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Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium.
Neurology. 2015 Jul 07; 85(1):89-95.Neur

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.

Authors+Show Affiliations

From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel. ksm1@cumc.columbia.edu.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.From the Departments of Neurology (K.M., R.N.A., H.M.-S., M.-X.T.) and Pathology and Cell Biology (L.C.), and Center for Human Genetics (L.C.), College of Physicians and Surgeons, Columbia University; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (K.M., R.N.A., M.-X.T., L.C.) and Department of Biostatistics, Mailman School of Public Health (Y.W., A.L.), Columbia University, New York; The Alan and Barbara Mirken Department of Neurology (D.R., R.S.-P., S.B.), Beth Israel Medical Center, New York, NY; Movement Disorders Unit, Department of Neurology, Tel Aviv Medical Center (A.M., N.G.), Sackler School of Medicine (A.O.U.), and Sagol School for Neurosciences (A.M., N.G.), Tel Aviv University; School of Health Related Professions (A.M.), Ben Gurion University, Beer Sheba, Israel; Departments of Genetics and Genomic Sciences and Neurology (L.O.), Mount Sinai School of Medicine, New York, NY; and Genetics Institute (A.O.U.), Tel Aviv Sourasky Medical Center, Israel.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26062626

Citation

Marder, Karen, et al. "Age-specific Penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium." Neurology, vol. 85, no. 1, 2015, pp. 89-95.
Marder K, Wang Y, Alcalay RN, et al. Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology. 2015;85(1):89-95.
Marder, K., Wang, Y., Alcalay, R. N., Mejia-Santana, H., Tang, M. X., Lee, A., Raymond, D., Mirelman, A., Saunders-Pullman, R., Clark, L., Ozelius, L., Orr-Urtreger, A., Giladi, N., & Bressman, S. (2015). Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology, 85(1), 89-95. https://doi.org/10.1212/WNL.0000000000001708
Marder K, et al. Age-specific Penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. Neurology. 2015 Jul 7;85(1):89-95. PubMed PMID: 26062626.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. AU - Marder,Karen, AU - Wang,Yuanjia, AU - Alcalay,Roy N, AU - Mejia-Santana,Helen, AU - Tang,Ming-Xin, AU - Lee,Annie, AU - Raymond,Deborah, AU - Mirelman,Anat, AU - Saunders-Pullman,Rachel, AU - Clark,Lorraine, AU - Ozelius,Laurie, AU - Orr-Urtreger,Avi, AU - Giladi,Nir, AU - Bressman,Susan, AU - ,, Y1 - 2015/06/10/ PY - 2014/11/01/received PY - 2015/03/12/accepted PY - 2015/6/12/entrez PY - 2015/6/13/pubmed PY - 2015/9/19/medline SP - 89 EP - 95 JF - Neurology JO - Neurology VL - 85 IS - 1 N2 - 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. SN - 1526-632X UR - https://www.unboundmedicine.com/medline/citation/26062626/Age_specific_penetrance_of_LRRK2_G2019S_in_the_Michael_J__Fox_Ashkenazi_Jewish_LRRK2_Consortium_ L2 - http://www.neurology.org/cgi/pmidlookup?view=long&amp;pmid=26062626 DB - PRIME DP - Unbound Medicine ER -