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

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

J Psychiatry Neurosci 2020;45(6):379-386 | PDF | Appendix

Hsin-An Chang, MD; Wen-Hui Fang, MD; Yia-Ping Liu, MD, PhD; Nian-Sheng Tzeng, MD; Jia-Fwu Shyu, MD, PhD; Fang-Jung Wan, MD, PhD; San-Yuan Huang, MD, PhD; Tieh-Ching Chang, NP; Chuan-Chia Chang, MD, PhD

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.


Submitted May 7, 2019; Revised Oct. 3, 2019; Accepted Jan. 12, 2020; Published online Apr. 15, 2020

Acknowledgments: The authors thank Ms. Hsiao-Hsin Hung for her assistance in preparing this manuscript. This study was supported in part by grants from the Medical Affairs Bureau of the Ministry of National Defense, Taipei, Taiwan (MAB-104-074), the Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (TSGH-C105-122) and the Ministry of Science and Technology of Taiwanese Government (MOST-107-2314-B-016-050).

Affiliations: From the Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (H.-A. Chang, Liu, Tzeng, Shyu, Wan, Huang, T.-C. Chang, C.-C. Chang); the Department of Family and Community Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Fang); the Department of Psychiatry, Cheng Hsin General Hospital, Taipei, Taiwan (Liu); the Laboratory of Cognitive Neuroscience, Department of Physiology, National Defense Medical Center, Taipei, Taiwan (Liu); and the Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan (Shyu).

Competing interests: None declared.

Contributors: H.-A. Chang, W.-H. Fang and C.-C. Chang designed the study. H.-A. Chang, W.-H. Fang, T.-C. Chang and C.-C. Chang acquired the data, which H.-A. Chang, W.-H. Fang, Y.-P. Liu, N.-S. Tzeng, J.-F. Shyu, F.-J. Wan, S.-Y. Huang and C.-C. Chang analyzed. H.-A. Chang, W.-H. Fang and C.-C. Chang wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.190092

Correspondence to: C.C. Chang, Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Nei-Hu District, Taipei 114, Taiwan; changcc@ndmctsgh.edu.tw