genotype and ancestry modulate brains dat availability in healthy humans基因型和祖先在健康人体内调节大脑的dat的可用性.pdfVIP

Genotype and Ancestry Modulate Brain’s DAT Availability in Healthy Humans 1 2 1 3 Elena Shumay *, John Chen , Joanna S. Fowler , Nora D. Volkow 1 Brookhaven National Laboratory, Department of Medicine, Upton, New York, United States of America, 2 Department of Preventive Medicine, State University of New York, Stony Brook, New York, United States of America, 3 National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, United States of America Abstract The dopamine transporter (DAT) is a principal regulator of dopaminergic neurotransmission and its gene (the SLC6A3) is a strong biological candidate gene for various behavioral- and neurological disorders. Intense investigation of the link between the SLC6A3 polymorphisms and behavioral phenotypes yielded inconsistent and even contradictory results. Reliance on objective brain phenotype measures, for example, those afforded by brain imaging, might critically improve detection of DAT genotype-phenotype association. Here, we tested the relationship between the DAT brain availability and the SLC6A3 genotypes using an aggregate sample of 95 healthy participants of several imaging studies. These studies employed positron emission tomography (PET) with [11C]cocaine wherein the DAT availability was estimated as Bmax/Kd; while the genotype values were obtained on two repeat polymorphisms - 3-UTR- and intron 8- VNTRs. The main findings are the following: 1) both polymorphisms analyzed as single genetic markers and in combination (haplotype) modulate DAT density in midbrain; 2) ethnic background and age influence the strength of these associations; and 3) age-related changes in DAT availability differ in the 3-UTR and intron8 – genotype groups. Citatio