Gene Report

Basic Information

Approved Symbol	BDNF
Approved Name	brain-derived neurotrophic factor
Name Alias	neurotrophin
Location	11p14.1
Position	chr11:27676440-27743605 (-)
External Links	Entrez Gene: 627 Ensembl: ENSG00000176697 UCSC: uc009yje.3 HGNC ID: 1033
No. of Studies (Positive/Negative)	23(17/6)
Type	Literature-origin; SNP mapped; Protein mapped

Positive relationships between BDNF and MDD (count: 8)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
Brain Derived Neurotrophic Factor (BDNF)	Lau, 2010	patients and normal controls	P-value<0.05	Significant effects of diagnosis and diagnosis-by-genotype i...... Significant effects of diagnosis and diagnosis-by-genotype interactions (F's>4, p's<0.05) characterized activations in amygdala and anterior hippocampal regions. Greater activations in patients than healthy adolescents were found. Critically, these hyperactivations were modulated by BDNF genotype: Met-carriers showed greater neural responses of emotional faces than Val/Val homozygotes in patients only. More...
BDNF	Schumacher, 2005	patients and normal controls	P-value=0.00006	Haplotype analysis of marker combination rs988748-(GT)n-rs62...... Haplotype analysis of marker combination rs988748-(GT)n-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). More...
BDNF	Licinio, 2009	patients and normal controls		Association analyses of patients with MDD and controls showe...... Association analyses of patients with MDD and controls showed that 6 SNPs in this gene were associated with MDD (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) More...
BDNF	Zhang, 2010	patients and normal controls	P-value<0.05	Further gene-gene interaction analyses showed a significant ...... Further gene-gene interaction analyses showed a significant effect of a two-locus BDNF/GSK3B interaction with MDD (GSK3B rs6782799 and BDNF rs7124442) (corrected P = 0.011), and also for a three-locus interaction (GSK3B rs6782799, BDNF rs6265 and BDNF rs7124442) (corrected P = 0.019). More...
BDNF	Sun, 2011	patients and normal controls	P-value<0.001	The analysis revealed a strong association between the BDNF ...... The analysis revealed a strong association between the BDNF G-712A genotype distribution and MD (p=0.0005). The frequency of the -712A allele was significantly higher in MD patients than in the healthy controls (p=0.0007). More...
BDNF	Kanellopoulos, 2011	patients and normal controls		elderly MDD BDNF val/val homozygotes had significantly highe...... elderly MDD BDNF val/val homozygotes had significantly higher right hippocampal volumes compared with nondepressed val/val subjects. In addition, depressed met carriers had an earlier age of onset of depressive illness than val/val homozygotes More...
BDNF	Oral E, 2012	patients and normal controls		The MDD group showed significantly poorer performance than t...... The MDD group showed significantly poorer performance than the control group in cognitive functions; they also had lower levels of BDNF than the control group. More...
BDNF	D'Addario C, 2013	patients and normal controls	P-value <0.05	A signi?cant reduction of BDNF gene expression in MDD subjec...... A signi?cant reduction of BDNF gene expression in MDD subjects (0.45, SD=10; p<.05, according to unpaired t test) versus controls(1.00, SD=21; Figure 1A)was observed. In addition, an increase of DNA methylation at BDNF gene promoter was observed in MDD patients, compared with control subjects (32.52% SD=2.03% vs.24.04% SD=2.08%; p <.05, according to unpaired t test; Figure 1B) More...

Positive relationships between BDNF and other components at different levels (count: 13)

Genetic/epigenetic locus					Protein and other molecule			Cell and molecular pathway			Neural system			Cognition and behavior		Symptoms and signs			Environment

