RT Journal Article
SR Electronic
T1 Promoter activity-based case-control association study on <em>SLC6A4</em> highlighting hypermethylation and altered amygdala volume in male patients with schizophrenia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.06.058792
DO 10.1101/2020.05.06.058792
A1 Tempei Ikegame
A1 Miki Bundo
A1 Naohiro Okada
A1 Yui Murata
A1 Shinsuke Koike
A1 Hiroko Sugawara
A1 Takeo Saito
A1 Masashi Ikeda
A1 Keiho Owada
A1 Masaki Fukunaga
A1 Fumio Yamashita
A1 Daisuke Koshiyama
A1 Tatsunobu Natsubori
A1 Norichika Iwashiro
A1 Tatsuro Asai
A1 Akane Yoshikawa
A1 Fumichika Nishimura
A1 Yoshiya Kawamura
A1 Jun Ishigooka
A1 Chihiro Kakiuchi
A1 Tsukasa Sasaki
A1 Osamu Abe
A1 Ryota Hashimoto
A1 Nakao Iwata
A1 Hidenori Yamasue
A1 Tadafumi Kato
A1 Kiyoto Kasai
A1 Kazuya Iwamoto
YR 2020
UL http://biorxiv.org/content/early/2020/05/08/2020.05.06.058792.abstract
AB Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using three independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all three cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.Competing Interest StatementThe authors have declared no competing interest.