Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene-environment study.
To investigate similarities and differences in the serotonergic diathesis for mood disorders and suicide attempts, we conducted a study in a cohort followed longitudinally for 22 years. A total of 1255 members of this cohort, which is representative of the French-speaking population of Quebec, were investigated. Main outcome measures included (1) mood disorders (bipolar disorder and major depression) and suicide attempts by early adulthood; (2) odds ratios and probabilities associated with 143 single nucleotide polymorphisms in 11 serotonergic genes, acting directly or as moderators in gene-environment interactions with childhood sexual or childhood physical abuse (CPA), and in gene-gene interactions; (3) regression coefficients for putative endophenotypes for mood disorders (childhood anxiousness) and suicide attempts (childhood disruptiveness). Five genes showed significant adjusted effects (HTR2A, TPH1, HTR5A, SLC6A4 and HTR1A). Of these, HTR2A variation influenced both suicide attempts and mood disorders, although through different mechanisms. In suicide attempts, HTR2A variants (rs6561333, rs7997012 and rs1885884) were involved through interactions with histories of sexual and physical abuse whereas in mood disorders through one main effect (rs9316235). In terms of phenotype-specific contributions, TPH1 variation (rs10488683) was relevant only in the diathesis for suicide attempts. Three genes contributed exclusively to mood disorders, one through a main effect (HTR5A (rs1657268)) and two through gene-environment interactions with CPA (HTR1A (rs878567) and SLC6A4 (rs3794808)). Childhood anxiousness did not mediate the effects of HTR2A and HTR5A on mood disorders, nor did childhood disruptiveness mediate the effects of TPH1 on suicide attempts. Of the serotonergic genes implicated in mood disorders and suicidal behaviors, four exhibited phenotype-specific effects, suggesting that despite their high concordance and common genetic determinants, suicide attempts and mood disorders may also have partially independent etiological pathways. To identify where these pathways diverge, we need to understand the differential, phenotype-specific gene-environment interactions such as the ones observed in the present study, using suitably powered samples.
Brezo
J
J
The McGill Group for Suicide Studies, Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada.
Bureau
A
A
Mérette
C
C
Jomphe
V
V
Barker
E D
ED
Vitaro
F
F
Hébert
M
M
Carbonneau
R
R
Tremblay
R E
RE
Turecki
G
G
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D002648:Child; D002650:Child Abuse, Sexual / Q000523:psychology; D004198:Disease Susceptibility; D004777:Environment; D004843:Epistasis, Genetic; D005190:Family / Q000523:psychology; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008954:Models, Biological; D019964:Mood Disorders / Q000453:epidemiology / Q000235:genetics / Q000523:psychology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D011792:Quebec / Q000453:epidemiology; D011985:Receptors, Serotonin / Q000235:genetics; D012307:Risk Factors; D012701:Serotonin / Q000235:genetics* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D013406:Suicide, Attempted / Q000523:psychology; D014365:Tryptophan Hydroxylase / Q000235:genetics; D055815:Young Adult
D011985:Receptors, Serotonin; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase