Influence of life stress, 5-HTTLPR genotype, and SLC6A4 methylation on gene expression and stress response in healthy Caucasian males

Biology of Mood & Anxiety Disorders

Elif A Duman¹  Turhan Canli² 

[1] Center for Life Sciences and Technologies, Bogazici University, Bebek, Istanbul, 34342, Turkey

[2] Program in Genetics, Stony Brook University, Stony Brook 11794, NY, USA

关键词: Depression;    Hypothalamic-pituitary-adrenal axis;    DNA methylation;    Gene expression;    Glucocorticoid receptor;    Serotonin transporter;    Early life stress;   

Others  :  1210960
DOI  :  10.1186/s13587-015-0017-x

 received in 2014-09-01, accepted in 2015-04-27,  发布年份 2015

【 摘 要 】

Background

Previous research reported that individual differences in the stress response were moderated by an interaction between individuals’ life stress experience and the serotonin transporter-linked polymorphic region (5-HTTLPR), a common polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4). Furthermore, this work suggested that individual differences in SLC6A4 DNA methylation could be one underlying mechanism by which stressful life events might regulate gene expression. The aim of this study was to understand the relation between early and recent life stress experiences, 5-HTTLPR genotype, and SLC6A4 methylation. In addition, we aimed to address how these factors influence gene expression and cortisol response to an acute psychosocial stressor, operationalized as the Trier Social Stress Test (TSST). In a sample of 105 Caucasian males, we collected early and recent life stress measures and blood samples to determine 5-HTTLPR genotype and SLC6A4 methylation. Furthermore, 71 of these participants provided blood and saliva samples before and after the TSST to measure changes in SLC6A4 and NR3C1 gene expression and cortisol response.

Results

Compared to S-group individuals, LL individuals responded with increased SLC6A4 mRNA levels to the TSST (t(66) = 3.71, P < .001) and also showed increased global methylation as a function of ELS (r (32) = .45, P = .008) and chronic stress (r (32) = .44, P = .010). Compared to LL individuals, S-group individuals showed reduced SLC6A4 mRNA levels (r (41) = −.31, P = .042) and increased F3 methylation (r (67) = .30, P = .015) as a function of ELS; as well as increased F1 methylation as a function of chronic stress and recent depressive symptoms (r = .41, P < .01), which correlated positively with NR3C1 expression (r (42) = .31, P = .040).

Conclusions

Both early and recent life stress alter DNA methylation as a function of 5-HTTLPR genotype. Some of these changes are also reflected in gene expression and cortisol response, differentially affecting individuals’ stress response in a manner that may confer susceptibility or resilience for psychopathology upon experiencing stressful life events.

【 授权许可】

   
2015 Duman and Canli; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Herman J, Prewitt C, Cullinan W. Neuronal circuit regulation of the hypothalamo-pituitary-adrenocortical stress axis. Crit Rev Neurobiol. 1996; 10:371-94.
• [2]Jørgensen H, Knigge U, Kjær A, Møller M, Warberg J. Serotonergic stimulation of corticotropin‐releasing hormone and pro‐opiomelanocortin gene expression. J Neuroendocrinol. 2002; 14:788-95.
• [3]Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D et al.. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996; 66:2621-4.
• [4]Lesch K, Bengel D, Heils A, Sabol S, Greenberg B, Petri S et al.. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996; 274:1527-31.
• [5]Wendland J, Martin B, Kruse M, Lesch K, Murphy D. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry. 2006; 11:224-6.
• [6]Caspi A, Sugden K, Moffitt T, Taylor A, Craig I, Harrington H et al.. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003; 301:386-9.
• [7]Munafò MR, Durrant C, Lewis G, Flint J. Gene × environment interactions at the serotonin transporter locus. Biol Psychiatry. 2009; 65:211-9.
• [8]Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry. 2010; 167:509-27.
• [9]Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J et al.. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression. JAMA. 2009; 301:2462-71.
• [10]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; 68:444-54.
• [11]Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Mol Psychiatry. 2010; 15:18-22.
• [12]Uher R, McGuffin P. The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry. 2008; 13:131-46.
• [13]Duncan LE, Keller MC. A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry. Am J Psychiatr. 2011; 168:1041-9.
• [14]Kinnally E, Tarara E, Mason W, Mendoza S, Abel K, Lyons L et al.. Serotonin transporter expression is predicted by early life stress and is associated with disinhibited behavior in infant rhesus macaques. Genes Brain Behav. 2010; 9:45-52.
• [15]Lee J-H, Kim HJ, Kim JG, Ryu V, Kim B-T, Kang D-W et al.. Depressive behaviors and decreased expression of serotonin reuptake transporter in rats that experienced neonatal maternal separation. Neurosci Res. 2007; 58:32-9.
• [16]Wankerl M, Miller R, Kirschbaum C, Hennig J, Stalder T, Alexander N. Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles. Transl Psychiatry. 2014; 4:e402.
• [17]Own LS, Iqbal R, Patel PD. Maternal separation alters serotonergic and HPA axis gene expression independent of separation duration in c57bl/6 mice. Brain Res. 2013; 1515:29-38.
• [18]Gardner KL, Hale MW, Lightman SL, Plotsky PM, Lowry CA. Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression. Brain Res. 2009; 1305:47-63.
• [19]Hellstrom IC, Dhir SK, Diorio JC, Meaney MJ. Maternal licking regulates hippocampal glucocorticoid receptor transcription through a thyroid hormone–serotonin–NGFI-A signalling cascade. Philos Trans R Soc B. 2012; 367:2495-510.
• [20]Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009; 10:397-409.
• [21]Belay H, Burton CL, Lovic V, Meaney MJ, Sokolowski M, Fleming AS. Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats. Behav Neurosci. 2011; 125:150-60.
• [22]Kirschbaum C, Pirke K, Hellhammer D. The ‘Trier Social Stress Test’ - a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993; 28:76-81.
• [23]Alexander N, Kuepper Y, Schmitz A, Osinsky R, Kozyra E, Hennig J. Gene-environment interactions predict cortisol responses after acute stress: implications for the etiology of depression. Psychoneuroendocrinology. 2009; 34:1294-303.
• [24]Mueller A, Armbruster D, Moser DA, Canli T, Lesch K-P, Brocke B et al.. Interaction of serotonin transporter gene-linked polymorphic region and stressful life events predicts cortisol stress response. Neuropsychopharmacology. 2011; 36:1332-9.
• [25]Canli T, Qiu M, Omura K, Congdon E, Haas BW, Amin Z et al.. Neural correlates of epigenesis. Proc Natl Acad Sci U S A. 2006; 103:16033-8.
• [26]Taylor SE, Way BM, Welch WT, Hilmert CJ, Lehman BJ, Eisenberger NI. Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology. Biol Psychiatry. 2006; 60:671-6.
• [27]Bagot R, Meaney M. Epigenetics and the biological basis of gene x environment interactions. J Am Acad Child Adolesc Psychiatry. 2010; 49:752-71.
• [28]Weaver I, Cervoni N, Champagne F, D’Alessio A, Sharma S, Seckl J et al.. Epigenetic programming by maternal behavior. Nat Neurosci. 2004; 7:847-54.
• [29]Szyf M, Weaver I, Meaney M. Maternal care, the epigenome and phenotypic differences in behavior. Reprod Toxicol. 2007; 24:9-19.
• [30]McGowan P, Sasaki A, D’Alessio A, Dymov S, Labonté B, Szyf M et al.. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009; 12:342-8.
• [31]Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics. 2008; 3:97-106.
• [32]Tyrka AR, Price LH, Marsit C, Walters OC, Carpenter LL. Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS One. 2012; 7:e30148.
• [33]Philibert R, Madan A, Andersen A, Cadoret R, Packer H, Sandhu H. Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island. Am J Med Genet B Neuropsychiatr Genet. 2007; 144:101-5.
• [34]Beach SRH, Brody GH, Todorov AA, Gunter TD, Philibert RA. Methylation at 5HTT mediates the impact of child sex abuse on women’s antisocial behavior: an examination of the Iowa adoptee sample. Psychosom Med. 2011; 73:83-7.
• [35]Devlin AM, Brain U, Austin J, Oberlander TF, Feil R. Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS One. 2010; 5:12201.
• [36]Kang H-J, Kim J-M, Stewart R, Kim S-Y, Bae K-Y, Kim S-W et al.. Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013; 44:23-8.
• [37]Kinnally EL, Capitanio JP, Leibel R, Deng L, LeDuc C, Haghighi F et al.. Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes Brain Behav. 2010; 9:575-82.
• [38]Ouellet-Morin I, Wong C, Danese A, Pariante C, Papadopoulos A, Mill J, Arseneault L. Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychol Med. 2012; 43(9):1-11.
• [39]Kinnally EL, Feinberg C, Kim D, Ferguson K, Leibel R, Coplan JD et al.. DNA methylation as a risk factor in the effects of early life stress. Brain Behav Immun. 2011; 25:1548-53.
• [40]Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B Neuropsychiatr Genet. 2008; 147:543-9.
• [41]Olsson C, Foley D, Parkinson-Bates M, Byrnes G, McKenzie M, Patton G et al.. Prospects for epigenetic research within cohort studies of psychological disorder: a pilot investigation of a peripheral cell marker of epigenetic risk for depression. Biol Psychol. 2010; 83:159-65.
• [42]Wang D, Szyf M, Benkelfat C, Provençal N, Turecki G, Caramaschi D et al.. Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression. PLoS One. 2012; 7:e39501.
• [43]van IJzendoorn MH, Caspers K, Bakermans-Kranenburg MJ, Beach SR, Philibert R. Methylation matters: interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma. Biol Psychiatry. 2010; 68:405-7.
• [44]Alexander N, Wankerl M, Hennig J, Miller R, Zänkert S, Steudte-Schmiedgen S et al.. DNA methylation profiles within the serotonin transporter gene moderate the association of 5-HTTLPR and cortisol stress reactivity. Translational Psychiatry. 2014; 4:e443.
• [45]Zhao J, Goldberg J, Bremner JD, Vaccarino V. Association between promoter methylation of serotonin transporter gene and depressive symptoms: a monozygotic twin study. Psychosom Med. 2013; 75:523-9.
• [46]Domschke K, Tidow N, Schwarte K, Deckert J, Lesch K-P, Arolt V, Zwanzger P, Baune BT. Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response. Int J Neuropsychopharmacol. 2014; 17(8):1167-76.
• [47]Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K et al.. Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatr. 1994; 151:1132-6.
• [48]Schulz P, Schlotz W. The Trier Inventory for the Assessment of Chronic Stress (TICS): scale construction, statistical testing, and validation of the scale work overload. Diagnostica. 1999; 45:8-19.
• [49]Schulz P, Schlotz W, Becker P. Trierer Inventar zum Chronischen Stress (TICS) [Trier Inventory for Chronic Stress (TICS)]. Hogrefe, Gottingen; 2004.
• [50]Beck AT, Steer RA, Brown GK. Beck Depression Inventory BDI-II Manual. 2nd ed. Psychological Corporation, Orlando, FL; 1996.
• [51]Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH. Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology. 2003; 28:916-31.
• [52]Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA. An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res. 2005; 29:8-16.
• [53]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-[Delta][Delta] CT method. Methods. 2001; 25:402-8.
• [54]Kim J, Kim JY, Issa JPJ. Aging and DNA methylation. Curr Chem Biol. 2009; 3:1-9.
• [55]Richardson B. Impact of aging on DNA methylation. Ageing Res Rev. 2003; 2:245-61.
• [56]Glatz K, Mössner R, Heils A, Lesch K. Glucocorticoid regulated human serotonin transporter (5 HTT) expression is modulated by the 5 HTT gene promotor linked polymorphic region. J Neurochem. 2003; 86:1072-8.
• [57]Messeguer X, Escudero R, Farré D, Núñez O, Martı́nez J, Albà MM. PROMO: detection of known transcription regulatory elements using species-tailored searches. Bioinformatics. 2002; 18:333-4.
• [58]Vasiliou SA, Ali FR, Haddley K, Cardoso MC, Bubb VJ, Quinn JP. The SLC6A4 VNTR genotype determines transcription factor binding and epigenetic variation of this gene in response to cocaine in vitro. Addict Biol. 2012; 17:156-70.
• [59]Kinnally E, Lyons L, Abel K, Mendoza S, Capitanio J. Effects of early experience and genotype on serotonin transporter regulation in infant rhesus macaques. Genes Brain Behav. 2008; 7:481-6.
• [60]Alasaari JS, Lagus M, Ollila HM, Toivola A, Kivimäki M, Vahtera J et al.. Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort. PLoS One. 2012; 7:e45813.
• [61]Sugawara H, Bundo M, Ishigooka J, Iwamoto K, Kato T. Epigenetic regulation of serotonin transporter in psychiatric disorders. J Genet Genomics. 2013; 40:325-9.
• [62]Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002; 34:13-25.
• [63]Nater U, Whistler T, Lonergan W, Mletzko T, Vernon S, Heim C. Impact of acute psychosocial stress on peripheral blood gene expression pathways in healthy men. Biol Psychol. 2009; 82:125-32.
• [64]Morita K, Saito T, Ohta M, Ohmori T, Kawai K, Teshima-Kondo S et al.. Expression analysis of psychological stress-associated genes in peripheral blood leukocytes. Neurosci Lett. 2005; 381:57-62.
• [65]Meaney MJ. Epigenetics and the biological definition of gene × environment interactions. Child Dev. 2010; 81:41-79.
• [66]Byun H-M, Siegmund KD, Pan F, Weisenberger DJ, Kanel G, Laird PW et al.. Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue-and individual-specific DNA methylation patterns. Hum Mol Genet. 2009; 18:4808-17.
• [67]Davies MN, Volta M, Pidsley R, Lunnon K, Dixit A, Lovestone S et al.. Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biol. 2012; 13:R43. BioMed Central Full Text
• [68]Provençal N, Suderman MJ, Guillemin C, Massart R, Ruggiero A, Wang D et al.. The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells. J Neurosci. 2012; 32:15626-42.
• [69]Ursini G, Bollati V, Fazio L, Porcelli A, Iacovelli L, Catalani A et al.. Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity. J Neurosci. 2011; 31:6692-8.
• [70]Kudielka B, Buske-Kirschbaum A, Hellhammer D, Kirschbaum C. HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender. Psychoneuroendocrinology. 2004; 29:83-98.
• [71]Carpenter LL, Tyrka AR, Ross NS, Khoury L, Anderson GM, Price LH. Effect of childhood emotional abuse and age on cortisol responsivity in adulthood. Biol Psychiatry. 2009; 66:69-75.
• [72]DeSantis SM, Baker NL, Back SE, Spratt E, Ciolino JD, Maria MS et al.. Gender differences in the effect of early life trauma on hypothalamic-pituitary-adrenal axis functioning. Depress Anxiety. 2011; 28:383-92.
• [73]Het S, Rohleder N, Schoofs D, Kirschbaum C, Wolf O. Neuroendocrine and psychometric evaluation of a placebo version of the ‘Trier Social Stress Test’. Psychoneuroendocrinology. 2009; 34:1075-86.
• [74]Jasinska AJ, Lowry CA, Burmeister M. Serotonin transporter gene, stress and raphe-raphe interactions: a molecular mechanism of depression. Trends Neurosci. 2012; 35:395-402.
• [75]Kaufman J, Yang B, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S et al.. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry. 2006; 59:673-80.
• [76]Comasco E, Åslund C, Oreland L, Nilsson KW. Three-way interaction effect of 5-HTTLPR, BDNF Val66Met, and childhood adversity on depression: a replication study. Eur Neuropsychopharmacol. 2013; 23:1300-6.
• [77]Dougherty L, Klein D, Congdon E, Canli T, Hayden E. Interaction between 5-HTTLPR and BDNF Val66Met polymorphisms on HPA axis reactivity in preschoolers. Biol Psychol. 2010; 83:93-100.
• [78]Uher R. Gene-environment interactions in common mental disorders: an update and strategy for a genome-wide search. Soc Psychiatry Psychiatr Epidemiol. 2014; 49:3-14.
• [79]Roth TL, Lubin FD, Funk AJ, Sweatt JD. Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009; 65:760-9.