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Exploring gene-environment interactions in Parkinson’s disease

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Abstract

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Applied Statistics Laboratory, General Electric Global Research Center, Niskayuna, NY, USA

    Colin C. McCulloch

  2. The Genomics Institute, Wadsworth Center, New York State Department of Health, PO Box 22002, Albany, NY, 12201-2002, USA

    Denise M. Kay, Jennifer S. Montimurro & Haydeh Payami

  3. Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

    Ali Samii & Cyrus P. Zabetian

  4. Parkinson’s Disease Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

    Ali Samii & Cyrus P. Zabetian

  5. Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

    Cyrus P. Zabetian

  6. Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

    Stewart A. Factor

  7. Parkinson’s Disease and Movement Disorder Clinic, Albany Medical Center, Albany, NY, USA

    Donald S. Higgins

  8. Department of Neurology, Oregon Health and Science University, Portland, OR, USA

    John G. Nutt

  9. Booth Gardner Parkinson’s Care Center, Evergreen Hospital Medical Center, Kirkland, WA, USA

    Alida Griffith & Berta C. Leis

  10. Virginia Mason Medical Center, Seattle, WA, USA

    John W. Roberts

Authors
  1. Colin C. McCulloch
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  2. Denise M. Kay
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  3. Stewart A. Factor
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  4. Ali Samii
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  5. John G. Nutt
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  6. Donald S. Higgins
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  7. Alida Griffith
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  8. John W. Roberts
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  9. Berta C. Leis
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  10. Jennifer S. Montimurro
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  11. Cyrus P. Zabetian
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  12. Haydeh Payami
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Corresponding author

Correspondence to Haydeh Payami.

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McCulloch, C.C., Kay, D.M., Factor, S.A. et al. Exploring gene-environment interactions in Parkinson’s disease. Hum Genet 123, 257–265 (2008). https://doi.org/10.1007/s00439-008-0466-z

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  • DOI: https://doi.org/10.1007/s00439-008-0466-z

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