Exploring gene-environment interactions in Parkinson's disease

Colin C. McCulloch, Denise M. Kay, Stewart A. Factor, Ali Samii, John Nutt, Donald S. Higgins, Alida Griffith, John W. Roberts, Berta C. Leis, Jennifer S. Montimurro, Cyrus P. Zabetian, Haydeh Payami

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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.

Original languageEnglish (US)
Pages (from-to)257-265
Number of pages9
JournalHuman Genetics
Volume123
Issue number3
DOIs
StatePublished - Apr 2008

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Gene-Environment Interaction
Coffee
Parkinson Disease
Smoking
Microtubule-Associated Proteins
Odds Ratio
Apolipoproteins E
Ubiquitin Thiolesterase
Synucleins
Logistic Models
Apolipoprotein E2
Apolipoprotein E3
Genes
Haplotypes
Research

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

McCulloch, C. C., Kay, D. M., Factor, S. A., Samii, A., Nutt, J., Higgins, D. S., ... Payami, H. (2008). Exploring gene-environment interactions in Parkinson's disease. Human Genetics, 123(3), 257-265. https://doi.org/10.1007/s00439-008-0466-z

Exploring gene-environment interactions in Parkinson's disease. / McCulloch, Colin C.; Kay, Denise M.; Factor, Stewart A.; Samii, Ali; Nutt, John; Higgins, Donald S.; Griffith, Alida; Roberts, John W.; Leis, Berta C.; Montimurro, Jennifer S.; Zabetian, Cyrus P.; Payami, Haydeh.

In: Human Genetics, Vol. 123, No. 3, 04.2008, p. 257-265.

Research output: Contribution to journalArticle

McCulloch, CC, Kay, DM, Factor, SA, Samii, A, Nutt, J, Higgins, DS, Griffith, A, Roberts, JW, Leis, BC, Montimurro, JS, Zabetian, CP & Payami, H 2008, 'Exploring gene-environment interactions in Parkinson's disease', Human Genetics, vol. 123, no. 3, pp. 257-265. https://doi.org/10.1007/s00439-008-0466-z
McCulloch CC, Kay DM, Factor SA, Samii A, Nutt J, Higgins DS et al. Exploring gene-environment interactions in Parkinson's disease. Human Genetics. 2008 Apr;123(3):257-265. https://doi.org/10.1007/s00439-008-0466-z
McCulloch, Colin C. ; Kay, Denise M. ; Factor, Stewart A. ; Samii, Ali ; Nutt, John ; Higgins, Donald S. ; Griffith, Alida ; Roberts, John W. ; Leis, Berta C. ; Montimurro, Jennifer S. ; Zabetian, Cyrus P. ; Payami, Haydeh. / Exploring gene-environment interactions in Parkinson's disease. In: Human Genetics. 2008 ; Vol. 123, No. 3. pp. 257-265.
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