The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case-control study and meta-analysis.
Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P = 0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I(2) = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and Asian populations. In addition, the data at hand suggest that the locus contributes to the liability of psychiatric disorders characterized by elevated suicidal rates, rather than affecting suicidal behavior of individuals suffering from a psychiatric disorder.
Saetre
Peter
P
Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.
Lundmark
Per
P
Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden.
Wang
August
A
Mental Health Center Amager, Copenhagen University Hospital, Copenhagen, Denmark.
Hansen
Thomas
T
Research Institute of Biological Psychiatry, Copenhagen University Hospital, Mental Health Centre Sct. Hans, Roskilde, Denmark.|Centre for Pharmacogenomics, University of Copenhagen, Copenhagen N, Denmark.
Rasmussen
Henrik B
HB
Research Institute of Biological Psychiatry, Copenhagen University Hospital, Mental Health Centre Sct. Hans, Roskilde, Denmark.
Djurovic
Srdjan
S
Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway.|Department of Psychiatry, Ullevål University Hospital, Oslo, Norway.
Melle
Ingrid
I
Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway.|Department of Psychiatry, Ullevål University Hospital, Oslo, Norway.
Andreassen
Ole A
OA
Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway.|Department of Psychiatry, Ullevål University Hospital, Oslo, Norway.
Werge
Thomas
T
Research Institute of Biological Psychiatry, Copenhagen University Hospital, Mental Health Centre Sct. Hans, Roskilde, Denmark.
Agartz
Ingrid
I
Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.|Institute of Psychiatry, University of Oslo, Oslo, Norway.|Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
Hall
Håkan
H
Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.
Terenius
Lars
L
Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.
Jönsson
Erik G
EG
Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden.
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D012701:Serotonin / Q000494:pharmacology; D013405:Suicide; D013406:Suicide, Attempted; D014365:Tryptophan Hydroxylase / Q000235:genetics*
D012701:Serotonin; D014365:Tryptophan Hydroxylase