- Research article
- Open Access
- Open Peer Review
This article has Open Peer Review reports available.
Study of the serotonin transporter (SLC6A4) and BDNF genes in French patients with non syndromic mental deficiency
© Tabagh et al; licensee BioMed Central Ltd. 2010
Received: 23 July 2009
Accepted: 22 February 2010
Published: 22 February 2010
Mental deficiency has been linked to abnormalities in cortical neuronal network connectivity and plasticity. These mechanisms are in part under the control of two interacting signalling pathways, the serotonergic and the brain-derived neurotrophic (BDNF) pathways. The aim of the current paper is to determine whether particular alleles or genotypes of two crucial genes of these systems, the serotonin transporter gene (SLC6A4) and the brain-derived neurotrophic factor gene (BDNF), are associated with mental deficiency (MD).
We analyzed four functional polymorphisms (rs25531, 5-HTTLPR, VNTR, rs3813034) of the SLC6A4 gene and one functional polymorphism (Val66 Met) of the BDNF gene in 98 patients with non-syndromic mental deficiency (NS-MD) and in an ethnically matched control population of 251 individuals.
We found no significant differences in allele and genotype frequencies in the five polymorphisms studied in the SLC6A4 and BDNF genes of NS-MD patients versus control patients. While the comparison of the patterns of linkage disequilibrium (D') in the control and NS-MD populations revealed a degree of variability it did not, however, reach significance. No significant differences in frequencies of haplotypes and genotypes for VNTR/rs3813034 and rs25531/5-HTTLPR were observed.
Altogether, results from the present study do not support a role for any of the five functional polymorphisms of SLC6A4 and BDNF genes in the aetiology of NS-RM. Moreover, they suggest no epistatic interaction in NS-MD between polymorphisms in BDNF and SLC6A4. However, we suggest that further studies on these two pathways in NS-MD remain necessary.
Mental deficiency (MD) is defined as an intelligence quotient (IQ) below 70 with impairments in social skills, self-care, and work. The prevalence of non-syndromic-MD (NS-MD) in developed countries is higher than 0.5% [1, 2]. A large proportion of NS-MD cases results from abnormalities in neuronal network connectivity and plasticity, and these require particular neurotrophic factors and neurotransmitters for proper establishment and functioning .
The expression level of 5-HTT is affected by several polymorphisms in the SLC6A4 gene (Figure 1). In the promoter region, both the rs25531 polymorphism (SNP A/G), which is part of a putative binding domain for the AP2 transcription factor, and the 5HTTLPR polymorphism (deletion/insertion) influence the expression levels of 5HTT [16, 17]. A neurophysiological imaging study in humans described an association between 5-HTTLPR and prefrontal cortex-limbic excitability, supporting a relation between 5-HTT and cognitive processing [18, 19]. 5HTT expression can also be affected by a variable number of tandem repeats (VNTR) in intron 2 and a SNP (rs3813034) in the 3'UTR of the SLC6A4 gene [20, 21].
The function of 5HTT is modulated by brain-derived neurotrophic factor (BDNF) as confirmed by experiments on BDNF-deficient mice [22, 23]. BDNF, a member of the growth factor family of neurotrophins, contributes to the activity-dependent synaptic development and survival of serotonergic neurons [9, 24]. In general, BDNF is known to have crucial roles during brain development as well as in adults by regulating synaptic transmission and plasticity. Indeed, modulation of BDNF expression in mice affects synaptic vesicle functioning and plasticity, leading to defects in spatial learning . The secreted protein, BDNF, is encoded by the BDNF gene located at 11p13 (Figure 1) . The SNP rs6255 (Val66 Met) in this gene affects the activity-dependent secretion of BDNF as well as short-term episodic memory in humans [27, 28].
When combined with the observation of abnormal serotonin and BDNF blood concentrations in several subjects with NS-MD, the evidence presented thus far suggets that the serotonergic and BDNF signalling systems may be implicated in the aetiology of NS-MD [29–31]. We therefore tested this hypothesis by analysing five functional polymorphisms in the SLC6A4 and BDNF genes in patients with NS-MD.
