Slc6a4, also known as the serotonin transporter gene, encodes the serotonin transporter (5-HTT, SERT), which modulates serotonin activity via sodium-dependent reuptake [3]. Serotonin is crucial in controlling pain, emotional, endocrine, and personality characteristics, and is involved in many physiological and pathological processes [3,4].

The SLC6A4 polymorphism has been associated with various psychiatric traits such as an increased risk of post-traumatic stress disorder, higher likelihood for depression, obsessive-compulsive disorder (OCD), increased hostility and criminal behaviour [6]. Its epigenetic alterations, like DNA hypermethylation, are related to schizophrenia pathophysiology [1]. Also, its functional nucleotide variations are associated with certain pathologic pain conditions [3]. Some studies found no association between SLC6A4 promoter and intron 2 variants and the risk of temporal lobe epilepsy, though the intron 2 VNTR seems to have opposite effects in different populations [2]. The SLC6A4 promoter polymorphism is not associated with alcohol dependence [5]. In addition, the SLC6A4 short/short allele amplifies the risk of anxiety-related mental illness when children experience food insecurity [7].

In conclusion, Slc6a4 is essential for regulating serotonin levels, which impacts multiple physiological and pathological processes. Studies on Slc6a4, including those on its polymorphisms and epigenetic changes, have provided insights into its role in various psychiatric and pain-related conditions, helping us better understand the underlying mechanisms of these diseases.

References:

1. Liu, Linlin, Hu, Yi, Lu, Yumei, Gao, Changqing, Nie, Shengjie. 2021. Sex-dependent DNA hypermethylation of SLC6A4 in patients with schizophrenia. In Neuroscience letters, 769, 136394. doi:10.1016/j.neulet.2021.136394. https://pubmed.ncbi.nlm.nih.gov/34910986/

2. Córdoba, Marta, Consalvo, Damián, Moron, Dolores Gonzalez, Kochen, Silvia, Kauffman, Marcelo Andrés. 2012. SLC6A4 gene variants and temporal lobe epilepsy susceptibility: a meta-analysis. In Molecular biology reports, 39, 10615-9. doi:10.1007/s11033-012-1949-5. https://pubmed.ncbi.nlm.nih.gov/23065262/

3. Huang, Cary, van Wijnen, Andre J, Im, Hee-Jeong. 2023. Serotonin Transporter (5-Hydroxytryptamine Transporter, SERT, SLC6A4) and Sodium-dependent Reuptake Inhibitors as Modulators of Pain Behaviors and Analgesic Responses. In The journal of pain, 25, 618-631. doi:10.1016/j.jpain.2023.10.008. https://pubmed.ncbi.nlm.nih.gov/37852405/

4. Murphy, Dennis L, Moya, Pablo R. 2011. Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional G×G and G×E differences in health and disease. In Current opinion in pharmacology, 11, 3-10. doi:10.1016/j.coph.2011.02.008. https://pubmed.ncbi.nlm.nih.gov/21439906/

5. Villalba, Karina, Attonito, Jennifer, Mendy, Angelico, Gasana, Janvier, Dorak, Tevfik M. . A meta-analysis of the associations between the SLC6A4 promoter polymorphism (5HTTLPR) and the risk for alcohol dependence. In Psychiatric genetics, 25, 47-58. doi:10.1097/YPG.0000000000000078. https://pubmed.ncbi.nlm.nih.gov/25710844/

6. Hande, Shyamala H, Krishna, Swathy M, Sahote, Komalroop Kaur, Ravidhran, Renuka, Das, Ranajit. . Population genetic variation of SLC6A4 gene, associated with neurophysiological development. In Journal of genetics, 100, . doi:. https://pubmed.ncbi.nlm.nih.gov/33764333/

7. Pilkay, S, Nolasco, M, Nunes, S, Trexler, N, Gump, B. . SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health. In Brain and behavior, 14, e3426. doi:10.1002/brb3.3426. https://pubmed.ncbi.nlm.nih.gov/38361316/