Genome-wide variant by serum urate interaction in Parkinson's disease.
OBJECTIVE
Serum urate levels have been associated with risk for and progression of Parkinson's disease (PD). Urate-related compounds are therapeutic candidates in neuroprotective efforts to slow PD progression. A urate-elevating agent is currently under investigation as a potential disease-modifying strategy in people with PD. However, PD is a heterogeneous disorder, and genetic variation may explain divergence in disease severity and progression.


METHODS
We conducted a genome-wide association study to identify gene variant × serum urate interaction effects on the striatal (123) I-ioflupane (DaTscan) binding ratio measured using single photon emission computed tomography in patients with possible PD from the Parkinson's Progression Markers Initiative (PPMI, n = 360). Follow-up analyses were conducted to assess gene variant × serum urate interaction effects on magnetic resonance imaging-derived regional brain volumes and clinical status. We then attempted to replicate our primary analysis in patients who entered the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) with a clinical diagnosis of PD (n = 349).


RESULTS
Rs1109303 (T>G) variant within the INPP5K gene on chromosome 17p13.3 demonstrated a genome-wide significant interaction with serum urate level to predict striatal dopamine transporter density among all PPMI participants (n = 359) with possible PD (p = 2.01 × 10(-8) ; after excluding participants with SWEDD [scan without evidence of dopaminergic deficit]: p = 1.12 × 10(-9) ; n = 316). Independent of striatal dopamine transporter density, similar effects on brain atrophy, bradykinesia, anxiety, and depression were observed. No effect was present in the PRECEPT sample at baseline; however, in non-SWEDD PD participants in PRECEPT (n = 309), we observed a significant longitudinal genotype × serum urate interaction effect, consistent in direction with the PPMI sample, on progression of striatal dopamine transporter density over the 22-month follow-up.


CONCLUSIONS
Genetic profile combined with serum urate level can be used to predict disease severity and potential disease progression in patients with PD. These results may be relevant to therapeutic efforts targeting the urate pathway.
Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Arash
A
Nazeri
Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Tina
T
Roostaei
Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Shokufeh
S
Sadaghiani
Cerebral Imaging Centre, Douglas Institute, Montreal, Quebec, Canada.|Departments of Psychiatry and Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
M Mallar
MM
Chakravarty
Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY.
Shirley
S
Eberly
Morton and Gloria Shulman Movement Disorders Clinic and Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Division of Neurology, Toronto, Ontario, Canada.|Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Anthony E
AE
Lang
Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.|Underserved Populations Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Aristotle N
AN
Voineskos
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001519:Behavior; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism; D018450:Disease Progression; D004298:Dopamine / Q000172:deficiency / Q000235:genetics; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009662:Nortropanes; D010300:Parkinson Disease / Q000097:blood* / Q000000981:diagnostic imaging / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D019275:Radiopharmaceuticals; D015899:Tomography, Emission-Computed, Single-Photon; D014527:Uric Acid / Q000097:blood*
D050483:Dopamine Plasma Membrane Transport Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; D014527:Uric Acid; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C519528:ioflupane; D004298:Dopamine