title: Aging modifies the effect of GCH1 RS11158026 on DAT uptake and Parkinson's disease clinical severity.
abstract: Novel single nucleotide polymorphisms within Parkinson's disease (PD) can predict disease risk, but their influence on clinical, cognitive, and neurobiological indices remains unexplored. We investigated differences between functional polymorphisms at RS11158026 coding for guanosine triphosphate cyclohydrolase-1 (GCH1), an essential enzyme for dopamine production in nigrostriatal cells. Among newly diagnosed, untreated PD subjects and age-matched controls from the Parkinson's Progression Markers Initiative, T allele carriers showed higher PD risk (odds ratio = 1.23, p = 0.048), earlier age of onset by 5 years (p = 0.003), and lower striatal dopamine reuptake transporter uptake (p = 0.003). Carriers also had increased cerebrospinal fluid α-synuclein (p = 0.016), worse motor function (p = 0.041), anxiety (p = 0.038), and executive function (p < 0.001). Strikingly, these effects were only in younger T carriers (<50 years), where aging quells the effects of these genetic factors. This suggests GCH1 variants affect early PD risk through altered dopamine uptake, and aging alters how genetic factors contribute to disease development. Future studies should investigate how aging modifies genotypes' contributions on PD risk and sequelae.
authors.affiliation: Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Webb
authors.affiliation: Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, USA; Neuroscience Graduate Program, Iowa State University, Ames, IA, USA; Department of Psychology, Iowa State University, Ames, IA, USA; Department of Neurology, University of Iowa, Iowa City, IA, USA. Electronic address: awillett@iastate.edu.
authors.forename: Auriel A
authors.initials: AA
authors.lastname: Willette
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology*; D000483:Alleles; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism*; D056344:Executive Function; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D011110:Polymorphism, Genetic; D012720:Severity of Illness Index; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid
chemical_list: D051844:alpha-Synuclein; D006136:GTP Cyclohydrolase; D004298:Dopamine
keywords: Age; DAT-SPECT; Guanosine triphosphate cyclohydrolase-1 (GCH1); Parkinson's Progression Marker Initiative (PPMI); Parkinson's disease