PT - JOURNAL ARTICLE AU - Chang, Hsin-An AU - Fang, Wen-Hui AU - Liu, Yia-Ping AU - Tzeng, Nian-Sheng AU - Shyu, Jia-Fwu AU - Wan, Fang-Jung AU - Huang, San-Yuan AU - Chang, Tieh-Ching AU - Chang, Chuan-Chia TI - Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder AID - 10.1503/jpn.190092 DP - 2020 Nov 01 TA - Journal of Psychiatry and Neuroscience PG - 379--386 VI - 45 IP - 6 4099 - http://jpn.ca/content/45/6/379.short 4100 - http://jpn.ca/content/45/6/379.full SO - J Psychiatry Neurosci2020 Nov 01; 45 AB - Background: 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–control studies. In the present study, in addition to conventional case–control 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.Methods: 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’ tendency toward neuroticism.Results: 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–control comparisons, we observed that the effect of tri-allelic genotype on GAD was significant, but only in women.Limitations: Participants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism.Conclusion: 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.