The patients with NS-MD (n = 98; 77 males and 21 females) were recruited in the genetics unit of the University hospital in Tours (France). All patients showed moderate to severe NS-MD and were submitted to a careful clinical examination, searching for specific signs of the NS-MD syndrome. The patients had no familial history of MD and were therefore considered sporadic. All were negative for fragile X mutation (FRAXA). The control group (n = 251) consisted of anonymous and unrelated French Caucasian individuals without MD. DNA was extracted from peripheral blood sample using a standard protocol. All patients or parents gave their informed consent.
The rs25531 and 5-HTTLPR in SLC6A4 were analyzed by RFLP as described in Wendland et al. . The PCR amplification step allowed to differentiate between the short (S, 484 bp) versus the long allele (L, 528 bp) of 5-HTTLPR. The restriction step using HpaII enzyme (Biolabs) permitted to identify the alleles (A/G) of rs25531, located 19 bp upstream of 5-HTTLPR. Thus, 10 patterns of migration corresponding to 10 genotypes (rs25531/5-HTTLPR) could be identified after electrophoresis on a 2% agarose gel (all primers and conditions are available upon request).
The VNTR (17 bp variable number of tandem repeats) in SLC6A4 was studied by PCR followed by electrophoresis on 3% agarose gel stained with ethidium bromide. PCR conditions for the amplification of the 9 (345 bp), 10 (360 bp) and 12 (390 bp) repeat alleles are described in Cook et al. .
The rs3813034 (G/T) in the 3'UTR region of SLC6A4 gene was genotyped by RFLP. PCR was performed on 100 ng of genomic DNA with 125 μM of each dNTP, 200 nM of primers, 1.5 mM MgCl2 and 0.02 U/μL of Taq DNA polymerase (Invitrogen), before incubation with MseI (Fermentas) and electrophoresis on a 2% agarose gel.
The rs6255 (G/A) in BDNF was studied by denaturing high performance liquid chromatography (dHPLC, WAVE System 3500 HT, Transgenomic). PCR was performed on 100 ng of genomic DNA with 125 μM of each dNTP, 200 nM of primers, 1.5 mM MgCl2 and 0.02 U/μL of Taq DNA polymerase (Invitrogen) (Tm: 59°C). PCR products were denaturated (96°C 5 min) and slowly renaturated (96°C to 50°C; 1°C/minute) before analysis by dHPLC at 60.2°C. For individuals showing only homoduplex formations (G/G or A/A homozygotes), 10 μL of PCR were mixed with 10 μL of a PCR product (standard) previously analyzed by DNA sequencing (G/G homozygote). The mixture was denaturated, renaturated, and analysed by dHPLC.
Allele and genotype frequencies in patients and controls were compared with a χ2 test. Odds ratios were estimated for alleles and genotypes http://www.hutchon.net/ConfidOR.htm . Linkage disequilibrium (parameter D') between markers was calculated using the software Haploview v.3.32, with the exception of rs25531 and 5HTTLPR polymorphisms for which chromosome phases could be obtained directly. LD patterns were analysed by Spearman rank correlation (Excel) between LD measures.
Analysis of SLC6A4 polymorphisms in NS-MD
Allelic distributions of polymorphisms in SLC6A4 and BDNF genes in the control and NS-MD populations.
MR vs Controls
Haplotypes and phased genotypes distributions for the rs25531 and 5-HTTLPR polymorphisms in the SLC6A4 gene in control and NS-MD populations.
MR vs Controls
Haplotypes (5HTT gene)
AS, GL, GS
Phased genotypes (5HTT gene)
Genotypes (5HTT/BDNF genes)
AL AL/Val Val
AL AL/Val Met
Haplotypes and genotypes distributions for the VNTR and rs3813034 polymorphisms in the SLC6A4 gene in controls and NS-MD patients.
