Aging Modifies the Effect of GCH1 RS11158026 on DAT Uptake and Parkinson's Disease Clinical Severity


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Age, DAT-SPECT, Guanosine Cyclohydrolase 1 (GCH1), Parkinson's disease, Parkinson's Progression Marker Initiative (PPMI)


Novel single nucleotide polymorphisms within Parkinson's disease (PD) can predict disease risk, but their influence on clinical, cognitive and neurobiological indices remain 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 DAT uptake (P=0.003). Carriers also had increased CSF 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.