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.

Figure 1

BDNF Val66Met allele frequencies in global populations. Frequencies of the Val66 allele (gray) and Met66 allele (black) are shown for each of the 57 populations in the HGDR-CEPH Human Diversity Panel and for CEPH pedigrees.

Figure 2

Global diversity and genealogy of BDNF haplotypes. (A) BDNF haplotypes comprised of 12 coding region SNPs observed in European, Asian, and Sub-Saharan African continental groups. Val66Met/rs6265 is indicated by an arrow (C = Val, T = Met). Shown is the ancestral haplotype (top) and eleven haplotypes above 2% frequency in at least one of the continental groups (dots = ancestral alleles, nucleotide letters = derived alleles), with frequencies shown to the right. (B) BDNF haplotype genealogical trees in European, Asian, and Sub-Saharan African groups. Trees are rooted at the predicted ancestral haplotype (square at top) and each haplotype is shown as a square of size proportional to frequency and branch length proportional to mutational distance. Unfilled squares indicate unobserved haplotypes that are necessary links. (C) BDNF haplotype frequencies in global populations are indicated by pie diagrams placed relative to population geographic locations.