title: Hopelessness, a potential endophenotpye for suicidal behavior, is influenced by TPH2 gene variants.
abstract: OBJECTIVE
  Hopelessness is one of the strongest risk factors for suicidal behavior but relevant genetic studies are poorly available. Tryptophan hydroxylase (TPH) is widely considered to be a good candidate for genetic association studies on depression and suicide, however, investigations on these complex, multifactorial phenotypes have resulted in conflicting data. We hypothesized that hopelessness could be a mediating phenotype between TPH2 gene, depression and suicidal behavior.
  
  
  METHODS
  Depressive phenotype and suicidal risk were investigated of 760 individuals from general population by Zung Self Rating Depression Scale (ZDS), Beck's Hopelessness Scale (BHS) and a detailed background questionnaire. All participants' DNA samples were genotyped for 7 tag SNPs in TPH2 gene. Generalized linear models were performed for single marker association studies and p-values were corrected by Bonferroni criteria. In haplotype analyses score tests were used and permutated p-values were computed.
  
  
  RESULTS
  Four SNPs of TPH2 gene showed association with hopelessness but only rs6582078 had a significant effect on the BHS scores after Bonferroni's correction; GG individuals had significantly higher BHS scores, while GT and TT had intermediate and lower BHS scores respectively (p=0.0047). Compared with other genotypes, homozygous GG individuals also had almost three times greater estimated suicidal risk, as did carriers of the AA genotype of rs6582078 (OR=2.87; p=0.005) and also of rs1352250 (OR=2.86; p=0.006). A risk and a protective haplotype of TPH2 gene were also identified in association with hopelessness. ZDS scores have not shown any association with TPH2 gene.
  
  
  CONCLUSIONS
  We found that hopelessness, with its allied increased suicidal risk was strongly associated with TPH2 gene variants in multiple tests. These findings suggest that TPH2 gene confers risk for suicidal behavior while hopelessness can be a potential endophenotype for suicidal vulnerability.
authors.affiliation: Department of Clinical and Theoretical Mental Health, Kutvolgyi Clinical Centre, Semmelweis University, Budapest, Hungary. lazaryjudit@yahoo.com
authors.forename: Judit
authors.initials: J
authors.lastname: Lazary
authors.forename: Veronika
authors.initials: V
authors.lastname: Viczena
authors.forename: Peter
authors.initials: P
authors.lastname: Dome
authors.forename: Diana
authors.initials: D
authors.lastname: Chase
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhasz
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bagdy
mesh_terms: D000328:Adult; D004644:Emotions / Q000502:physiology*; D058068:Endophenotypes; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D012307:Risk Factors; D059020:Suicidal Ideation; D013405:Suicide / Q000523:psychology; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D055815:Young Adult
chemical_list: C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase