Exploring gene-environment interactions in Parkinson’s disease
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The objective of this study was to explore combined effects of four candidate susceptibility genes and two exposures on Parkinson’s disease (PD) risk; namely, α-synuclein (SNCA) promoter polymorphism REP1, microtubule-associated protein tau (MAPT) H1/H2 haplotypes, apolipoprotein E (APOE) ε2/ε3/ε4 polymorphism, ubiquitin carboxy-terminal esterase L1 (UCHL1) S18Y variant, cigarette smoking and caffeinated coffee consumption. 932 PD patients and 664 control subjects from the NeuroGenetics Research Consortium, with complete data on all six factors, were studied. Uniform protocols were used for diagnosis, recruitment, data collection and genotyping. A logistic regression model which included gene-exposure interactions was applied. Likelihood ratio tests (LRTs) were used for significance testing and Bayesian inference was used to estimate odds ratios (ORs). MAPT (P = 0.007), SNCA REP1 (P = 0.012), smoking (P = 0.001), and coffee (P = 0.011) were associated with PD risk. Two novel interactions were detected: APOE with coffee (P = 0.005), and REP1 with smoking (P = 0.021). While the individual main effects were modest, each yielding OR < 1.6, the effects were cumulative, with some combinations reaching OR = 12.6 (95% CI: 5.9–26.8). This study provides evidence for the long-held notion that PD risk is modulated by cumulative and interactive effects of genes and exposures. Furthermore, the study demonstrates that while interaction studies are useful for exploring risk relationships that might otherwise go undetected, results should be interpreted with caution because of the inherent loss of power due to multiple testing. The novel findings of this study that warrant replication are the evidence for interaction of coffee with APOE, and of smoking with REP1 on PD risk.
We thank the research subjects for participation in this study. This study was supported by Michael J. Fox Foundation Edmond J. Safra Global Genetics Consortia Grant; National Institutes of Health grants NS R01-36960 and K08-NS044138; VA Merit Award; Parkinson’s Disease, Mental Health and Geriatric Research Education and Clinical Centers at the VA Puget Sound Health Care System, Close to A Cure: A Fund for Parkinson’s Research of the Foundation for the Carolinas, and New York State Department of Health Wadsworth Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
- Draper NR, Smith H (1998) Applied regression analysis, 3rd edn. Wiley, New YorkGoogle Scholar
- Genkin A, Lewis D, Madigan D (2007) Large-scale Bayesian logistic regression for text categorization. technometrics (in press)Google Scholar
- Harrell FE (2001) Regression modeling strategies: with applications to linear models, logistic regression and survival analysis. Springer, New YorkGoogle Scholar
- Hutter CM, Samii A, Factor SA, Nutt JG, Higgins DS, Bird TD, Griffith A, Roberts JW, Leis BC, Montimurro JS, Kay DM, Edwards KL, Payami H, Zabetian CP (2007) Lack of evidence for an association between UCHL1 S18Y and Parkinson’s disease. Eur J Neurol [Epub ahead of print 18 Dec 2007]Google Scholar
- Kay DM, Montimurro JS, Payami H (2008) Genetics. In: Factor SA, Weiner WJ (eds) Parkinson’s Disease: diagnosis and clinical management, 2nd edn. Demos Medical Publishing, New YorkGoogle Scholar
- Kruger R, Vieira-Saecker AMM, Kuhn W, Berg D, Muller T, HKuhnl N, Fuchs GA, Storch A, Hungs M, Woitalla D, Przuntek H, Epplen JT, Schols L, Riess O (1999) Increased susceptibility to sporadic Parkinson’s disease by a certain combined alpha-synuclein/apolipoprotein E genotype. Ann Neurol 45:611–617PubMedCrossRefGoogle Scholar
- Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. J Am Med Assoc 296:661–670CrossRefGoogle Scholar
- Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos E, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson W, Lazzarini A, Duvoisin R, Di Iorio G, Golbe L, Nussbaum R (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
- Powers KM, Kay DM, Factor SA, Zabetian CP, Higgins DS, Samii A, Nutt JG, Griffith A, Leis B, Roberts JW, Martinez ED, Montimurro JS, Checkoway H, Payami H (2007) Combined effects of smoking, coffee, and NSAIDs on Parkinson’s disease risk. movement disorders [Epub ahead of print 6 Nov 2007]Google Scholar
- Santner D, Duffy T (1989) The statistical analysis of discreet data. Springer, New YorkGoogle Scholar
- Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841PubMedCrossRefGoogle Scholar
- Thomas A, Hara B, Ligges l, Sturtz S (2006) Making BUGS open. R News 6:12–17Google Scholar