title: Parent of origin effect and allelic expression imbalance of the serotonin transporter in bipolar disorder and suicidal behaviour.
abstract: Suicide and suicidal behaviour are a major health concern worldwide particularly in patients with mood disorders. Family, adoption and twin studies show that genetics influences suicidal behaviour. The serotonin transporter (5HTT) plays an important role in the pathophysiology of mood disorders and may also be involved in suicidal behaviour since 5HTT binding is decreased in the brain of suicide completers. Because the effect of genomic imprinting in the 5HTT gene on suicidal behaviour has not been investigated, we analysed the parent-of-origin effect (POE) of four 5HTT markers and the differential expression of the 5HTT G2651T (rs1042173) alleles in suicide attempters affected by bipolar disorder. We performed a family based association study and ETDT/QTDT analyses of the rs25531, HTTLPR, VNTR-2 and G2651T polymorphisms in 312 nuclear families with at least one subject affected by bipolar disorder. The main outcomes investigated in this study are bipolar disorder diagnosis, suicide attempts, suicidal behaviour severity and age at onset of bipolar disorder. We also compared the allele-specific mRNA levels in lymphoblastoid cells from 13 bipolar suicide attempters and 8 bipolar non-suicide attempters. Allele 2651T was transmitted significantly more often to bipolar patients (P = 0.042). There was no significant difference between maternal and paternal transmission ratios. Furthermore, there was no significant difference in the ratio of T/G-specific mRNA expression between bipolar attempters and non-attempters. These data do not support a role for differential allelic expression of 5HTT for suicidal behaviour in bipolar disorder. Small sample size and the fact that RNA was obtained from lymphoblastoid cell lines were some of the limitations of this study.
authors.affiliation: Neurobiology of Schizophrenia Section, Neuroscience Department, Centre for Addiction and Mental Health Toronto, Toronto, ON, Canada.
authors.forename: Crystal
authors.initials: C
authors.lastname: Pinto
authors.forename: Renan P
authors.initials: RP
authors.lastname: Souza
authors.forename: Diane
authors.initials: D
authors.lastname: Lioult
authors.forename: Mawahib
authors.initials: M
authors.lastname: Semeralul
authors.forename: James L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Warsh
authors.forename: Albert H
authors.initials: AH
authors.lastname: Wong
authors.forename: Vincenzo De
authors.initials: VD
authors.lastname: Luca
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D000437:Alcoholism / Q000150:complications / Q000523:psychology; D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D015870:Gene Expression / Q000502:physiology; D056726:Genetic Association Studies; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010290:Parents; D011110:Polymorphism, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D019966:Substance-Related Disorders / Q000150:complications / Q000523:psychology; D059020:Suicidal Ideation; D013406:Suicide, Attempted / Q000523:psychology*; D016896:Treatment Outcome
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D004247:DNA