Eric Yu1,2, Uladzislau Rudakou1,2, Lynne Krohn1,2, Kheireddin Mufti1,2, Jennifer A Ruskey2,3, Farnaz Asayesh2,3, Mehrdad A Estiar1,2, Dan Spiegelman2,3, Matthew Surface4, Stanley Fahn4, Cheryl H Waters4, Lior Greenbaum5,6,7, Alberto J Espay8, Yves Dauvilliers9, Nicolas Dupré10,11, Guy A Rouleau1,2,3, Sharon Hassin-Baer7,12, Edward A Fon2,3, Roy N Alcalay4,13, Ziv Gan-Or1,2,3. 1. Department of Human Genetics, McGill University, Montréal, Quebec, Canada. 2. Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec, Canada. 3. Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada. 4. Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA. 5. The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel. 6. The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel. 7. Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 8. UC Gardner Neuroscience Institute and Gardner Family Center for Parkinson's Disease and Movement Disorders, Cincinnati, Ohio, USA. 9. Department of Neurology, National Reference Center for Narcolepsy, Sleep Unit, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Montpellier, France. 10. Division of Neurosciences, CHU de Québec, Université Laval, Laval, Quebec, Canada. 11. Department of Medicine, Faculty of Medicine, Université Laval, Laval, Quebec, Canada. 12. Department of Neurology, Movement Disorders Institute, Sheba Medical Center, Ramat-Gan, Israel. 13. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA.
Abstract
BACKGROUND: Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. OBJECTIVES: Our aim was to examine the association between heterozygous PRKN variants, including single-nucleotide variants and copy-number variations (CNVs), and PD. METHODS: We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late-onset (63.97 ± 7.79 years, 63% men) and 553 early-onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single-nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. RESULTS: We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single-nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected P = 0.55). No associations with age at onset and in stratified analyses were found. CONCLUSIONS: Heterozygous single-nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients.
BACKGROUND: Biallelic PRKN mutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. OBJECTIVES: Our aim was to examine the association between heterozygous PRKN variants, including single-nucleotide variants and copy-number variations (CNVs), and PD. METHODS: We fully sequenced PRKN in 2809 PD patients and 3629 healthy controls, including 1965 late-onset (63.97 ± 7.79 years, 63% men) and 553 early-onset PD patients (43.33 ± 6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single-nucleotide variants and CNVs in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. RESULTS: We did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single-nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected P = 0.55). No associations with age at onset and in stratified analyses were found. CONCLUSIONS: Heterozygous single-nucleotide variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pretrial screening and for clinical and basic science studies targeting specifically PRKN patients.
Authors: William Zhu; Xiaoping Huang; Esther Yoon; Sara Bandres-Ciga; Cornelis Blauwendraat; Kimberly J Billingsley; Joshua H Cade; Beverly P Wu; Victoria H Williams; Alice B Schindler; Janet Brooks; J Raphael Gibbs; Dena G Hernandez; Debra Ehrlich; Andrew B Singleton; Derek P Narendra Journal: Brain Date: 2022-06-30 Impact factor: 15.255
Authors: Diana A Olszewska; Allan McCarthy; Owen A Ross; Tim Lynch; Alexandra I Soto-Beasley; Ronald L Walton Journal: Ir J Med Sci Date: 2021-03-22 Impact factor: 2.089
Authors: Elif Irem Sarihan; Eduardo Pérez-Palma; Lisa-Marie Niestroj; Douglas Loesch; Miguel Inca-Martinez; Andrea R V R Horimoto; Mario Cornejo-Olivas; Luis Torres; Pilar Mazzetti; Carlos Cosentino; Elison Sarapura-Castro; Andrea Rivera-Valdivia; Elena Dieguez; Victor Raggio; Andres Lescano; Vitor Tumas; Vanderci Borges; Henrique B Ferraz; Carlos R Rieder; Artur F Schumacher-Schuh; Bruno L Santos-Lobato; Carlos Velez-Pardo; Marlene Jimenez-Del-Rio; Francisco Lopera; Sonia Moreno; Pedro Chana-Cuevas; William Fernandez; Gonzalo Arboleda; Humberto Arboleda; Carlos E Arboleda-Bustos; Dora Yearout; Cyrus P Zabetian; Timothy A Thornton; Timothy D O'Connor; Dennis Lal; Ignacio F Mata Journal: Mov Disord Date: 2020-11-05 Impact factor: 10.338