Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: a 22-year longitudinal gene–environment study

Abstract

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.

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

“…A recent meta-analysis supports the association of this polymorphism (rs6295), as well as a more upstream HTR1A promoter polymorphism (rs878567), with MDD [45,115].…”

Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment

“…Second, the G allele of SNP rs4583306 of SLC6A4 (in an LD block) has been linked to panic disorder (Strug et al 2008) and mood disorder in subjects who experienced childhood physical abuse (Brezo et al 2009), whereas the heterozygotes were overrepresented in our college sample. Third, it was reported that the G allele of SNP rs10488683 of TPH1 was linked to the diathesis for suicide attempts (Brezo et al 2009), whereas our study showed a slight overrepresentation of the A allele homozygotes among college students. Finally, for SLC18A2 rs4752045, the CC genotype showed a lower level of depressive symptoms in an elderly population (Christiansen et al 2007).…”

Genetic Research on Sleep, Sleep Disturbances and Associated Difficulties

“…Однако сейчас большая часть исследований генов триптофан-гидроксилазы приходится на долю гена TPH1. Результаты исследований ассоциаций полиморфных локусов гена TPH1 с суицидальным поведени-ем, нарушениями настроения и другими психическими расстройствами противоречивы (Тиходеев, 2007;Гайсина и др., 2008;Brezo et al, 2010;Saetre et al, 2010). Наиболее исследуемым в гене ТРН1 является поли-морфный локус rs1800532, расположенный в интроне 7 и вовлеченный в процессы сплайсинга, трансляции или стабильности мРНК (Hong et al, 2001).…”

“…Полиморфные локусы гена SLC6A4 интенсивно исследовались на ассоциацию с суицидальным поведением (Gaysina et al, 2006;Mann et al, 2009;Brezo et al, 2010;Linkowska et al, 2010;Zupanc et al, 2010;Zalsman et al, 2011;Božina et al, 2012). Литературные данные указывают на ассо-циацию аллеля S (или L G ) с депрессией (Zalsman et al, 2006) и суицидаль-ным поведением (Kraft et al, 2008;Neves et al, 2008Neves et al, , 2010.…”