Sex-specific pathways among tri-allelic serotonin transporter polymorphism, trait neuroticism and generalized anxiety disorder

• Published in: Journal of psychiatry & neuroscience 2020-11, Vol.45 (6), p.379-386
• Main Authors: Chang, Hsin-An, MD, Fang, Wen-Hui, MD, Liu, Yia-Ping, MD, PhD, Tzeng, Nian-Sheng, MD, Shyu, Jia-Fwu, MD, PhD, Wan, Fang-Jung, MD, PhD, Huang, San-Yuan, MD, PhD, Chang, Tieh-Ching, NP, Chang, Chuan-Chia, MD, PhD
• Format: Article
• Language: English
• Subjects: Anxiety; Anxiety disorders; Cardiovascular disease; Chronic illnesses; Comorbidity; Demographic aspects; Gene polymorphism; Generalized anxiety disorder; Genetic aspects; Genetic polymorphisms; Genotype & phenotype; Health aspects; Likert scale; Mental disorders; Neurosis; Neuroticism; Personality; Personality traits; Physiological aspects; Polymerase chain reaction; Polymorphism; Psychiatric/Mental Health; Psychological aspects; Research Paper; Restriction fragment length polymorphism; Serotonin; Serotonin transporter; Sex differences (Psychology); Transport proteins; Twins; Womens health
• ISSN: 1180-4882; 1488-2434
• DOI: 10.1503/jpn.190092

ABSTRACTBackgroundNeuroticism 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. MethodsWe 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. ResultsUsing 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. LimitationsParticipants were restricted to Han Chinese, and we used only 1 questionnaire to assess neuroticism. ConclusionThese 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.