensitivity analyses using weighted median MR (Figure) and MR-Egger provided less precise estimates but had a similar direction and magnitude. We did not identify any causal association between neuroticism and cardioembolic stroke. One explanation is that most cases of cardioembolic stroke are caused by atrial fibrillation, which has a different risk factor profile to other subtypes. No significant association between genetically determined stroke and neuroticism was identified in the reverse MR analysis.Download figureDownload PowerPointFigure. Association between genetic liability to neuroticism and stroke. Odds ratios are expressed per 1-SD increase liability to neuroticism.Observational studies showed that neuroticism was positively associated with smoking behavior. We then conducted a network MR analysis. We obtained summary-level genetic data for smoking initiation from the GWAS and Sequencing Consortium of Alcohol and Nicotine Use. Traditional MR approach showed that neuroticism had a causal effect on smoking initiation (OR, 1.28 [95% CI, 1.15–1.42]; P=6.2×10−6) but not vice versa; and smoking had causal effects on any stroke (OR, 1.18 [95% CI, 1.08–1.30]; P=0.0005), any ischemic stroke (OR, 1.16 [95% CI, 1.06–1.28]; P=0.002), and large artery stroke (OR, 1.58 [95% CI, 1.27–1.97]; P=4.5×10−5). We then used multivariable MR to conduced a mediation analysis. The proportion of the total effect of neuroticism on any stroke, any ischemic stroke, and large artery stroke mediated through smoking was estimated to be 28.6%, 27.1%, and 31.5%, respectively.The strength of this study is the MR design and the use of the large GWASs of exposure and outcomes. This study has limitations. The results from an MR study can be violated by pleiotropy, which describes a genetic variant that is associated with multiple traits. However, the overall causal estimate based on all genetic variants is unlikely to be biased, as limited evidence supports the existence of directional pleiotropy, and sensitivity analyses yielded similar results. Another shortcoming is that all participants of the GWASs used in this study were of European ancestry, genetic studies in more general populations are expected to enhance the generalizability of the conclusion. Finally, we did not investigate the association between anxiety and depression with stroke. These psychiatric disorders overlapping from neuroticism may be relevant to the findings.In summary, genetic liability to neuroticism is associated with an increased risk of stroke, which is partially mediated by increasing smoking behavior.Nonstandard Abbreviations and AcronymsGWASgenome-wide association studyMRMendelian randomizationORodds ratioSources of FundingThis work was supported by the National Natural Science Foundation of China (no. 82070356).Disclosures None.FootnotesFor Sources of Funding and Disclosures, see page e743.Correspondence to: Qiming Liu, MD, Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Rd, Changsha, Hunan 410011, P.R.China. Email [email protected]edu.cnReferences1. Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, et al.; AFGen Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; International Genomics of Blood Pressure (iGEN-BP) Consortium; INVENT Consortium; STARNET; BioBank Japan Cooperative Hospital Group; COMPASS Consortium; EPIC-CVD Consortium; EPIC-InterAct Consortium; International Stroke Genetics Consortium (ISGC); METASTROKE Consortium; Neurology Working Group of the CHARGE Consortium; NINDS Stroke Genetics Network (SiGN); UK Young Lacunar DNA Study; MEGASTROKE Consortium. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018; 50:524–537. doi: 10.1038/s41588-018-0058-3CrossrefMedlineGoogle Scholar2. Nagel M, Watanabe K, Stringer S, Posthuma D, van der Sluis S. Item-level analyses reveal genetic heterogeneity in neuroticism.Nat Commun. 2018; 9:905. doi: 10.1038/s41467-018-03242-8Google Scholar Previous Back to top Next FiguresReferencesRelatedDetails November 2021Vol 52, Issue 11Article InformationMetrics Download: 243 © 2021 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.121.036131PMID: 34583526 Originally publishedSeptember 29, 2021 Keywordsanxietydepressionischemic strokeneuroticismstatisticsPDF download Advertisement SubjectsEpidemiologyIschemic Stroke