title: Genetic variation in brain-derived neurotrophic factor val66met allele is associated with altered serotonin-1A receptor binding in human brain.
abstract: Brain Derived Neurotrophic Factor (BDNF) regulates brain synaptic plasticity. BDNF affects serotonin signaling, increases serotonin levels in brain tissue and prevents degeneration of serotonin neurons. These effects have hardly been studied in human brain. We examined the relationship of the functional val66met polymorphism of the BDNF gene to serotonin 1A (5-HT(1A)) receptor binding in vivo. 50 healthy volunteers (HV) and 50 acutely depressed, unmedicated patients with major depressive disorder (MDD) underwent PET scanning with the 5-HT(1A) receptor ligand, [(11)C]WAY-100635 and a metabolite corrected arterial input function. A linear mixed effects model compared 5-HT(1A) receptor binding potential (BP(F), proportional to the number of available receptors) in 13 brain regions of interest between met allele carriers (met/met and val/met) and noncarriers (val/val) using sex and C-1019G genotype of the 5-HT(1A) receptor promoter functional polymorphism as covariates. There was an interaction between diagnosis and allele (F=4.23, df=1, 94, p=0.042), such that met allele carriers had 17.4% lower BP(F) than non-met carriers in the HV group (t=2.6, df=96, p=0.010), but not in the MDD group (t=-0.4, df=96, p=0.58). These data are consistent with a model where the met allele of the val66met polymorphism causes less proliferation of serotonin synapses, and consequently fewer 5-HT(1A) receptors. In MDD, however, the effect of the val66met polymorphism is not detectable, possibly due to a ceiling effect of over-expression of 5-HT(1A) receptors in mood disorders.
authors.affiliation: Department of Psychiatry, Columbia University New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032, USA; Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA. Electronic address: mal9151@nyp.org.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lan
authors.affiliation: Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA; Department of Biostatistics, Columbia University School of Public Health, 722 West 168th Street, 6th Floor, New York, NY 10032, USA.
authors.forename: R Todd
authors.initials: RT
authors.lastname: Ogden
authors.affiliation: Department of Psychiatry, Columbia University New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032, USA; Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA.
authors.forename: Yung-Yu
authors.initials: YY
authors.lastname: Huang
authors.affiliation: Department of Psychiatry, Columbia University New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032, USA; Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Oquendo
authors.affiliation: Department of Psychiatry, Columbia University New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032, USA; Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Sullivan
authors.affiliation: Department of Psychiatry, Columbia University New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032, USA; Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Miller
authors.affiliation: Department of Psychiatry, Columbia University New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032, USA; Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Milak
authors.affiliation: Department of Psychiatry, Columbia University New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10032, USA; Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, 1051 Riverside Drive, Box 42, New York, NY 10021, USA; Department of Radiology, Columbia University College of Physicians and Surgeons, 180 Fort Washington Avenue, 3rd Floor, Harkness Pavilion, Room 313, New York, NY 10032, USA.
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.affiliation: Department of Psychiatry and Behavioral Science, Department of Radiology, Stony Brook Medicine, Health Sciences Center, T16, Rm-020, Stony Brook, NY 11794-8160, USA.
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001921:Brain / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003863:Depression / Q000235:genetics* / Q000378:metabolism; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D011725:Pyridines / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D013223:Statistics as Topic; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; C112544:desmethyl-WAY 100635; D044282:Receptor, Serotonin, 5-HT1A; C579455:BDNF protein, human
keywords: BDNF; Brain; Depression; PET; Serotonin; [(11)C]WAY-100635