BDNF variation and mood disorders, a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects
Abstract
The brain-derived neurotrophic factor (BDNF) gene is critical for neuronal function and survival, and is likely to be important in psychiatric disorders. In this study, we used single-nucleotide polymorphism (SNP) discovery, functional analyses, and genetic association studies to better understand the potential role of BDNF sequence variation in behavior. Screening 480 unrelated individuals for SNPs and genotyping was performed in US Caucasian, American Indian, and African American populations. Lifetime DSM-III-R psychiatric diagnoses were assigned and the Tridimensional Personality Questionnaire (TPQ) was administered to measure anxious temperament (harm avoidance (HA)) and novelty seeking (NS). A novel SNP (-281 C>A) in promoter 1 was discovered that had decreased DNA binding in vitro and decreased basal reporter gene activity in transfected rat hippocampal neurons. The frequency of the -281 A allele was 0.03 in a Caucasian sample, but was virtually absent in other populations. Association analyses in a community-based sample showed that individuals with the -281 A allele (13 heterozygotes) had lower TPQ HA (F=4.8, p<0.05). In contrast, the Met 66 allele was associated with increased HA (F=4.1, p=0.02) and was most abundant in individuals with both anxiety disorders and major depression (p<0.05). Among the Val66Val homozygotes, individuals who were -281 CA heterozygotes had significantly lower HA than the -281 CC homozygotes (p<0.01). Our results suggest that in this population, the low activity -281 A allele may be protective against anxiety and psychiatric morbidity, whereas Met 66 may be a risk allele.
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Having the Val66Met allele of the BDNF gene has consequences on hippocampal volume, memory and mood disorders.
“Yet another example is the consequence of having the Val66Met allele of the BDNF gene on hippocampal volume, memory and mood disorders (Hariri et al., 2003; Pezawas et al., 2004; Jiang et al., 2005; Szeszko et al., 2005).”
From Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators (2008) · cites this paper as Jiang et al., 2005
Having the Val66Met allele of the BDNF gene affects hippocampal volume, memory, and mood disorders.
“Yet another example is the consequence of having the Val66Met allele of the brain-derived neurotrophic factor (BDNF) gene on hippocampal volume, memory, and mood disorders.54-57”
From Protective and damaging effects of stress mediators: central role of the brain (2006) · cites this paper as [57]
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- Authors
- Jiang, X., Xu, K., Hoberman, J., Tian, F., Marko, A. J., Waheed, J. F., Harris, C. R., Marini, A. M., Enoch, M.-A., & Lipsky, R. H.
- Affiliations
- National Institutes of Health (US)
- Uniformed Services University of the Health Sciences (US)
- Corresponding author
- Lipsky, Robert H
- Venue
- Neuropsychopharmacology
- Published
- 2005-03-16
- Volume
- 30
- Issue
- 7
- Pages
- 1353-1361
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2019522971
- Cited by
- 244
- References
- 45
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 2 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 6 · 2016: 12 · 2015: 15 · 2014: 12 · 2013: 16 · 2012: 17
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (Z01AA000325, Z01-AA00325)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- brain-derived neurotrophic factor, BDNF gene, promoter polymorphism, BDNF Val66Met polymorphism, anxiety disorders, harm avoidance, novelty seeking, major depressive disorder, mood disorders, genetic association, DNA binding, risk alleles, protective alleles, personality traits
- MeSH terms
- Adult, Animals, Anxiety, Cells, Cultured, Embryo, Mammalian, Female, Gene Frequency, Genotype, Hippocampus, Humans, Male, Methionine, Middle Aged, Neurons, Personality Inventory, Promoter Regions, Genetic, RNA, Messenger, Transfection, Valine, Genetic Variation, Brain-Derived Neurotrophic Factor, Amino Acid Substitution, Mood Disorders, Reverse Transcriptase Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Electrophoretic Mobility Shift Assay, Diagnostic and Statistical Manual of Mental Disorders, Rats
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