Name in Literature	Related Components
Level	Approved Name (Name in Literature)	Type	Reference	Research Type	Statistical Result	Relation Description	All
BDNF		CRHR1(CRHR1)	gene	Xiao Z, 2011	patients and normal controls	P-value = 0.05	BDNF and CRHR1 interactions were found in the significant 2-...... BDNF and CRHR1 interactions were found in the significant 2-locus, gene-gene interaction models (p = 0.05) using a generalized multifactor dimensionality reduction (GMDR) method. More...
BDNF		Cyclic AMP-responsive element-binding protein 1(cAMP response element-binding protein (CREB))	protein	Schmidt HD, 2010	animal model		BDNF levels as well as expression of pCREB and pERK were ele...... BDNF levels as well as expression of pCREB and pERK were elevated in the hippocampus of adult mice receiving peripheral BDNF More...
BDNF		mapkkk cascade(signal-regulated kinase (ERK))	pathway	Schmidt HD, 2010	animal model		BDNF levels as well as expression of pCREB and pERK were ele...... BDNF levels as well as expression of pCREB and pERK were elevated in the hippocampus of adult mice receiving peripheral BDNF More...
BDNF		Hippocampus(hippocampus)	brain morphology and function	Frodl, 2007	patients and normal controls	P-value=0.006	Significantly smaller hippocampal volumes were observed for ...... Significantly smaller hippocampal volumes were observed for patients and for controls carrying the Met-BDNF allele compared with subjects homozygous for the Val-BDNF allele (P = .006). More...
Brain Derived Neurotrophic Factor (BDNF)		Amygdala(amygdala)	brain morphology and function	Lau, 2010	patients and normal controls	P-value<0.05	Significant effects of diagnosis and diagnosis-by-genotype i...... Significant effects of diagnosis and diagnosis-by-genotype interactions (F's>4, p's<0.05) characterized activations in amygdala and anterior hippocampal regions. Greater activations in patients than healthy adolescents were found. Critically, these hyperactivations were modulated by BDNF genotype: Met-carriers showed greater neural responses of emotional faces than Val/Val homozygotes in patients only. More...
Brain Derived Neurotrophic Factor (BDNF)		anterior hippocampus(anterior hippocampal regions)	brain morphology and function	Lau, 2010	patients and normal controls	P-value<0.05	Significant effects of diagnosis and diagnosis-by-genotype i...... Significant effects of diagnosis and diagnosis-by-genotype interactions (F's>4, p's<0.05) characterized activations in amygdala and anterior hippocampal regions. Greater activations in patients than healthy adolescents were found. Critically, these hyperactivations were modulated by BDNF genotype: Met-carriers showed greater neural responses of emotional faces than Val/Val homozygotes in patients only. More...
Val66Met BDNF		left hippocampus(left hippocampus)	brain morphology and function	Gonul, 2011	patients and normal controls		among Val homozygotes depressed patients had significantly s...... among Val homozygotes depressed patients had significantly smaller left hippocampal volumes compared to controls. More...
BDNF		Hippocampus(hippocampal volumes)	brain morphology and function	Kanellopoulos, 2011	patients and normal controls		elderly MDD BDNF val/val homozygotes had significantly highe...... elderly MDD BDNF val/val homozygotes had significantly higher right hippocampal volumes compared with nondepressed val/val subjects. More...
brain-derived neurotrophic factor (BDNF)		anhedonic-like behavior from animal model(anhedonic-like behavior)	cognition and behavior	Autry, 2009	animal model		The loss of BDNF lowers the threshold for female mice studie...... The loss of BDNF lowers the threshold for female mice studied at random throughout estrus to display anxiogenic and anhedonic behaviors after chronic stress compared with wild-type female mice. More...
BDNF		Suicide(suicide attempt)	symptoms	Iga, 2007	patients and normal controls		The dose of Met allele had significant effects on psychotic ...... The dose of Met allele had significant effects on psychotic feature and suicidal behavior and family history More...
BDNF		Life events(negative life events)	environment	Yang, 2010	patients and normal controls	P-value<0.05	We observed a significant three-way interaction among BDNF r...... We observed a significant three-way interaction among BDNF rs6265, GSK3B rs6782799, and negative life events (corrected P-value, 0.011-0.012; cross-validation consistency, 7; prediction error, 0.4349). More...
BDNF		Stress(early life stress)	environment	Quinn CR, 2012	patients only		Key findings indicated that BDNF and 5-HTT polymorphisms in ...... Key findings indicated that BDNF and 5-HTT polymorphisms in combination with ELS contributed to the development of non-melancholic depression. An interaction between BDNF and ELS increased the risk of non-melancholia by 3.327, whereas the interaction between 5-HTT and ELS increased risk by 2.406. More...
BDNF		Stress(stress)	environment	Fuchikami M, 2009	animal model		SIS significantly decreased the levels of total BDNF mRNA wi...... SIS significantly decreased the levels of total BDNF mRNA with significantly reduced levels of exons I and IV mRNA followed by a significant reduction in BDNF protein 4 h after SIS. More...