MR vs Controls
Analysis of the BDNF Val66 Met polymorphism in NS-MD
Hardy Weinberg distribution was respected for the alleles of the BDNF gene in the two populations. We developed a rapid genotyping method using dHPLC to analyze the allelic distribution of the rs6255 (Val66 Met) polymorphism in the BDNF gene (Figure 1). A first analysis by dHPLC allowed to identify the heterozygote genotypes (G/A), and a second analysis, in presence of a standard, allowed to discriminate between G/G or A/A homozygotes. We did not find a significant association between NS-MD and alleles of the rs6255 polymorphism (χ2 = 0.40; p = 0.53) (Table 1).
Several studies have suggested a synergistic interaction between the serotonergic and the BDNF signalling systems . We did not observe an association between NS-MD and the 5HTTLPR/rs6255, rs25531 (AP2)/rs6255, or rs3813034/rs6255 genotypes (data not shown). No association was found between NS-MD and a particular combination of AP2-5HTTLPR (AL or others) of the SLC6A4 gene and rs6255 (A or G) of the BDNF gene.
We here report the first genetic study on the serotonin transporter and the brain-derived neurotrophic factor genes in NS-MD. We have investigated five functional polymorphisms in these genes in control individuals and NS-MD patients matched for origin (Central France) and ethnicity (Caucasian).
Power calculations had shown that with the given sample sizes we should be able to detect differences in allelic frequencies of 12% for 5-HTTLPR, 12% for VNTR, 13% for rs3813034, and 10% for BDNF rs6255 (alpha of 5%, power of 80%). Functional studies have reported that the S allele of 5-HTTLPR was associated with a lower expression of 5-HTT and a lower serotonin reuptake activity [12, 36, 37]. Our results do not support a direct role for the S allele of 5-HTTLPR in NS-MD. Wendland et al.  suggested that the effect of 5-HTTLPR on SLC6A4 expression may be due to a nearby (19 bp) rs25531 polymorphism in the promoter. The G allele of this polymorphism is located in a consensus binding site for AP2, a family of transcription factors described as positive or negative regulators of transcription . Data from Hu and colleagues  has shown that the G allele of rs25531 was associated with a decreased expression of 5-HTT mRNA compared to the A allele. We did not detect differences in rs25531 allelic frequencies between NS-MD and control patients. Moreover, we have observed that the frequency of the GS haplotype in both NS-MD and control patients was very low, suggesting that the G allele of rs25531 was not a risk factor for NS-MD. No statistically significant difference was observed between control and NS-MD patients for genotypes and allelic distributions of the VNTR and rs3813034.
Brain-derived neurotrophic factor (BDNF) is a key regulatory protein of serotonin levels in several brain regions. The pro-BDNF protein is cleaved to form a mature protein before being secreted. The rs6255 polymorphism (Val66 Met), which affects this cleavage, has been associated with impaired hippocampal functioning and decreased scores on the Logical Memory subtest of the Wechsler Memory Scale-Revised . Moreover, Harris et al.  have shown that the rs6255 genotype contributes to age-related changes in reasoning skills, which are closely related to general intelligence. Thus, a number of studies support an important role for BDNF in cognition processes, and particularly in learning and memory. We did not observe an association between a particular allele or a genotype of rs6255 and French patients with NS-MD. However, it will be interesting to further analyze the complex BDNF locus in neurodevelopmental diseases such as NS-MD. Indeed, recent studies, which have reported a detailed characterization of the BDNF gene locus, have indicated 17 and 13 alternative transcripts for BDNF and anti-BDNF, respectively . Anti-BDNF are antisense transcripts expressed from the opposite strand of the BDNF gene .
Serotonergic and BDNF signalling systems have significant interactions with overlapping functional targets . Genetic epistasis between these two systems was confirmed by studies on BDNF and SLC6A4 transgenic mice [23, 24]. In the present study on NS-MD patients we observed no genetic interactions between Val66 Met in BDNF and the four polymorphisms studied in SLC6A4. Particularly, we did not find a relation between the Met allele in BDNF and the S allele in SLC6A4, as described in children with high depressive scores . However, these latter results obtained by Kauffman et al.  have been challenged by several studies reporting that the Met allele is protective for anxiety and depression [43, 44].
The present study suggests that the SLC6A4 and BDNF genes have no major effect on the aetiology of NS-MD. Moreover we did not find a gene-by-gene interaction in NS-MD patients between polymorphisms in the BDNF and SLC6A4 genes. However, further studies will be necessary to fully reject the implication of SLC6A4 and BDNF in NS-MD. Indeed the expression of these two genes is regulated by epigenetic processes, and these may still be impaired in NS-MD [45, 46]. Moreover, effects on mRNA splicing, protein localization, and properties of 5-HTT and BDNF could be possible mechanisms for influencing NS-MD risk.
This work was supported by INSERM, Université François Rabelais de Tours, Fondation pour la Recherche Médicale.
- Roeleveld N, Zielhuis GA, Gabreels F: The prevalence of mental deficiency: a critical review of recent literature. Dev Med Child Neurol. 1997, 39: 125-132.View ArticlePubMedGoogle Scholar
- Leonard H, Wen X: The epidemiology of mental deficiency: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev. 2002, 8: 117-134. 10.1002/mrdd.10031.View ArticlePubMedGoogle Scholar
- Dierssen M, Ramakers GJ: Dendritic pathology in mental deficiency: from molecular genetics to neurobiology. Genes Brain Behav. 2006, 5 (Suppl 2): 48-60. 10.1111/j.1601-183X.2006.00224.x.View ArticlePubMedGoogle Scholar
- Strobel A, Dreisbach G, Muller J, Goschke T, Brocke B, Lesch KP: Genetic Variation of Serotonin Function and Cognitive Control. J Cogn Neurosci. 2007Google Scholar
- Whitaker-Azmitia PM: Serotonin and brain development: role in human developmental diseases. Brain Res Bull. 2001, 56: 479-485. 10.1016/S0361-9230(01)00615-3.View ArticlePubMedGoogle Scholar
- Persico AM, Mengual E, Moessner R, Hall FS, Revay RS, Sora I, Arellano J, DeFelipe J, Gimenez-Amaya JM, Conciatori M, Marino R, Baldi A, Cabib S, Pascucci T, Uhl GR, Murphy DL, Lesch KP, Keller F: Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J Neurosci. 2001, 21: 6862-6873.PubMedGoogle Scholar
- Gaspar P, Cases O, Maroteaux L: The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci. 2003, 4: 1002-1012. 10.1038/nrn1256.View ArticlePubMedGoogle Scholar
- Wellman CL, Izquierdo A, Garrett JE, Martin KP, Carroll J, Millstein R, Lesch KP, Murphy DL, Holmes A: Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. J Neurosci. 2007, 27: 684-691. 10.1523/JNEUROSCI.4595-06.2007.View ArticlePubMedGoogle Scholar
- Mamounas LA, Altar CA, Blue ME, Kaplan DR, Tessarollo L, Lyons WE: BDNF promotes the regenerative sprouting, but not survival, of injured serotonergic axons in the adult rat brain. J Neurosci. 2000, 20: 771-782.PubMedGoogle Scholar
- Salichon N, Gaspar P, Upton AL, Picaud S, Hanoun N, Hamon M, De Maeyer E, Murphy DL, Mossner R, Lesch KP, Hen R, Seif I: Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-ht transporter knock-out mice. J Neurosci. 2001, 21: 884-96.PubMedGoogle Scholar
- Bradley CC, Blakely RD: Alternative splicing of the human serotonin transporter gene. J Neurochem. 1997, 69: 1356-1367.View ArticlePubMedGoogle Scholar
- Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S, Grüsser SM, Flor H, Schumann G, Mann K, Büchel C: Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci. 2005, 8: 20-21. 10.1038/nn1366.View ArticlePubMedGoogle Scholar
- Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR: 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005, 8: 828-834. 10.1038/nn1463.View ArticlePubMedGoogle Scholar
- Watson C, Hoeft F, Garrett AS, Hall SS, Reiss AL: Aberrant brain activation during gaze processing in boys with fragile X syndrome. Arch Gen Psychiatry. 2008, 65: 1315-1323. 10.1001/archpsyc.65.11.1315.View ArticlePubMedPubMed CentralGoogle Scholar
