Parkinson's disease (PD) is a common and disabling condition in the expanding elderly population of the US and worldwide. Its etiology remains unknown and both genetic and environmental factors have been suspected. The long-term goal of the proposed studies is to clarify the etiology of PD and to identify means to prevent it. Specifically, we will study the association of PD with susceptibility genes previously found associated with novelty seeking behavior, substance use (tobacco, alcohol, and caffeine), and anxiety and depressive disorders. The hypotheses tested derive directly from our current work and preliminary findings. We will employ the case-unaffected sibling control study design and analyses will use a generalization of the sibling transmission disequilibrium test, or S-TDT. In total, nine candidate susceptibility genes will be considered, of which only five have undergone limited study for PD. The candidate susceptibility genes include three detoxification genes, three dopaminergic genes, and three serotonergic genes. We will include 800 cases of PD referred to the Mayo Clinic from a 120-mile radius or from a 5-state region during approximately a 10- year period. We will also include their eligible siblings age 40 years or above, projecting that blood DNA samples will be available for 563 affected probands or siblings and 1,180 unaffected siblings stratified in 521 informative sibships. Sibships with multiple affected or unaffected siblings will be included. PD cases will undergo a clinical assessment and blood sampling, and provide family information through a face-to-face interview followed by a written mail-in form. All living siblings ages 40 and above will be screened for PD using a validated telephone instrument. Subjects screening negative for PD will provide DNA with mail-in blood sampling kits only. Persons screening positive will be clinically assessed at the Mayo Clinic or at home, and blood DNA samples will be directly obtained. Genotyping will be performed using polymerase chain reaction methods and will be blinded to affected or unaffected status. The study will avoid population stratification bias by using sibling controls. The candidate susceptibility genes selected for primary analyses relate to personality traits, substance use, and psychiatric diseases that we have found associated with PD. The selection of these genes represents a major paradigm shift. We will also establish a large DNA bank for rapid and efficient testing of new genetic hypothesis for PD. This application is submitted in response to RFA ES- 00-002 ('The Role of the Environment in Parkinson's Disease""""""""). We specifically address the RFA's objectives of evaluating endogenous (including biomarkers) and exogenous (including dietary and lifestyle) susceptibility factors for PD using molecular epidemiology tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES010751-01
Application #
6212797
Study Section
Special Emphasis Panel (ZES1-LKB-C (D1))
Program Officer
Lawler, Cindy P
Project Start
2000-09-30
Project End
2005-06-30
Budget Start
2000-09-30
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$447,750
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Wang, Lisa; Heckman, Michael G; Aasly, Jan O et al. (2017) Evaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study. Neurobiol Aging 49:217.e1-217.e4
Biernacka, Joanna M; Chung, Sun Ju; Armasu, Sebastian M et al. (2016) Genome-wide gene-environment interaction analysis of pesticide exposure and risk of Parkinson's disease. Parkinsonism Relat Disord 32:25-30
Chung, Sun Ju; Biernacka, Joanna M; Armasu, Sebastian M et al. (2014) Alpha-synuclein repeat variants and survival in Parkinson's disease. Mov Disord 29:1053-7
Markopoulou, Katerina; Biernacka, Joanna M; Armasu, Sebastian M et al. (2014) Does ?-synuclein have a dual and opposing effect in preclinical vs. clinical Parkinson's disease? Parkinsonism Relat Disord 20:584-9; discussion 584
Heckman, Michael G; Elbaz, Alexis; Soto-Ortolaza, Alexandra I et al. (2014) Protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants. Neurobiol Aging 35:266.e5-14
Ahmed, Ismaïl; Lee, Pei-Chen; Lill, Christina M et al. (2014) Lack of replication of the GRIN2A-by-coffee interaction in Parkinson disease. PLoS Genet 10:e1004788
Theuns, Jessie; Verstraeten, Aline; Sleegers, Kristel et al. (2014) Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology 83:1906-13
Chung, Sun Ju; Armasu, Sebastian M; Anderson, Kari J et al. (2013) Genetic susceptibility loci, environmental exposures, and Parkinson's disease: a case-control study of gene-environment interactions. Parkinsonism Relat Disord 19:595-9
Lill, Christina M; Roehr, Johannes T; McQueen, Matthew B et al. (2012) Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database. PLoS Genet 8:e1002548
Chung, Sun Ju; Armasu, Sebastian M; Biernacka, Joanna M et al. (2012) Genomic determinants of motor and cognitive outcomes in Parkinson's disease. Parkinsonism Relat Disord 18:881-6

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