{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T02:05:05Z","timestamp":1773108305091,"version":"3.50.1"},"reference-count":55,"publisher":"Canadian Science Publishing","issue":"6","license":[{"start":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T00:00:00Z","timestamp":1604188800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.nrcresearchpress.com\/page\/about\/CorporateTextAndDataMining"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Psychiatry Neurosci"],"published-print":{"date-parts":[[2020,11]]},"abstract":"<jats:sec><jats:title>Background:<\/jats:title><jats:p> Neuroticism personality trait is recognized as an important endophenotypic predictor of generalized anxiety disorder (GAD). Furthermore, endophenotype-based pathway approaches have recently been shown to have greater advantages for gene-finding strategies than traditional case\u2013control studies. In the present study, in addition to conventional case\u2013control methods, we used pathway analyses to test whether the tri-allelic serotonin transporter promoter polymorphism (combining 5-HTTLPR and rs25531) is associated with risk of GAD through its effects on trait neuroticism. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p> We included 2236 Han Chinese adults in this study, including 736 patients with GAD and 1500 healthy participants. We genotyped the 5-HTTLPR and rs25531 polymorphisms using the polymerase chain reaction restriction fragment length polymorphism method. We used the Neuroticism scale of the Maudsley Personality Inventory (MPI) short version (MPI-Neuroticism) to measure participants\u2019 tendency toward neuroticism. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p> Using endophenotype-based path analyses, we found significant indirect effects of the tri-allelic genotype on risk of GAD, mediated by MPI-Neuroticism in both men and women. Compared to women carrying the S'S' genotype, women carrying the L' allele had higher levels of MPI-Neuroticism, which in turn were associated with higher risk of GAD. Men, however, showed the opposite pattern. Using traditional case\u2013control comparisons, we observed that the effect of tri-allelic genotype on GAD was significant, but only in women. <\/jats:p><\/jats:sec><jats:sec><jats:title>Limitations:<\/jats:title><jats:p> Participants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion:<\/jats:title><jats:p> These findings are the first to show that the tri-allelic 5-HTTLPR polymorphism is associated with elevated risk of GAD, and that this effect is mediated via increased trait neuroticism, a sex-dependent risk pathway. <\/jats:p><\/jats:sec>","DOI":"10.1503\/jpn.190092","type":"journal-article","created":{"date-parts":[[2020,10,30]],"date-time":"2020-10-30T12:35:07Z","timestamp":1604061307000},"page":"379-386","source":"Crossref","is-referenced-by-count":9,"title":["Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety 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