Project III: Vitamin D Concentrations, Genetic Modifiers, and Parkinson Disease Parkinson disease (PD) results from genetic and environmental factors and complex interactions between them. Basic science, epidemiology and genetic studies have accumulated evidence supporting a role of vitamin D (vit D) in PD susceptibility. In addition to vit D providing neuroprotection for dopaminergic neurons, low vit D concentrations are more common in and increase risk of PD. Also, vitamin D receptor (VDR) gene polymorphisms appear to modulate risk for and age at onset of PD. However, these VDR polymorphism effects on PD risk vary in different study populations. One explanation is that genetic effects are dependent on 'exposure'to vit D, which varies across populations. For example, in osteoporosis, genetic factors modulate the apparent protective effects of vit D. Because vit D concentration is largely determined by diet and sunlight exposure, vit D blood concentration is modifiable. Vit D supplementation is a potential therapeutic strategy if the link between vit D and PD can be confirmed and better understood. We will jointly analyze the effects of environmental exposure (25-hydroxy-vitamin D (25[OH]D) concentration from blood plasma samples) and the common genetic variants on risk and age at onset of PD. Built on the previous epidemiologic and genetic studies, this study will also provide valuable insights on a gene-environment interaction that may play an important role in PD pathogenesis. Importantly, results of the study will guide future efforts to determine if vit D supplementation can treat or prevent PD, and if people with a certain genetic makeup benefit more from vit D supplementation than others. We hypothesize that plasma vit D concentration modifies the genetic effects of vit D-related genes and that genetic factors modify the effect of vit D on the risk of developing PD. To test our hypothesis, we have developed three specific aims: 1) Evaluate the association of plasma vit D level and risk and age at onset of PD in three case-control samples. 2) Conduct analysis to identify potential vit D-gene interactions underlying PD risk or age at onset. 3) Thoroughly examine vit D-associated genes for functional variants that explain their associations with PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS071674-05
Application #
8740569
Study Section
Special Emphasis Panel (ZNS1-SRB-E)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
5
Fiscal Year
2014
Total Cost
$186,145
Indirect Cost
$64,482
Name
University of Miami School of Medicine
Department
Type
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Hui, Ken Y; Fernandez-Hernandez, Heriberto; Hu, Jianzhong et al. (2018) Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med 10:
Barbier, E; Johnstone, A L; Khomtchouk, B B et al. (2017) Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2. Mol Psychiatry 22:1746-1758
Noyce, Alastair J; Kia, Demis A; Hemani, Gibran et al. (2017) Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study. PLoS Med 14:e1002314
Wahlestedt, Claes (2017) Emerging Epigenetic Therapies in Neuroscience: Focus on Bromodomain-Containing Drug Targets. Neuropsychopharmacology 42:374
Belle, Kinsley; Shabazz, Francelethia S; Nuytemans, Karen et al. (2017) Generation of disease-specific autopsy-confirmed iPSCs lines from postmortem isolated Peripheral Blood Mononuclear Cells. Neurosci Lett 637:201-206
Giri, Anamika; Mok, Kin Y; Jansen, Iris et al. (2017) Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population. Neurobiol Aging 50:167.e11-167.e13
Heilig, M; Barbier, E; Johnstone, A L et al. (2017) Reprogramming of mPFC transcriptome and function in alcohol dependence. Genes Brain Behav 16:86-100
Khorkova, Olga; Wahlestedt, Claes (2017) Oligonucleotide therapies for disorders of the nervous system. Nat Biotechnol 35:249-263
Wang, Xin; Li, Nuomin; Xiong, Nian et al. (2017) Genetic Variants of Microtubule Actin Cross-linking Factor 1 (MACF1) Confer Risk for Parkinson's Disease. Mol Neurobiol 54:2878-2888
Jansen, Iris E; Ye, Hui; Heetveld, Sasja et al. (2017) Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biol 18:22

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