Identification and functional characterization of the extremely long allele of the serotonin transporter-linked polymorphic region

Tempei Ikegame,Masashi Ikeda,Yutaka Nakachi,Yosuke Hidaka,Mamoru Hashimoto,Hiroko Sugawara,Minoru Takebayashi,Chihiro Kakiuchi,Tatsuro Asai,Miki Bundo,Satoshi Takeo ,Takeshi Kato ,Nakao Iwata,Kiyoto Kasai ,Tsukasa Sasaki,Y Murata ,Emi Kiyota,Tomohisa Ishikawa,Risa Watanabe,Kazuya Iwamoto

doi:10.1038/s41398-021-01242-9

Abstract

SLC6A4, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (N = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL28-A. An in vitro luciferase assay revealed that XL28-A has no transcriptional activity. XL28-A was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL28-A is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.

Highlights

The serotonin transporter (5-HTT) encoded by SLC6A4 is a key molecule that regulates serotonergic neurotransmission at the synaptic cleft, affecting emotions and stress responses
Human studies indicate that dysregulation of 5-HTT in the serotonergic system is implicated in the emotional and behavioral disturbances of psychiatric disorders, including anxiety, depression, bipolar disorders (BD), schizophrenia (SZ), and autism[4]
We examined rare alleles (AF < 5%) and found three known S variants (S14-B, S14-D and S14-E), one known L variant (L16-B), and three known XL alleles (XL19-A, XL20-A, and XL22-A)

Summary

Introduction

The serotonin transporter (5-HTT) encoded by SLC6A4 is a key molecule that regulates serotonergic neurotransmission at the synaptic cleft, affecting emotions and stress responses. Human studies indicate that dysregulation of 5-HTT in the serotonergic system is implicated in the emotional and behavioral disturbances of psychiatric disorders, including anxiety, depression, bipolar disorders (BD), schizophrenia (SZ), and autism[4]. SLC6A4 has a functional polymorphism (serotonin transporter-linked polymorphic region, 5-HTTLPR) in its promoter region. Most of the studies and several meta-analyses claimed that the S allele confers sensitivity to environmental stress, which in turn increases vulnerability to anxiety and depressive symptoms[10,11,12], it remains controversial[13,14], and the recent largest meta-analysis and case-control studies failed to replicate this finding[15,16]

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Results

Conclusion