PT  - JOURNAL ARTICLE
AU  - Tempei Ikegame
AU  - Miki Bundo
AU  - Naohiro Okada
AU  - Yui Murata
AU  - Shinsuke Koike
AU  - Hiroko Sugawara
AU  - Takeo Saito
AU  - Masashi Ikeda
AU  - Keiho Owada
AU  - Masaki Fukunaga
AU  - Fumio Yamashita
AU  - Daisuke Koshiyama
AU  - Tatsunobu Natsubori
AU  - Norichika Iwashiro
AU  - Tatsuro Asai
AU  - Akane Yoshikawa
AU  - Fumichika Nishimura
AU  - Yoshiya Kawamura
AU  - Jun Ishigooka
AU  - Chihiro Kakiuchi
AU  - Tsukasa Sasaki
AU  - Osamu Abe
AU  - Ryota Hashimoto
AU  - Nakao Iwata
AU  - Hidenori Yamasue
AU  - Tadafumi Kato
AU  - Kiyoto Kasai
AU  - Kazuya Iwamoto
TI  - Promoter activity-based case-control association study on <em>SLC6A4</em> highlighting hypermethylation and altered amygdala volume in male patients with schizophrenia
AID  - 10.1101/2020.05.06.058792
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.06.058792
4099  - http://biorxiv.org/content/early/2020/05/08/2020.05.06.058792.short
4100  - http://biorxiv.org/content/early/2020/05/08/2020.05.06.058792.full
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.