title: Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles.
abstract: The serotonin transporter (SERT) gene-linked polymorphic region (5-HTTLPR) has been implicated in moderating the link between life stress and depression. However, respective molecular pathways of gene-environment (GxE) interaction are largely unknown. Sustained alterations in SERT gene expression profiles, possibly mediated by epigenetic modifications, are a frequent correlate of depression and may thus constitute a putative mediator of GxE interaction. Here, we aimed to investigate joint effects of 5-HTTLPR and self-reported environmental adversity throughout the lifespan (prenatal, early and recent stress/trauma) on in vivo SERT mRNA expression in peripheral blood cells. To further evaluate whether environmentally induced changes in SERT expression are mediated by epigenetic modifications, we analyzed 83 CpG sites within a 799-bp promoter-associated CpG island of the SERT gene using the highly sensitive method of bisulfite pyrosequencing. Participants were 133 healthy young adults. Our findings show that both the 5-HTTLPR S allele and maternal prenatal stress/child maltreatment are associated with reduced in vivo SERT mRNA expression in an additive manner. Remarkably, individuals carrying both the genetic and the environmental risk factors exhibited 32.8% (prenatal stress) and 56.3% (child maltreatment) lower SERT mRNA levels compared with those without any risk factor. Our data further indicated that changes in SERT mRNA levels were unlikely to be mediated by DNA methylation profiles within the SERT CpG island. It is thus conceivable that the persistent changes in SERT expression may in turn relate to altered serotonergic functioning and possibly convey differential disease vulnerability associated with 5-HTTLPR and early adversity.
authors.affiliation: Department of Biopsychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wankerl
authors.affiliation: Department of Biopsychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: R
authors.identifier: 0000000286655248
authors.initials: R
authors.lastname: Miller
authors.affiliation: Department of Biopsychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kirschbaum
authors.affiliation: Department of Psychology, Center for Psychobiology and Behavioral Medicine, University of Giessen, Giessen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hennig
authors.affiliation: Department of Biopsychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Stalder
authors.affiliation: Department of Biopsychology, Technische Universität Dresden, Dresden, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Alexander
mesh_terms: D000328:Adult; D002648:Child; D002649:Child Abuse / Q000523:psychology*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D003863:Depression; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins