Abstract
A large number of studies have examined associations between brain-derived neurotrophic factor (BDNF) gene polymorphisms and depressive symptoms. However, results still remain controversial. Recent studies suggested a significant age and gender effect on the heritability of depression. The potential neurobiological pathways that could possibly mediate this relationship have not been examined so far. Since BDNF is involved in the regulation of neurotransmitter production, a mediating role of neurotransmitters seems plausible. The present study aims to examine the association between three common BDNF single-nucleotid polymorphisms (SNPs; rs7103411, rs7124442, and rs6265) and depressive symptoms in a community-based elderly population taking into account the serum levels of four neurotransmitters, serotonin, dopamine, adrenalin, and noradrenalin, as potential mediating factors. We also examined whether age and gender had a modifying effect on this association. We collected and analyzed the genetic and laboratory data as well as Center for Epidemiologic Studies-Depression scores of 350 community-dwelling elderly individuals (aged 65+ years). We found that the BDNF rs6265 polymorphism was related to the severity of depressive symptoms, and that this association was independent of neurotransmitter levels. Stratified analyses showed that this association was restricted to older individuals (≥74 years) and men. The associations of SNPs rs7103411 or rs7124442 SNP with depressive symptoms were not statistically significant. This study importantly adds to the existing literature by affirming previous assumptions on an age and gender difference in the relation between BDNF genotype and depression. We moreover first-time report a missing mediating role of neurotransmitters in this association.
Similar content being viewed by others
References
Angelucci F, Brene S, Mathe AA (2005) BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatr 10(4):345–352
Bath KG, Lee FS (2006) Variant BDNF (Val66Met) impact on brain structure and function. Cogn Affect Behav Neurosci 6(1):79–85
Becker JB, Monteggia LM, Perrot-Sinal TS, Romeo RD, Taylor JR, Yehuda R, Bale TL (2007) Stress and disease: is being female a predisposing factor? J Neurosci 27(44):11851–11855
Bohlen v, Halbach O (2011) Involvement of BDNF in age-dependent alterations in the hippocampus. Front Aging Neurosci (in press)
Borroni B, Archetti S, Costanzi C, Grassi M, Ferrari M, Radeghieri A, Caimi L, Caltagirone C, Di Luca M, Padovani A (2009) Role of BDNF Val66Met functional polymorphism in Alzheimer’s disease-related depression. Neurobiol Aging 30(9):1406–1412
Cahill L (2006) Why sex matters for neuroscience. Nat Rev Neurosci 7(6):477–484
Campbell S, Marriott M, Nahmias C, MacQueen GM (2004) Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 161(4):598–607
Chen L, Lawlor DA, Lewis SJ, Yuan W, Abdollahi MR, Timpson NJ, Day IN, Ebrahim S, Smith GD, Shugart YY (2008) Genetic association study of BDNF in depression: finding from two cohort studies and a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 147B(6):814–821
Curtis AL, Bethea T, Valentino RJ (2006) Sexually dimorphic responses of the brain norepinephrine system to stress and corticotropin-releasing factor. Neuropsychopharmacology 31(3):544–554
Cuzick J (1985) A Wilcoxon-type test for trend. Stat Med 4(1):87–90
Dal Forno G, Palermo MT, Donohue JE, Karagiozis H, Zonderman AB, Kawas CH (2005) Depressive symptoms, sex, and risk for Alzheimer’s disease. Ann Neurol 57(3):381–387
Delgado PL (2000) Depression: the case for a monoamine deficiency. J Clin Psychiatr 61(Suppl 6):7–11
den Heijer T, Tiemeier H, Luijendijk HJ, van der Lijn F, Koudstaal PJ, Hofman A, Breteler MM (2011) A study of the bidirectional association between hippocampal volume on magnetic resonance imaging and depression in the elderly. Biol Psychiatr 70(2):191–197
Domschke K, Lawford B, Laje G, Berger K, Young R, Morris P, Deckert J, Arolt V, McMahon FJ, Baune BT (2010) Brain-derived neurotrophic factor ( BDNF) gene: no major impact on antidepressant treatment response. Int J Neuropsychopharmacol 13(1):93–101
Duman RS (2004) Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med 5(1):11–25
Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54(7):597–606
Ebmeier KP, Donaghey C, Steele JD (2006) Recent developments and current controversies in depression. Lancet 367(9505):153–167
Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198
Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jager M, Leinsinger G, Bottlender R, Hahn K, Moller HJ (2002) Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry 159(7):1112–1118
Hajek T, Kopecek M, Hoschl C (2011) Reduced hippocampal volumes in healthy carriers of brain-derived neurotrophic factor Val66Met polymorphism: Meta-analysis. World J Biol Psychiatr (in press)
Hautzinger M, Bailer M (1993) Allgemeine Depressionsskala. ADS. Testmappe mit Handanweisung. Beltz, Weinheim
Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 48(4):186–189
Huang R, Huang J, Cathcart H, Smith S, Poduslo SE (2007) Genetic variants in brain-derived neurotrophic factor associated with Alzheimer’s disease. J Med Genet 44(2):e66
Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF, Yang YM (2006) The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging 27(12):1834–1837
Karege F, Perret G, Bondolfi G, Schwald M, Bertschy G, Aubry JM (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109(2):143–148
Kato M, Serretti A (2008) Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatr 15(5):473–500
Keil U, Liese A, Hense H, Filipiak B, Doring A, Stieber J, Lowel H (1998) Classical risk factors and their impact on incident non-fatal and fatal myocardial infarction and all-cause mortality in southern Germany: results from the MONICA Augsburg cohort study 1984–1992. Eur Hear J 19(8):1197
Laakso MP, Soininen H, Partanen K, Lehtovirta M, Hallikainen M, Hanninen T, Helkala EL, Vainio P, Riekkinen PJ Sr (1998) MRI of the hippocampus in Alzheimer’s disease: sensitivity, specificity, and analysis of the incorrectly classified subjects. Neurobiol Aging 19(1):23–31
Levinson DF (2006) The genetics of depression: a review. Biol Psychiatr 60(2):84–92
Lopez-Leon S, Janssens AC, Tiemeier H, Hofman A, Aulchenko YS, Snijders PJ, Claes S, Oostra BA, van Duijn CM (2008) Angiotensinogen M235T polymorphism and symptoms of depression in a population-based study and a family-based study. Psychiatr Genet 18(4):162–166
Madeira MD, Lieberman AR (1995) Sexual dimorphism in the mammalian limbic system. Prog Neurobiol 45(4):275–333
Malisic EJ, Jankovic RN, Radulovic SS (2010) An intronic variant in the TP53 gene in Serbian women with cervical or ovarian cancer. Cancer Genet Cytogenet 198(2):173–175
Maren S, Hobin JA (2007) Hippocampal regulation of context-dependent neuronal activity in the lateral amygdala. Learn Mem 14(4):318–324
McAllister AK, Katz LC, Lo DC (1999) Neurotrophins and synaptic plasticity. Annu Rev Neurosci 22:295–318
McEwen BS (2000) The neurobiology of stress: from serendipity to clinical relevance. Brain Res 886(1–2):172–189
Mercader JM, Ribases M, Gratacos M, Gonzalez JR, Bayes M, de Cid R, Badia A, Fernandez-Aranda F, Estivill X (2007) Altered brain-derived neurotrophic factor blood levels and gene variability are associated with anorexia and bulimia. Genes Brain Behav 6(8):706–716
O’Donnell P, Grace AA (1995) Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J Neurosci 15(5 Pt 1):3622–3639
Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van Broeckhoven C, Mendlewicz J (2005) No implication of brain-derived neurotrophic factor (BDNF) gene in unipolar affective disorder: evidence from Belgian first and replication patient-control studies. Eur Neuropsychopharmacol 15(5):491–495
Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR (2008) Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatr 13(7):709–716
Radloff LS (1977) The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1(3):385–401
Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A, Dahle C, Gerstorf D, Acker JD (2005) Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 15(11):1676–1689
Ribeiro L, Busnello JV, Cantor RM, Whelan F, Whittaker P, Deloukas P, Wong ML, Licinio J (2007) The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in Mexican-Americans. Neuroreport 18(12):1291–1293
Robinson DS, Sourkes TL, Nies A, Harris LS, Spector S, Bartlett DL, Kaye IS (1977) Monoamine metabolism in human brain. Arch Gen Psychiatr 34(1):89–92
Ryu SY, Kwon MJ, Lee SB, Yang DW, Kim TW, Song IU, Yang PS, Kim HJ, Lee AY (2010) Measurement of precuneal and hippocampal volumes using magnetic resonance volumetry in Alzheimer’s disease. J Clin Neurol 6(4):196–203
Saczynski JS, Beiser A, Seshadri S, Auerbach S, Wolf PA, Au R (2010) Depressive symptoms and risk of dementia: the Framingham Heart Study. Neurology 75(1):35–41
Sapolsky RM (2000) Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatr 57(10):925–935
Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatr 122(5):509–522
Schmidt W, Roesler A, Kretzschmar K, Ladwig K, Junker R, Berger K (2004) Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population. J Am Geriatr Soc 52(7):1045–1050
Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, Schulze TG, Deschner M, Schmal C, Hofels S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M, Nothen MM, Cichon S (2005) Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatr 58(4):307–314
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93(9):3908–3913
Steffens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF, MacFall JR, Krishnan KR (2000) Hippocampal volume in geriatric depression. Biol Psychiatr 48(4):301–309
Suchanek R, Owczarek A, Kowalczyk M, Kucia K, Kowalski J (2011) Association between C-281A and val66met functional polymorphisms of BDNF gene and risk of recurrent major depressive disorder in Polish population. J Mol Neurosci 43(3):524–530
Surtees PG, Wainwright NW, Willis-Owen SA, Sandhu MS, Luben R, Day NE, Flint J (2007) No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults. J Psychiatr Res 41(5):404–409
Taylor WD, Zuchner S, McQuoid DR, Steffens DC, Speer MC, Krishnan KR (2007) Allelic differences in the brain-derived neurotrophic factor Val66Met polymorphism in late-life depression. Am J Geriatr Psychiatr 15(10):850–857
Troisi A (2001) Gender differences in vulnerability to social stress: a Darwinian perspective. Physiol Behav 73(3):443–449
Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet B Neuropsychiatr Genet 123B(1):19–22
Verhagen M, van der Meij A, van Deurzen PA, Janzing JG, Arias-Vasquez A, Buitelaar JK, Franke B (2010) Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity. Mol Psychiatr 15(3):260–271
Videbech P, Ravnkilde B (2004) Hippocampal volume and depression: a meta-analysis of MRI studies. Am J Psychiatr 161(11):1957–1966
Ying SY, Chang CP, Lin SL (2010) Intron-mediated RNA interference, intronic microRNAs, and applications. Methods Mol Biol 629:205–237
Zhang K, Yang C, Xu Y, Sun N, Yang H, Liu J, Xu Q, Shen Y (2008) Genetic association of the interaction between the BDNF and GSK3B genes and major depressive disorder in a Chinese population. J Neural Transm 117(3):393–401
Zhang K, Yang C, Xu Y, Sun N, Yang H, Liu J, Xu Q, Shen Y (2010) Genetic association of the interaction between the BDNF and GSK3B genes and major depressive disorder in a Chinese population. J Neural Transm 117(3):393–401
Zubenko GS, Hughes HB 3rd, Maher BS, Stiffler JS, Zubenko WN, Marazita ML (2002) Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression. Am J Med Genet 114(8):980–987
Zubenko GS, Hughes HB, Stiffler JS, Brechbiel A, Zubenko WN, Maher BS, Marazita ML (2003) Sequence variations in CREB1 cosegregate with depressive disorders in women. Mol Psychiatr 8(6):611–618
Acknowledgments
The MEMO study is supported by the German Research Society (Deutsch Forschungsgemeinschaft, grant: BE1996/1-1). Data assessment was done within the framework of the Cooperative Health Research in the Augsburg Region (KORA).
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Czira, M.E., Wersching, H., Baune, B.T. et al. Brain-derived neurotrophic factor gene polymorphisms, neurotransmitter levels, and depressive symptoms in an elderly population. AGE 34, 1529–1541 (2012). https://doi.org/10.1007/s11357-011-9313-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11357-011-9313-6