Positive relationship network of BDNF in MK4MDD

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Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between BDNF and MDD (count: 5)

Name in Literature	Reference	Research Type	Relation Description
BDNF	Tsai SJ, 2003	Patients and nomal controls	No significant differences were demonstrated for the genotyp...... No significant differences were demonstrated for the genotype or allele frequency of the BDNF polymorphism comparing the MDD and control groups. More...
BDNF	Hong CJ, 2003	Patients and nomal controls	The genotype and allele frequencies for the BDNF gene Val66M...... The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing depression groups (total, bipolar disorder or major depression) and control subjects. Furthermore, it was not demonstrated that this BDNF polymorphism was associated with age of onset or suicidal history in our mood disorder patients. More...
BDNF	Liu X, 2009	Patients and nomal controls	No significant associations with MDD were demonstrated for t...... No significant associations with MDD were demonstrated for three SNPs. More...
BDNF	Zou YF, 2010	Patients and nomal controls	In the multivariate regression analysis, there was no signif...... In the multivariate regression analysis, there was no significant association between severity of depression and BDNF Val66Met polymorphism. More...
BDNF	Evinova A, 2012	patients and normal controls	We found no significant association of either the BDNF G196A...... We found no significant association of either the BDNF G196A or MTHFR C677T polymorphisms with major depressive disorder neither in female nor male group of patients. More...

Negative relationships between BDNF and other components at different levels (count: 1)

Genetic/epigenetic locus					Protein and other molecule			Cell and molecular pathway			Neural system			Cognition and behavior		Symptoms and signs			Environment

Name in Literature	Level	Approved Name (Name in Literature)	Type	Reference	Research Type	Statistical Result	Relation Description
Name in Literature	Related Components
BDNF		Hippocampus(hippocampal volume)	brain morphology and function	Cole, 2011	patients and normal controls		Hippocampal volume normalized by intracranial volume (ICV) s...... Hippocampal volume normalized by intracranial volume (ICV) showed no significant difference between 5HTTLPR S allele carriers and L/L homozygotes or between BDNF Met allele carriers and Val/Val homozygotes in the group of healthy individuals. More...

BDNF related SNPs in MK4MDD (count: 9)

#rs	Location	Annotation	No. of Studies (Positive/Negative)
rs7103873	chr11:27700317(Forward)	downstream_gene_variant; intron_variant; nc_transcript_variant; NMD_transcript_variant	1(0/1)
rs28722151	chr11:27681176(Forward)	5_prime_UTR_variant; downstream_gene_variant; intron_variant; nc_transcript_variant; NMD_transcript_variant; non_coding_exon_variant; upstream_gene_variant	1(1/0)
rs11030101	chr11:27680744(Forward)	5_prime_UTR_variant; downstream_gene_variant; intron_variant; nc_transcript_variant; NMD_transcript_variant; non_coding_exon_variant; upstream_gene_variant	2(1/1)
rs6265	chr11:27679916(Forward)	3_prime_UTR_variant; downstream_gene_variant; intron_variant; missense_variant; nc_transcript_variant; NMD_transcript_variant; non_coding_exon_variant	7(5/2)
rs2030324	chr11:27726915(Forward)	intron_variant; nc_transcript_variant; upstream_gene_variant	1(0/1)
rs11030103	chr11:27682333(Forward)	downstream_gene_variant; intron_variant; nc_transcript_variant; NMD_transcript_variant; upstream_gene_variant	1(1/0)
rs10835210	chr11:27695910(Forward)	intron_variant; nc_transcript_variant; NMD_transcript_variant	1(0/1)
rs41282918	chr11:27678780(Forward)	3_prime_UTR_variant; downstream_gene_variant; intron_variant; nc_transcript_variant; NMD_transcript_variant; non_coding_exon_variant	1(1/0)
rs12273539	chr11:27683311(Forward)	downstream_gene_variant; intron_variant; nc_transcript_variant; NMD_transcript_variant; upstream_gene_variant	1(1/0)

BDNF related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Brain-derived neurotrophic factor	P23560	20(19/1)	Literature-origin

BDNF related GO terms (count: 37)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0008021	synaptic vesicle	cellular component	IEA