- Meyer-Lindenberg A, Hariri AR, Munoz KE, Mervis CB, Mattay VS, Morris CA, Berman KF: Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci. 2005, 8: 991-993. 10.1038/nn1494.View ArticlePubMedGoogle Scholar
- Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al: Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996, 274: 1527-1531. 10.1126/science.274.5292.1527.View ArticlePubMedGoogle Scholar
- 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. 10.1097/01.ALC.0000150008.68473.62.View ArticlePubMedGoogle Scholar
- Fallgatter AJ, Bartsch AJ, Herrmann MJ: Electrophysiological measurements of anterior cingulate function. J Neural Transm. 2002, 109: 977-988. 10.1007/s007020200080.View ArticlePubMedGoogle Scholar
- Canli T, Lesch KP: Long story short: the serotonin transporter in emotion regulation and social cognition. Nat Neurosci. 2007, 10: 1103-1109. 10.1038/nn1964.View ArticlePubMedGoogle Scholar
- MacKenzie A, Quinn JA: serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA. 1999, 96: 15251-15255. 10.1073/pnas.96.26.15251.View ArticlePubMedPubMed CentralGoogle Scholar
- Battersby S, Ogilvie AD, Blackwood DH, Shen S, Muqit MM, Muir WJ, Teague P, Goodwin GM, Harmar AJ: Presence of multiple functional polyadenylation signals and a single nucleotide polymorphism in the 3' untranslated region of the human serotonin transporter gene. J Neurochem. 1999, 72: 1384-1388. 10.1046/j.1471-4159.1999.721384.x.View ArticlePubMedGoogle Scholar
- Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang SJ, Tolliver T, Lesch KP, Lu B, Murphy DL: Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. J Neurosci Res. 2005, 79: 756-771. 10.1002/jnr.20410.View ArticlePubMedGoogle Scholar
- Daws LC, Munn JL, Valdez MF, Frosto-Burke T, Hensler JG: Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): in vivo studies in BDNF-deficient mice. J Neurochem. 2007, 101: 641-651. 10.1111/j.1471-4159.2006.04392.x.View ArticlePubMedGoogle Scholar
- Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM: BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Res. 1996, 710: 11-20. 10.1016/0006-8993(95)01289-3.View ArticlePubMedGoogle Scholar
- Yamada MK, Nakanishi K, Ohba S, Nakamura T, Ikegaya Y, Nishiyama N, Matsuki N: Brain-derived neurotrophic factor promotes the maturation of GABAergic mechanisms in cultured hippocampal neurons. J Neurosci. 2002, 22: 7580-7585.PubMedGoogle Scholar
- Liu QR, Walther D, Drgon T, Polesskaya O, Lesnick TG, Strain KJ, de Andrade M, Bower JH, Maraganore DM, Uhl GR: Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease. Am J Med Genet B Neuropsychiatr Genet. 2005, 134: 93-103.View ArticleGoogle Scholar
- Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR: The BDNF val66 met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003, 112: 257-269. 10.1016/S0092-8674(03)00035-7.View ArticlePubMedGoogle Scholar
- Miyajima F, Ollier W, Mayes A, Jackson A, Thacker N, Rabbitt P, Pendleton N, Horan M, Payton A: Brain-derived neurotrophic factor polymorphism Val66 Met influences cognitive abilities in the elderly. Genes Brain Behav. 2008, 7: 411-417. 10.1111/j.1601-183X.2007.00363.x.View ArticlePubMedGoogle Scholar
- Singh VK, Singh EA, Warren RP: Hyperserotoninemia and serotonin receptor antibodies in children with autism but not mental deficiency. Biol Psychiatry. 1997, 41: 753-755. 10.1016/S0006-3223(96)00522-7.View ArticlePubMedGoogle Scholar
- Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, Hansen RL, Phillips TM: Neuropeptides and neurotrophins in neonatal blood of children with autism or mental deficiency. Ann Neurol. 2001, 49: 597-606. 10.1002/ana.1024.View ArticlePubMedGoogle Scholar
- Miyazaki K, Narita N, Sakuta R, Miyahara T, Naruse H, Okado N, Narita M: Serum neurotrophin concentrations in autism and mental deficiency: a pilot study. Brain Dev. 2004, 26: 292-295. 10.1016/S0387-7604(03)00168-2.View ArticlePubMedGoogle Scholar
- Wendland JR, Martin BJ, Kruse MD, Lesch KP, Murphy DL: Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry. 2006, 113: 224-226. 10.1038/sj.mp.4001789.View ArticleGoogle Scholar
- Cook EH, Courchesne R, Lord C, Cox NJ, Yan S, Lincoln A, Haas R, Courchesne E, Leventhal BL: Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry. 1997, 2: 247-250. 10.1038/sj.mp.4000266.View ArticlePubMedGoogle Scholar
- Bland JM, Altman DG: Statistics Notes: The odds ratio. BMJ. 2000, 320: 1468-10.1136/bmj.320.7247.1468.View ArticlePubMedPubMed CentralGoogle Scholar
- Martinowich K, Lu B: Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology. 2008, 33: 73-83. 10.1038/sj.npp.1301571.View ArticlePubMedGoogle Scholar
- Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, Lesch KP: Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996, 66: 2621-2624.View ArticlePubMedGoogle Scholar
- Collier DA, Stöber G, Li T, Heils A, Catalano M, Di Bella D, Arranz MJ, Murray RM, Vallada HP, Bengel D, Müller CR, Roberts GW, Smeraldi E, Kirov G, Sham P, Lesch KP: A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry. 1996, 1: 453-460.PubMedGoogle Scholar
- Eckert D, Buhl S, Weber S, Jager R, Schorle H: The AP-2 family of transcription factors. Genome Biol. 2005, 6: 246-10.1186/gb-2005-6-13-246.View ArticlePubMedPubMed CentralGoogle Scholar
- Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D: Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet. 2006, 78: 815-826. 10.1086/503850.View ArticlePubMedPubMed CentralGoogle Scholar
- Harris SE, Fox H, Wright AF, Hayward C, Starr JM, Whalley LJ, Deary IJ: The brain-derived neurotrophic factor Val66 Met polymorphism is associated with age-related change in reasoning skills. Mol Psychiatry. 2006, 11: 505-513. 10.1038/sj.mp.4001799.View ArticlePubMedGoogle Scholar
- Pruunsild P, Kazantseva A, Aid T, Palm K, Timmusk T: Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics. 2007, 397-406. 10.1016/j.ygeno.2007.05.004.Google Scholar
- Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter J: Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry. 2006, 59: 673-680. 10.1016/j.biopsych.2005.10.026.View ArticlePubMedGoogle Scholar
- Hünnerkopf R, Strobel A, Gutknecht L, Brocke B, Lesch KP: Interaction between BDNF Val66 Met and dopamine transporter gene variation influences anxiety-related traits. Neuropsychopharmacology. 2007, 32: 2552-2560. 10.1038/sj.npp.1301383.View ArticlePubMedGoogle Scholar
- Frodl T, Schüle C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Möller HJ, Meisenzahl EM: Association of the brain-derived neurotrophic factor Val66 Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry. 2007, 64: 410-416. 10.1001/archpsyc.64.4.410.View ArticlePubMedGoogle Scholar
- Philibert R, Madan A, Andersen A, Cadoret R, Packer H, Sandhu H: Serotonin transporter MDNA levels are associated with the methylation of an upstream CpG island. Am J Med Genet B Neuropsychiatr Genet. 2007, 144: 101-105.View ArticleGoogle Scholar
- Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M: Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem. 2007, 14: 268-276. 10.1101/lm.500907.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/11/30/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.