PMID- 19255578 OWN - NLM STAT- MEDLINE DCOM- 20101203 LR - 20220309 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 15 IP - 8 DP - 2010 Aug TI - Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. PG - 810-5 LID - 10.1038/mp.2009.24 [doi] AB - 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. FAU - Petryshen, T L AU - Petryshen TL AD - Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. petryshen@chgr.mgh.harvard.edu FAU - Sabeti, P C AU - Sabeti PC FAU - Aldinger, K A AU - Aldinger KA FAU - Fry, B AU - Fry B FAU - Fan, J B AU - Fan JB FAU - Schaffner, S F AU - Schaffner SF FAU - Waggoner, S G AU - Waggoner SG FAU - Tahl, A R AU - Tahl AR FAU - Sklar, P AU - Sklar P LA - eng GR - R01 MH062137-02/MH/NIMH NIH HHS/United States GR - R01 MH062137-01A2/MH/NIMH NIH HHS/United States GR - R01 MH062137-04/MH/NIMH NIH HHS/United States GR - R01 MH062137-03/MH/NIMH NIH HHS/United States GR - R01 MH062137-05/MH/NIMH NIH HHS/United States GR - R01 MH062137/MH/NIMH NIH HHS/United States GR - CAPMC/CIHR/Canada PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20090303 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Brain-Derived Neurotrophic Factor) RN - AE28F7PNPL (Methionine) RN - HG18B9YRS7 (Valine) SB - IM MH - Brain-Derived Neurotrophic Factor/*genetics MH - *Gene Frequency MH - Genetics, Population/*methods MH - Genotype MH - Humans MH - Linkage Disequilibrium MH - Methionine/genetics MH - Polymorphism, Single Nucleotide/*genetics MH - Valine/genetics PMC - PMC2888876 MID - NIHMS93880 EDAT- 2009/03/04 09:00 MHDA- 2010/12/14 06:00 PMCR- 2011/02/01 CRDT- 2009/03/04 09:00 PHST- 2009/03/04 09:00 [entrez] PHST- 2009/03/04 09:00 [pubmed] PHST- 2010/12/14 06:00 [medline] PHST- 2011/02/01 00:00 [pmc-release] AID - mp200924 [pii] AID - 10.1038/mp.2009.24 [doi] PST - ppublish SO - Mol Psychiatry. 2010 Aug;15(8):810-5. doi: 10.1038/mp.2009.24. Epub 2009 Mar 3.