title: Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium.
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).
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.affiliation: 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.
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Roy N
authors.initials: RN
authors.lastname: Alcalay
authors.affiliation: 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.
authors.forename: Helen
authors.initials: H
authors.lastname: Mejia-Santana
authors.affiliation: 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.
authors.forename: Ming-Xin
authors.initials: MX
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Annie
authors.initials: A
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Deborah
authors.initials: D
authors.lastname: Raymond
authors.affiliation: 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.
authors.forename: Anat
authors.initials: A
authors.lastname: Mirelman
authors.affiliation: 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.
authors.forename: Rachel
authors.initials: R
authors.lastname: Saunders-Pullman
authors.affiliation: 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.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Clark
authors.affiliation: 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.
authors.forename: Laurie
authors.initials: L
authors.lastname: Ozelius
authors.affiliation: 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.
authors.forename: Avi
authors.initials: A
authors.lastname: Orr-Urtreger
authors.affiliation: 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.
authors.forename: Nir
authors.initials: N
authors.lastname: Giladi
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Bressman
mesh_terms: D000367:Age Factors; D000368:Aged; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007585:Jews / Q000235:genetics*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000175:diagnosis* / Q000235:genetics*; D019683:Penetrance; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases