Association between a genetic variant in the serotonin transporter gene (SLC6A4) and suicidal behavior in patients with schizophrenia

Behavioral and Brain Functions

Eva Lindholm Carlström¹  Peter Saetre¹  Anders Rosengren⁴  Johan H Thygesen⁴  Srdjan Djurovic²  Ingrid Melle²  Ole A Andreassen²  Thomas Werge⁴  Ingrid Agartz³  Håkan Hall¹  Lars Terenius¹  Erik G Jönsson¹ 

[1] Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, R5:00, Stockholm, Sweden

[2] TOP project, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway

[3] Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway

[4] Research Institute of Biological Psychiatry, Copenhagen University Hospital, Mental Health Centre Sct. Hans, Roskilde, Denmark

关键词: Schizophrenia;    Association;    Serotonin transporter gene;    Suicide ideation;   

Others  :  797523
DOI  :  10.1186/1744-9081-8-24

 received in 2011-10-25, accepted in 2012-04-25,  发布年份 2012

【 摘 要 】

Background

The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT) is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case–control sample.

Methods

Patients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs) were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9).

Results

We observed an allele association between the SNP rs16965628, located in intron one of SLC6A4, and attempted suicide (adjusted p-value 0.01), among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals.

Conclusion

The gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn.

【 授权许可】

   
2012 Lindholm Carlstrom et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Carlborg A, Winnerbäck K, Jönsson EG, Jokinen J, Nordström P: Suicide in schizophrenia. Expert Rev Neurother 2010, 10:1153-1164.
• [2]Hor K, Taylor M: Suicide and schizophrenia: a systematic review of rates and risk factors. J Psychopharmacol 2010, 24:81-90.
• [3]Pompili M, Amador XF, Girardi P, Harkavy-Friedman J, Harrow M, Kaplan K, Krausz M, Lester D, Meltzer HY, Modestin J, et al.: Suicide risk in schizophrenia: learning from the past to change the future. Ann Gen Psychiatry 2007, 6:10. BioMed Central Full Text
• [4]Glowinski AL, Bucholz KK, Nelson EC, Fu Q, Madden PA, Reich W, Heath AC: Suicide attempts in an adolescent female twin sample. J Am Acad Child Adolesc Psychiatry 2001, 40:1300-1307.
• [5]Statham DJ, Heath AC, Madden PA, Bucholz KK, Bierut L, Dinwiddie SH, Slutske WS, Dunne MP, Martin NG: Suicidal behaviour: an epidemiological and genetic study. Psychol Med 1998, 28:839-855.
• [6]Willour VL, Seifuddin F, Mahon PB, Jancic D, Pirooznia M, Steele J, Schweizer B, Goes FS, Mondimore FM, Mackinnon DF, et al.: A genome-wide association study of attempted suicide. Mol Psychiatry 2011,  : .
• [7]Gingrich JA, Ansorge MS, Merker R, Weisstaub N, Zhou M: New lessons from knockout mice: The role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders. CNS Spectr 2003, 8:572-577.
• [8]Manuck SB, Flory JD, McCaffery JM, Matthews KA, Mann JJ, Muldoon MF: Aggression, impulsivity, and central nervous system serotonergic responsivity in a nonpatient sample. Neuropsychopharmacology 1998, 19:287-299.
• [9]Neumeister A: Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull 2003, 37:99-115.
• [10]Neumeister A, Nugent AC, Waldeck T, Geraci M, Schwarz M, Bonne O, Bain EE, Luckenbaugh DA, Herscovitch P, Charney DS, Drevets WC: Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry 2004, 61:765-773.
• [11]Li D, He L: Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior. Mol Psychiatry 2007, 12:47-54.
• [12]Lin PY, Tsai G: Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis. Biol Psychiatry 2004, 55:1023-1030.
• [13]Mann JJ: Neurobiology of suicidal behaviour. Nat Rev Neurosci 2003, 4:819-828.
• [14]Stanley M, Mann JJ: Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 1983, 1:214-216.
• [15]Stanley M, Virgilio J, Gershon S: Tritiated imipramine binding sites are decreased in the frontal cortex of suicides. Science 1982, 216:1337-1339.
• [16]Mann JJ, Huang YY, Underwood MD, Kassir SA, Oppenheim S, Kelly TM, Dwork AJ, Arango V: A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 2000, 57:729-738.
• [17]Courtet P, Jollant F, Castelnau D, Buresi C, Malafosse A: Suicidal behavior: relationship between phenotype and serotonergic genotype. Am J Med Genet C Semin Med Genet 2005, 133C:25-33.
• [18]Bellivier F, Chaste P, Malafosse A: Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2004, 124B:87-91.
• [19]Rujescu D, Giegling I, Sato T, Hartmann AM, Moller HJ: Genetic variations in tryptophan hydroxylase in suicidal behavior: analysis and meta-analysis. Biol Psychiatry 2003, 54:465-473.
• [20]Saetre P, Lundmark P, Wang A, Hansen T, Rasmussen HB, Djurovic S, Melle I, Andreassen OA, Werge T, Agartz I, et al.: The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case–control study and meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2009, 153B:387-396.
• [21]Anguelova M, Benkelfat C, Turecki G: A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol Psychiatry 2003, 8:646-653.
• [22]Holmes A, Lit Q, Murphy DL, Gold E, Crawley JN: Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav 2003, 2:365-380.
• [23]Holmes A, Murphy DL, Crawley JN: Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 2003, 54:953-959.
• [24]Hariri AR, Drabant EM, Weinberger DR: Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing. Biol Psychiatry 2006, 59:888-897.
• [25]Cheng R, Juo SH, Loth JE, Nee J, Iossifov I, Blumenthal R, Sharpe L, Kanyas K, Lerer B, Lilliston B, et al.: Genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health genetics initiative suggests putative loci for bipolar disorder, psychosis, suicide, and panic disorder. Mol Psychiatry 2006, 11:252-260.
• [26]Hesselbrock V, Dick D, Hesselbrock M, Foroud T, Schuckit M, Edenberg H, Bucholz K, Kramer J, Reich T, Goate A, et al.: The search for genetic risk factors associated with suicidal behavior. Alcohol Clin Exp Res 2004, 28:70S-76S.
• [27]Willour VL, Zandi PP, Badner JA, Steele J, Miao K, Lopez V, MacKinnon DF, Mondimore FM, Schweizer B, McInnis MG, et al.: Attempted suicide in bipolar disorder pedigrees: evidence for linkage to 2p12. Biol Psychiatry 2007, 61:725-727.
• [28]Zubenko GS, Maher BS, Hughes HB, Zubenko WN, Scott Stiffler J, Marazita ML: Genome-wide linkage survey for genetic loci that affect the risk of suicide attempts in families with recurrent, early-onset, major depression. Am J Med Genet B Neuropsychiatr Genet 2004, 129:47-54.
• [29]Butler AW, Breen G, Tozzi F, Craddock N, Gill M, Korszun A, Maier W, Middleton LT, Mors O, Owen MJ, et al.: A genomewide linkage study on suicidality in major depressive disorder confirms evidence for linkage to 2p12. Am J Med Genet B Neuropsychiatr Genet 2010, 153:1465-1473.
• [30]Hansen T, Olsen L, Lindow M, Jakobsen KD, Ullum H, Jonsson E, Andreassen OA, Djurovic S, Melle I, Agartz I, et al.: Brain expressed microRNAs implicated in schizophrenia etiology. PLoS One 2007, 2:e873.
• [31]Jönsson EG, Larsson K, Vares M, Hansen T, Wang AG, Djurovic S, Rönningen KS, Andreassen OA, Agartz I, Werge T, et al.: Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: an association study. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:976-982.
• [32]Kähler AK, Djurovic S, Kulle B, Jönsson EG, Agartz I, Hall H, Opjordsmoen S, Jakobsen KD, Hansen T, Melle I, et al.: Association analysis of schizophrenia on 18 genes involved in neuronal migration: MDGA1 as a new susceptibility gene. Am J Med Genet B Neuropsychiatr Genet 2008, 147B:1089-1100.
• [33]Saetre P, Agartz I, De Franciscis A, Lundmark P, Djurovic S, Kähler A, Andreassen OA, Jakobsen KD, Rasmussen HB, Werge T, et al.: Association between a disrupted-in-schizophrenia 1 (DISC1) single nucleotide polymorphism and schizophrenia in a combined Scandinavian case–control sample. Schizophr Res 2008, 106:237-241.
• [34]Wigginton JE, Abecasis GR: PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 2005, 21:3445-3447.
• [35]Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, et al.: The structure of haplotype blocks in the human genome. Science 2002, 296:2225-2229.
• [36]Barrett JC, Fry B, Maller J, Daly MJ: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005, 21:263-265.
• [37]Dudbridge F: Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003, 25:115-121.
• [38]Dudbridge F: Likelihood-based association analysis for nuclear families and unrelated subjects with missing genotype data. Hum Hered 2008, 66:87-98.
• [39]De Luca V, Zai G, Tharmalingam S, de Bartolomeis A, Wong G, Kennedy JL: Association study between the novel functional polymorphism of the serotonin transporter gene and suicidal behaviour in schizophrenia. Eur Neuropsychopharmacol 2006, 16:268-271.
• [40]Dubertret C, Hanoun N, Ades J, Hamon M, Gorwood P: Family-based association study of the 5-HT transporter gene and schizophrenia. Int J Neuropsychopharmacol 2005, 8:87-92.
• [41]Lin C, Tang W, Hu J, Gao L, Huang K, Xu Y, He G, Liang P, Feng G, He L, Shi Y: Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia in the Han Chinese population. Neurosci Lett 2009, 453:210-213.
• [42]Saiz PA, Garcia-Portilla MP, Arango C, Morales B, Alvarez V, Coto E, Fernandez JM, Bascaran MT, Bousono M, Bobes J: Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31:741-745.
• [43]Vijayan NN, Iwayama Y, Koshy LV, Natarajan C, Nair C, Allencherry PM, Yoshikawa T, Banerjee M: Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population. J Hum Genet 2009, 54:538-542.
• [44]Zaboli G, Jonsson EG, Gizatullin R, De Franciscis A, Asberg M, Leopardi R: Haplotype analysis confirms association of the serotonin transporter (5-HTT) gene with schizophrenia but not with major depression. Am J Med Genet B Neuropsychiatr Genet 2008, 147:301-307.
• [45]Tsai SJ, Hong CJ, Liou YJ: Recent molecular genetic studies and methodological issues in suicide research. Prog Neuropsychopharmacol Biol Psychiatry 2011, 35:809-817.
• [46]Arango V, Huang YY, Underwood MD, Mann JJ: Genetics of the serotonergic system in suicidal behavior. J Psychiatr Res 2003, 37:375-386.
• [47]Gonda X, Fountoulakis KN, Harro J, Pompili M, Akiskal HS, Bagdy G, Rihmer Z: The possible contributory role of the S allele of 5-HTTLPR in the emergence of suicidality. J Psychopharmacol 2011, 25:857-866.
• [48]Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274:1527-1531.
• [49]Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, et al.: Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 2006, 78:815-826.
• [50]Martin J, Cleak J, Willis-Owen SA, Flint J, Shifman S: Mapping regulatory variants for the serotonin transporter gene based on allelic expression imbalance. Mol Psychiatry 2007, 12:421-422.
• [51]Levinson DF: Meta-analysis in psychiatric genetics. Curr Psychiatry Rep 2005, 7:143-151.
• [52]Furlong RA, Ho L, Walsh C, Rubinsztein JS, Jain S, Paykel ES, Easton DF, Rubinsztein DC: Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. Am J Med Genet 1998, 81:58-63.
• [53]Lotrich FE, Pollock BG: Meta-analysis of serotonin transporter polymorphisms and affective disorders. Psychiatr Genet 2004, 14:121-129.
• [54]Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT: Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet 2005, 133B:110-115.
• [55]Cho HJ, Meira-Lima I, Cordeiro Q, Michelon L, Sham P, Vallada H, Collier DA: Population-based and family-based studies on the serotonin transporter gene polymorphisms and bipolar disorder: a systematic review and meta-analysis. Mol Psychiatry 2005, 10:771-781.
• [56]McEachin RC, Saccone NL, Saccone SF, Kleyman-Smith YD, Kar T, Kare RK, Ade AS, Sartor MA, Cavalcoli JD, McInnis MG: Modeling complex genetic and environmental influences on comorbid bipolar disorder with tobacco use disorder. BMC Med Genet 2010, 11:14.
• [57]Feinn R, Nellissery M, Kranzler HR: Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence. Am J Med Genet B Neuropsychiatr Genet 2005, 133B:79-84.
• [58]McHugh RK, Hofmann SG, Asnaani A, Sawyer AT, Otto MW: The serotonin transporter gene and risk for alcohol dependence: a meta-analytic review. Drug Alcohol Depend 2010, 108:1-6.
• [59]Lopez-Leon S, Janssens AC, Gonzalez-Zuloeta Ladd AM, Del-Favero J, Claes SJ, Oostra BA, van Duijn CM: Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry 2008, 13:772-785.
• [60]Clarke H, Flint J, Attwood AS, Munafo MR: Association of the 5- HTTLPR genotype and unipolar depression: a meta-analysis. Psychol Med 2010, 40:1767-1778.
• [61]Daray FM, Thommi SB, Ghaemi SN: The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis. Bipolar Disord 2010, 12:702-706.
• [62]Biernacka JM, McElroy SL, Crow S, Sharp A, Benitez J, Veldic M, Kung S, Cunningham JM, Post RM, Mrazek D, Frye MA: Pharmacogenomics of antidepressant induced mania: a review and meta-analysis of the serotonin transporter gene (5HTTLPR) association. J Affect Disord 2012, 136:e21-29.
• [63]Karg K, Burmeister M, Shedden K, Sen S: The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry 2011, 68:444-454.
• [64]Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR: Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression A Meta-analysis. Jama-Journal of the American Medical Association 2009, 301:2462-2471.
• [65]Schinka JA, Busch RM, Robichaux-Keene N: A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Mol Psychiatry 2004, 9:197-202.
• [66]Sen S, Burmeister M, Ghosh D: Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet 2004, 127B:85-89.
• [67]Munafo MR, Freimer NB, Ng W, Ophoff R, Veijola J, Miettunen J, Jarvelin MR, Taanila A, Flint J: 5-HTTLPR genotype and anxiety-related personality traits: a meta-analysis and new data. Am J Med Genet B Neuropsychiatr Genet 2009, 150B:271-281.
• [68]Fan JB, Sklar P: Meta-analysis reveals association between serotonin transporter gene STin2 VNTR polymorphism and schizophrenia. Mol Psychiatry 2005, 10:928-938.
• [69]Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L: Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 2008, 40:827-834.
• [70]Shi J, Gershon ES, Liu C: Genetic associations with schizophrenia: meta-analyses of 12 candidate genes. Schizophr Res 2008, 104:96-107.
• [71]Rao D, Jönsson EG, Paus S, Ganguli R, Nöthen M, Nimgaonkar VL: Schizophrenia and the serotonin transporter gene. Psychiatr Genet 1998, 8:207-212.
• [72]Wendland JR, Moya PR, Kruse MR, Ren-Patterson RF, Jensen CL, Timpano KR, Murphy DL: A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder. Hum Mol Genet 2008, 17:717-723.
• [73]Morey RA, Hariri AR, Gold AL, Hauser MA, Munger HJ, Dolcos F, McCarthy G: Serotonin transporter gene polymorphisms and brain function during emotional distraction from cognitive processing in posttraumatic stress disorder. BMC Psychiatry 2011, 11:76. BioMed Central Full Text
• [74]Diaconu G, Turecki G: Obsessive-compulsive personality disorder and suicidal behavior: evidence for a positive association in a sample of depressed patients. J Clin Psychiatry 2009, 70:1551-1556.
• [75]Panagioti M, Gooding P, Tarrier N: Post-traumatic stress disorder and suicidal behavior: A narrative review. Clin Psychol Rev 2009, 29:471-482.
• [76]Jönsson EG, Saetre P, Vares M, Andreou D, Larsson K, Timm S, Rasmussen HB, Djurovic S, Melle I, Andreassen OA, et al.: DTNBP1, NRG1, DAOA, DAO and GRM3 polymorphisms and schizophrenia: an association study. Neuropsychobiology 2009, 59:142-150.