title: Population genetic study of the brain-derived neurotrophic factor (BDNF) gene.
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. F(ST) analyses to assess diversity in the HapMap populations determined that the Val66Met F(ST) 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 99 th percentile compared with HapMap data (P=4.6 x 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.
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. petryshen@chgr.mgh.harvard.edu
authors.forename: T L
authors.initials: TL
authors.lastname: Petryshen
authors.forename: P C
authors.initials: PC
authors.lastname: Sabeti
authors.forename: K A
authors.initials: KA
authors.lastname: Aldinger
authors.forename: B
authors.initials: B
authors.lastname: Fry
authors.forename: J B
authors.initials: JB
authors.lastname: Fan
authors.forename: S F
authors.initials: SF
authors.lastname: Schaffner
authors.forename: S G
authors.initials: SG
authors.lastname: Waggoner
authors.forename: A R
authors.initials: AR
authors.lastname: Tahl
authors.forename: P
authors.initials: P
authors.lastname: Sklar
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D005787:Gene Frequency; D005828:Genetics, Population / Q000379:methods*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008715:Methionine / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D008715:Methionine; D014633:Valine