title: Serotonin transporter gene methylation is associated with hippocampal gray matter volume.
abstract: BACKGROUND
  The serotonin transporter (5-HTT) and the 5-HTTLPR/rs25531 polymorphisms in its gene (SLC6A4) have been associated with depression, increased stress-response, and brain structural alterations such as reduced hippocampal volumes. Recently, epigenetic processes including SLC6A4 promoter methylation were shown to be affected by stress, trauma, or maltreatment and are regarded to be involved in the etiology of affective disorders. However, neurobiological correlates of SLC6A4 promoter methylation have never been studied or compared to genotype effects by means of human neuroimaging hitherto
  
  
  METHODS
  Healthy subjects were recruited in two independent samples (N = 94, N = 95) to obtain structural gray matter images processed by voxel-based morphometry (VBM8), focusing on hippocampal, amygdala, and anterior cingulate gyrus gray matter structure. SLC6A4 promoter methylation within an AluJb element and 5-HTTLPR/rs25531 genotypes were analyzed in view of a possible impact on local gray matter volume
  
  
  RESULTS
  Strong associations of AluJb methylation and hippocampal gray matter volumes emerged within each sample separately, which in the combined sample withstood most conservative alpha-corrections for the entire brain. The amygdala, insula, and caudate nucleus showed similar associations. The 5-HTTLPR/rs25531 showed no main effect on gray matter, and the effect of methylation rates on hippocampal structure was comparable among the genotype groups
  
  
  CONCLUSIONS
  Methylation within the AluJb appears to have strong effects on hippocampal gray matter volumes, indicating that epigenetic processes can alter brain structures crucially involved in stress-related disorders. Different ways of regulating SLC6A4 expression might involve exonization or transcription factor binding as potentially underlying mechanisms, which, however, is speculative and warrants further investigation.
authors.affiliation: Department of Psychiatry, University of Münster, Münster, Germany; Department of Psychiatry, University of Marburg, Marburg, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Dannlowski
authors.forename: Harald
authors.initials: H
authors.lastname: Kugel
authors.forename: Ronny
authors.initials: R
authors.lastname: Redlich
authors.forename: Adriane
authors.initials: A
authors.lastname: Halik
authors.forename: Ilona
authors.initials: I
authors.lastname: Schneider
authors.forename: Nils
authors.initials: N
authors.lastname: Opel
authors.forename: Dominik
authors.initials: D
authors.lastname: Grotegerd
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwarte
authors.forename: Christiane
authors.initials: C
authors.lastname: Schettler
authors.forename: Oliver
authors.initials: O
authors.lastname: Ambrée
authors.forename: Stephan
authors.initials: S
authors.lastname: Rust
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.forename: Walter
authors.initials: W
authors.lastname: Heindel
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
authors.forename: Thomas
authors.initials: T
authors.lastname: Suslow
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.forename: Christa
authors.initials: C
authors.lastname: Hohoff
mesh_terms: D000328:Adult; D001931:Brain Mapping; D019175:DNA Methylation / Q000502:physiology*; D005260:Female; D005838:Genotype; D066128:Gray Matter / Q000033:anatomy & histology*; D006624:Hippocampus / Q000033:anatomy & histology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins
keywords: 5-HTTLRP; Alu element; DNA methylation; MRI; epigenetics; hippocampus