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- W2896542059 abstract "Brain-derived neurotrophic factor (BDNF) is a growth factor that is found in the brain and the periphery. Higher circulating levels have been shown to reduce risk of stroke, depression and dementia and are associated with exercise, caloric restriction and social enrichment. BDNF agonists and antagonists have been shown to alter memory and improve function and recovery in Huntington, Alzheimer and stroke mouse models. Genetic variation in BDNF also modifies smoking patterns. However the genetic determinants of BDNF levels, beyond the SNP rs6265, remain uncertain. Hence, a genome wide association study in the CHARGE cohorts was carried out to identify novel genetic loci associated with circulating BDNF levels. Serum or Plasma BDNF levels were measured on 11,785 subjects of European descent from 4 studies: FHS, AGES, SHIP and RS. Individual cohorts performed a GWAS of BDNF using Haplotype Reference Consortium or 1000Genomes imputed genotype dosages. Phenotypes were adjusted for sex, age and population stratification. Variants with minor allele frequency<0.01 were filtered out. The association results were combined using the effective sample-size weighted Z-score meta-analysis in METAL because of the differences in BDNF source and assay. We additionally performed pathway analyses and two sample Mendelian Randomization analyses on the top association results. Seven independent SNPs (rsq<0.3) reached genome-wide significance (p<5x10−8). The top associated SNPs were rs75945125 (p=6.1x10−13, near BDNF), rs467369 (p=2.6x10−11, BRD3), rs13084580 (p=6.4x10−11, CSRNP1), rs3824987 (p=2.2x10−10, KDELC2), rs71329093 (p=1.2x10−9, RUNX1), rs2242882(p=3.1x10−9, RUNX1) and rs1488831 (p=3.6x10−9, BDNF-AS). The polygenic heritability of BDNF is 30%. All 7 loci together explained 2.6% variation in circulating BDNF. Top biological pathways from pathway analyses include regulation of translation, metalloexopeptidase activity, RNA processing, intracellular protein traffic, peroxisome, myosin complex, lipid and fatty acid binding, obesity and insulin sensitivity. Two sample Mendelian randomization analyses provide support for a potential causal role of BDNF on cardioembolism. These results have uncovered new genetic association with circulating BDNF, implicating genes with a substantial role in regulating various gene expression. Our results more than double the proportion of variance explained and they provide a foundation for a better understanding of BDNF regulation and function." @default.
- W2896542059 created "2018-10-26" @default.
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- W2896542059 date "2018-07-01" @default.
- W2896542059 modified "2023-10-16" @default.
- W2896542059 title "P1‐004: GENOME‐WIDE ASSOCIATION STUDY OF 11,785 INDIVIDUALS IDENTIFIES SEVEN LOCI ASSOCIATED WITH BRAIN‐DERIVED NEUROTROPHIC FACTOR" @default.
- W2896542059 doi "https://doi.org/10.1016/j.jalz.2018.06.005" @default.
- W2896542059 hasPublicationYear "2018" @default.
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