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

Overview

Journal Neurology

Specialty Neurology

Date 2015 Jun 12

PMID 26062626

Citations 87

Authors

Karen Marder

Yuanjia Wang

Roy N Alcalay

Helen Mejia-Santana

Ming-Xin Tang

Annie Lee

Deborah Raymond

Anat Mirelman

Rachel Saunders-Pullman

Lorraine Clark

Laurie Ozelius

Avi Orr-Urtreger

Nir Giladi

Susan Bressman

Affiliations

Soon will be listed here.

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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References

Kasten M, Kertelge L, Bruggemann N, van der Vegt J, Schmidt A, Tadic V . Nonmotor symptoms in genetic Parkinson disease. Arch Neurol. 2010; 67(6):670-6. DOI: 10.1001/archneurol.67.6.670. View

Hentati F, Trinh J, Thompson C, Nosova E, Farrer M, Aasly J . LRRK2 parkinsonism in Tunisia and Norway: a comparative analysis of disease penetrance. Neurology. 2014; 83(6):568-9. PMC: 4142000. DOI: 10.1212/WNL.0000000000000675. View

Marras C, Saunders-Pullman R . The complexities of hormonal influences and risk of Parkinson's disease. Mov Disord. 2014; 29(7):845-8. PMC: 4347401. DOI: 10.1002/mds.25891. View

Alcalay R, Mirelman A, Saunders-Pullman R, Tang M, Mejia Santana H, Raymond D . Parkinson disease phenotype in Ashkenazi Jews with and without LRRK2 G2019S mutations. Mov Disord. 2013; 28(14):1966-71. PMC: 3859844. DOI: 10.1002/mds.25647. View

Mirelman A, Alcalay R, Saunders-Pullman R, Yasinovsky K, Thaler A, Gurevich T . Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene. Mov Disord. 2015; 30(7):981-6. PMC: 4478229. DOI: 10.1002/mds.26213. View

Alcalay R, Caccappolo E, Mejia-Santana H, Tang M, Rosado L, Ross B . Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. Arch Neurol. 2010; 67(9):1116-22. PMC: 3329730. DOI: 10.1001/archneurol.2010.194. View

Alcalay R, Mejia-Santana H, Mirelman A, Saunders-Pullman R, Raymond D, Palmese C . Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease. Parkinsonism Relat Disord. 2014; 21(2):106-10. PMC: 4306614. DOI: 10.1016/j.parkreldis.2014.09.033. View

Clark L, Ross B, Wang Y, Mejia-Santana H, Harris J, Louis E . Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology. 2007; 69(12):1270-7. PMC: 3624967. DOI: 10.1212/01.wnl.0000276989.17578.02. View

Struewing J, Hartge P, Wacholder S, Baker S, Berlin M, McAdams M . The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997; 336(20):1401-8. DOI: 10.1056/NEJM199705153362001. View

10.

Ozelius L, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M . LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2006; 354(4):424-5. DOI: 10.1056/NEJMc055509. View

11.

Wang Y, Liang B, Tong X, Marder K, Bressman S, Orr-Urtreger A . Efficient Estimation of Nonparametric Genetic Risk Function with Censored Data. Biometrika. 2015; 102(3):515-532. PMC: 4581539. DOI: 10.1093/biomet/asv030. View

12.

Wang Y, Clark L, Louis E, Mejia-Santana H, Harris J, Cote L . Risk of Parkinson disease in carriers of parkin mutations: estimation using the kin-cohort method. Arch Neurol. 2008; 65(4):467-74. PMC: 2836931. DOI: 10.1001/archneur.65.4.467. View

13.

Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons E . LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord. 2006; 12(7):410-9. DOI: 10.1016/j.parkreldis.2006.04.001. View

14.

Goldwurm S, Tunesi S, Tesei S, Zini M, Sironi F, Primignani P . Kin-cohort analysis of LRRK2-G2019S penetrance in Parkinson's disease. Mov Disord. 2011; 26(11):2144-5. DOI: 10.1002/mds.23807. View

15.

Wooten G, Currie L, Bovbjerg V, Lee J, Patrie J . Are men at greater risk for Parkinson's disease than women?. J Neurol Neurosurg Psychiatry. 2004; 75(4):637-9. PMC: 1739032. DOI: 10.1136/jnnp.2003.020982. View

16.

Saunders-Pullman R, Mirelman A, Wang C, Alcalay R, San Luciano M, Ortega R . Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker?. Ann Clin Transl Neurol. 2014; 1(9):670-8. PMC: 4241794. DOI: 10.1002/acn3.95. View

17.

Gupte M, Alcalay R, Mejia-Santana H, Raymond D, Saunders-Pullman R, Roos E . Interest in genetic testing in Ashkenazi Jewish Parkinson's disease patients and their unaffected relatives. J Genet Couns. 2014; 24(2):238-46. PMC: 4331260. DOI: 10.1007/s10897-014-9756-x. View

18.

Hughes A, Ben-Shlomo Y, Daniel S, Lees A . What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology. 1992; 42(6):1142-6. DOI: 10.1212/wnl.42.6.1142. View

19.

Clark L, Wang Y, Karlins E, Saito L, Mejia-Santana H, Harris J . Frequency of LRRK2 mutations in early- and late-onset Parkinson disease. Neurology. 2006; 67(10):1786-91. DOI: 10.1212/01.wnl.0000244345.49809.36. View

20.

Wacholder S, Hartge P, Struewing J, Pee D, McAdams M, Brody L . The kin-cohort study for estimating penetrance. Am J Epidemiol. 1998; 148(7):623-30. DOI: 10.1093/aje/148.7.623. View