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. 2015 Jul 7;85(1):89-95.
doi: 10.1212/WNL.0000000000001708. Epub 2015 Jun 10.

Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Karen Marder  1 , Yuanjia Wang  2 , Roy N Alcalay  2 , Helen Mejia-Santana  2 , Ming-Xin Tang  2 , Annie Lee  2 , Deborah Raymond  2 , Anat Mirelman  2 , Rachel Saunders-Pullman  2 , Lorraine Clark  2 , Laurie Ozelius  2 , Avi Orr-Urtreger  2 , Nir Giladi  2 , Susan Bressman  2 ; LRRK2 Ashkenazi Jewish Consortium
Collaborators, Affiliations

Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium

Karen Marder et al. Neurology. .

Abstract

Objective: Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers.

Methods: The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available.

Results: Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p < 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18-0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p = 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p < 0.001).

Conclusion: Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted.

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Figures

Figure 1
Figure 1. Age-specific cumulative risk of LRRK2 G2019S Parkinson disease in first-degree relatives
Estimated age-specific risk of PD in LRRK2 G2019S carriers (solid red line) and noncarriers (solid black line) and their confidence intervals (dashed lines). Estimation obtained from 2,266 first-degree relatives of 473 probands using kin-cohort methods under a Cox proportional hazards model. The hazard ratio of LRRK2 G2019S mutation was estimated to be 2.89.
Figure 2
Figure 2. Age-specific cumulative risk of LRRK2 G2019S PD in male and female first-degree relatives
(A) Estimated age-specific risk of Parkinson disease (PD) in male LRRK2 G2019S carriers (solid red line) and male noncarriers (solid black line) and their confidence intervals (dashed lines). Estimation obtained from 1,151 first-degree male relatives of 448 probands using kin-cohort methods under a Cox proportional hazards model. The hazard ratio of LRRK2 G2019S mutation was estimated to be 1.55. (B) Estimated age-specific risk of PD in female LRRK2 G2019S carriers (solid red line) and female noncarriers (solid black line) and their confidence intervals (dashed lines). Estimation obtained from 1,115 first-degree female relatives of 436 probands using kin-cohort methods under a Cox proportional hazards model. The hazard ratio of LRRK2 G2019S mutation was estimated to be 5.03.
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References

    1. Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004;44:595–600. - PubMed
    1. Healy DG, Falchi M, O'Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol 2008;7:583–590. - PMC - PubMed
    1. Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 2006;354:424–425. - PubMed
    1. Clark LN, Wang Y, Karlins E, et al. Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology 2006;67:1786–1791. - PubMed
    1. Orr-Urtreger A, Shifrin C, Rozovski U, et al. The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect? Neurology 2007;69:1595–1602. - PubMed

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