TY - JOUR
T1 - Identification and functional characterization of the extremely long allele of the serotonin transporter-linked polymorphic region
AU - Ikegame, Tempei
AU - Hidaka, Yosuke
AU - Nakachi, Yutaka
AU - Murata, Yui
AU - Watanabe, Risa
AU - Sugawara, Hiroko
AU - Asai, Tatsuro
AU - Kiyota, Emi
AU - Saito, Takeo
AU - Ikeda, Masashi
AU - Sasaki, Tsukasa
AU - Hashimoto, Mamoru
AU - Ishikawa, Tomohisa
AU - Takebayashi, Minoru
AU - Iwata, Nakao
AU - Kakiuchi, Chihiro
AU - Kato, Tadafumi
AU - Kasai, Kiyoto
AU - Bundo, Miki
AU - Iwamoto, Kazuya
N1 - Funding Information:
We would like to thank the following researchers for the sample collection: Akane Yoshikawa, Fumichika Nishimura, and Yoshiya Kawamura. This work was partly supported by Japan Society for the Promotion of Science KAKENHI (16H06395, 16H06399, 16K21720, 18H02753, 18H05428, 18H05430, 18H05435, 18K07567, and 19K17056) and AMED (JP20dm0107097, JP20km0405201, JP20km0405208, JP20dm0107123, JP20dm0207074, JP20dk0207025, JP20dm0307001, JP20dm0307004, and JP20dm0207069). This work was supported in part by UTokyo Center for Integrative Science of Human Behavior (CiSHuB), and by the International Research Center for Neurointelligence (WPI-IRCN) at The University of Tokyo Institutes for Advanced Study (UTIAS).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
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U2 - 10.1038/s41398-021-01242-9
DO - 10.1038/s41398-021-01242-9
M3 - Article
C2 - 33574244
AN - SCOPUS:85100749484
VL - 11
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 1
M1 - 119
ER -