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Population genetic study of the brain-derived neurotrophic factor (BDNF) gene

Molecular Psychiatry volume 15, pages 810–815 (2010)Cite this article

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.

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Acknowledgements

We thank Dr Manuel Ferreira for analytical assistance, and Dr Roy Perlis, Dr James Potash, Dr Melvin McInnis and Dr J Raymond De Paulo for their valuable comments on the paper. The HGDR-CEPH Human Genome Diversity Cell Line Panel DNA was obtained from David Reich, MD. This study was supported by the NIMH grant R01 MH062137, postdoctoral fellowships from the Canadian Institutes for Health Research (TLP) and the Charles A King Trust, Bank of America, Co-Trustee (JBF), Young Investigator awards from the National Alliance on Schizophrenia and Depression (TLP and JBF), and a Burroughs Wellcome Career Award in the Biomedical Sciences (PCS).

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Authors and Affiliations

  1. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    T L Petryshen, K A Aldinger, J B Fan, S G Waggoner, A R Tahl & P Sklar

  2. Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    T L Petryshen & P Sklar

  3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    T L Petryshen, K A Aldinger, J B Fan, S G Waggoner, A R Tahl & P Sklar

  4. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    P C Sabeti, B Fry & S F Schaffner

  5. Department of Organismic and Evolutionary Biology, Center for Systems Biology, Harvard University, Cambridge, MA, USA

    P C Sabeti

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  1. T L Petryshen
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Correspondence to T L Petryshen.

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Petryshen, T., Sabeti, P., Aldinger, K. et al. Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Mol Psychiatry 15, 810–815 (2010). https://doi.org/10.1038/mp.2009.24

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