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0072347	response to anesthetic	biological process	IEA
GO:0007611	learning or memory	biological process	IEA
GO:0051965	positive regulation of synapse assembly	biological process	IDA[19036963]
GO:0055093	response to hyperoxia	biological process	IEA
GO:0007631	feeding behavior	biological process	IEA
GO:0042490	mechanoreceptor differentiation	biological process	IEA
GO:0048170	positive regulation of long-term neuronal synaptic plasticity	biological process	IEA
GO:0007412	axon target recognition	biological process	IEA
GO:0033189	response to vitamin A	biological process	IEA
GO:0045843	negative regulation of striated muscle tissue development	biological process	IEA
GO:0008038	neuron recognition	biological process	IEA
GO:0016358	dendrite development	biological process	IEA
GO:0007399	nervous system development	biological process	TAS[2236018]
GO:0006120	mitochondrial electron transport, NADH to ubiquinone	biological process	IEA
GO:0007411	axon guidance	biological process	IEA
GO:0008083	growth factor activity	molecular function	IEA
GO:0042596	fear response	biological process	IEA
GO:0014076	response to fluoxetine	biological process	IEA
GO:0009725	response to hormone stimulus	biological process	IEA
GO:0014047	glutamate secretion	biological process	IEA
GO:0001666	response to hypoxia	biological process	IEA
GO:0045666	positive regulation of neuron differentiation	biological process	IEA
GO:0048471	perinuclear region of cytoplasm	cellular component	ISS
GO:0048839	inner ear development	biological process	IEA
GO:0019222	regulation of metabolic process	biological process	IEA
GO:0021675	nerve development	biological process	IEA
GO:0005169	neurotrophin TRKB receptor binding	molecular function	IEA
GO:0046668	regulation of retinal cell programmed cell death	biological process	IEA
GO:0005576	extracellular region	cellular component	IEA
GO:0007406	negative regulation of neuroblast proliferation	biological process	IEA
GO:0002544	chronic inflammatory response	biological process	IEA
GO:0005737	cytoplasm	cellular component	ISS
GO:0048172	regulation of short-term neuronal synaptic plasticity	biological process	IEA
GO:0043524	negative regulation of neuron apoptotic process	biological process	IEA
GO:0060079	regulation of excitatory postsynaptic membrane potential	biological process	IEA
GO:0001657	ureteric bud development	biological process	IEA

BDNF related KEGG pathways (count: 3)

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa05016	huntingtons disease	Huntington's disease	Huntington disease (HD) is an autosomal-dominant neurodegene...... Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by a CAG repeat expansion in the IT15 gene, which results in a long stretch of polyglutamine close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. In the cytoplasm, full-length mHtt can interfere with BDNF vesicular transport on microtubules. This mutant protein also may lead to abnormal endocytosis and secretion in neurons, because normal Htt form a complex with the proteins Hip1, clathrin and AP2 that are involved in endocytosis. In addition, mHtt affects Ca2+ signaling by sensitizing InsP3R1 to activation by InsP3, stimulating NR2B/NR1 NMDAR activity, and destabilizing mitochondrial Ca2+ handling. As a result, stimulation of glutamate receptors leads to supranormal Ca2+ responses in HD MSN and mitochondrial Ca2+ overload. The mHtt translocates to the nucleus, where it forms intranuclear inclusions, though they are not primarily responsible for toxicity. Nuclear toxicity is believed to be caused by interference with gene transcription, leading to loss of transcription of neuroprotective molecules such as BDNF. While mHtt binds to p53 and upregulates levels of nuclear p53 as well as p53 transcriptional activity. Augmented p53 mediates mitochondrial dysfunction. More...
hsa04722	neurotrophin signaling_pathway	Neurotrophin signaling pathway	Neurotrophins are a family of trophic factors involved in di...... Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory. More...
hsa04010	mapk signaling_pathway	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a hig...... The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli. More...

BDNF related BioCarta pathways (count: 0)

BDNF related Reactome pathways (count: 0)

BDNF related interactors from protein-protein interaction data in HPRD (count: 10)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
BDNF	NOS3	No	in vitro	10493752
BDNF	BDNF	Yes	in vitro	8174548 , 7961712
BDNF	CADPS2	No	in vitro;in vivo	14715936
BDNF	ESR1	Yes	in vitro	11923430
BDNF	NCAM1	Yes	in vitro	10760298
BDNF	NTRK2	Yes	in vitro;in vivo	9312147
BDNF	CPE	No	in vitro	15664176
BDNF	SORT1	Yes	in vitro;in vivo	15987945
BDNF	MBTPS1	No	in vitro	9990022
BDNF	NTF3	No	in vitro	7703225

Gene Report

Literature-origin GO terms

Gene mapped GO terms

Gene mapped KEGG pathways