RESEARCH ARTICLE The Tryptophan Hydroxylase 1 (TPH1) Gene, Schizophrenia Susceptibility, and Suicidal Behavior: A Multi-Centre Case–Control Study and Meta-Analysis † Peter Saetre, 1 * Per Lundmark, 2 August Wang, 3 Thomas Hansen, 4,5 Henrik B. Rasmussen, 4 Srdjan Djurovic, 6,7,8 Ingrid Melle, 6,7,8 Ole A. Andreassen, 6,7,8 Thomas Werge, 4 Ingrid Agartz, 1,6,9 Ha  kan Hall, 1 Lars Terenius, 1 and Erik G. J€ onsson 1 1 Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden 2 Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden 3 Mental Health Center Amager, Copenhagen University Hospital, Copenhagen, Denmark 4 Research Institute of Biological Psychiatry, Copenhagen University Hospital, Mental Health Centre Sct. Hans, Roskilde, Denmark 5 Centre for Pharmacogenomics, University of Copenhagen, Copenhagen N, Denmark 6 Institute of Psychiatry, University of Oslo, Oslo, Norway 7 Department of Medical Genetics, Ulleva  l University Hospital, Oslo, Norway 8 Department of Psychiatry, Ulleva  l University Hospital, Oslo, Norway 9 Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway Received 23 January 2009; Accepted 7 May 2009 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 ¼ 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 ¼ 0.84). A systematic literature review and meta-analysis support the A218C polymor- phism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.07–1.29). Association studies on sui- cide attempts are however conflicting (heterogeneity index I 2 ¼ 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among indi- viduals diagnosed with a psychiatric disorder (OR ¼ 0.96 [0.80–1.16]). We conclude that the TPH1 A218/A779 locus in- creases 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 † This article was published online on 12 June 2009. An error was subsequently identified. August Wang was not included in the list of authors. This notice is included in the online and print versions to indicate that both have been corrected 11 February 2010. Additional Supporting Information may be found in the online version of this article. Grant sponsor: Copenhagen Hospital Corporation Research Fund; Grant sponsor: Danish National Psychiatric Research Foundation; Grant sponsor: Danish Agency for Science; Grant sponsor: Research Council of Norway; Grant numbers: 147787, 167153; Grant sponsor: Eastern Norway Health Authority (Helse Øst RHF); Grant number: 123/2004; Grant sponsor: Swedish Research Council; Grant number: K2007-62X- 15077-04-1; Grant sponsor: The Knut and Alice Wallenberg Foundation; Grant number: KAW 2005.0256. *Correspondence to: Dr. Peter Saetre, R5:00, Stockholm SE-171 76, Sweden. E-mail: peter.saetre@ki.se Published online 12 June 2009 in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/ajmg.b.30991 How to Cite this Article: Saetre P, Lundmark P, Wang A, Hansen T, Rasmussen HB, Djurovic S, Melle I, Andreassen OA, Werge T, Agartz I, Hall H, Terenius L, J€ onsson EG. 2010. The Tryptophan Hydroxylase 1 (TPH1) Gene, Schizophrenia Susceptibility, and Suicidal Behavior: A Multi-Centre Case–Control Study and Meta-Analysis. Am J Med Genet Part B 153B:387–396. Ó 2009 Wiley-Liss, Inc. 387 Neuropsychiatric Genetics