Population genetic study of the brain-derived neurotrophic factor (BDNF) gene
Open Access
- 3 March 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Psychiatry
- Vol. 15 (8), 810-815
- https://doi.org/10.1038/mp.2009.24
Abstract
Genetic variants in the brain-derived neurotrophic factor (BDNF) gene, predominantly the functional Val66Met polymorphism, have been associated with risk of bipolar disorder and other psychiatric disorders. However, not all studies support these findings, and overall the evidence for the association of BDNF with disease risk is weak. As differences in population genetic structure between patient samples could cause discrepant or spurious association results, we investigated this possibility by carrying out population genetic analyses of the BDNF genomic region. Substantial variation was detected in BDNF coding region single-nucleotide polymorphism (SNP) allele and haplotype frequencies between 58 global populations, with the derived Met allele of Val66Met ranging in frequency from 0 to 72% across populations. FST analyses to assess diversity in the HapMap populations determined that the Val66Met FST value was at the 99.8th percentile among all SNPs in the genome. As the BDNF population genetic differences may be due to local selection, we performed the long-range haplotype test for selection using 68 SNPs spanning the BDNF genomic region in 12 European-derived pedigrees. Evidence for positive selection was found for a high-frequency Val-carrying haplotype, with a relative extended haplotype homozygosity value above the 99th percentile compared with HapMap data (P=4.6 × 10−4). In conclusion, we observed considerable BDNF allele and haplotype diversity among global populations and evidence for positive selection at the BDNF locus. These phenomena can have a profound impact on the detection of disease susceptibility genes and must be considered in gene association studies of BDNF.Keywords
This publication has 39 references indexed in Scilit:
- Brain-derived neurotrophic factor and risk of schizophrenia: An association study and meta-analysisBiochemical and Biophysical Research Communications, 2007
- Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related BehaviorScience, 2006
- Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain‐derived neurotrophic factor genePsychiatry and Clinical Neurosciences, 2006
- A haplotype map of the human genomeNature, 2005
- The yin and yang of neurotrophin actionNature Reviews Neuroscience, 2005
- Effect of the BDNF Val66Met genotype on episodic memory in schizophreniaSchizophrenia Research, 2005
- Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populationsHuman Molecular Genetics, 2004
- The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal FunctionCell, 2003
- Detecting recent positive selection in the human genome from haplotype structureNature, 2002
- A Comprehensive Human Linkage Map with Centimorgan DensityScience, 1994