Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson's disease

Prabhjyot Saini; Uladzislau Rudakou; Eric Yu; Jennifer A Ruskey; Farnaz Asayesh; Sandra B Laurent; Dan Spiegelman; Stanley Fahn; Cheryl Waters; Oury Monchi; Yves Dauvilliers; Nicolas Dupré; Lior Greenbaum; Sharon Hassin-Baer; Alberto J Espay; Guy A Rouleau; Roy N Alcalay; Edward A Fon; Ronald B Postuma; Ziv Gan-Or

doi:10.1016/j.neurobiolaging.2020.10.019

Association study of DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 with Parkinson's disease

Neurobiol Aging. 2021 Apr:100:119.e7-119.e13. doi: 10.1016/j.neurobiolaging.2020.10.019. Epub 2020 Oct 31.

Authors

Prabhjyot Saini¹, Uladzislau Rudakou¹, Eric Yu¹, Jennifer A Ruskey², Farnaz Asayesh², Sandra B Laurent¹, Dan Spiegelman², Stanley Fahn³, Cheryl Waters³, Oury Monchi⁴, Yves Dauvilliers⁵, Nicolas Dupré⁶, Lior Greenbaum⁷, Sharon Hassin-Baer⁸, Alberto J Espay⁹, Guy A Rouleau¹⁰, Roy N Alcalay¹¹, Edward A Fon², Ronald B Postuma², Ziv Gan-Or¹²

Affiliations

¹ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
² Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada.
³ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
⁴ Department of Clinical Neurosciences and Department of Radiology, University of Calgary, Calgary, Alberta, Canada; Cumming School of Medicine, Hotchkiss Brain Institute, Calgary, Alberta, Canada.
⁵ Department of Neurology, National Reference Center for Narcolepsy, Sleep Unit, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, Montpellier, France.
⁶ Division of Neurosciences, CHU de Québec, Université Laval, Quebec City, Quebec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, Quebec, Canada.
⁷ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel; The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel.
⁸ Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Neurology, The Movement Disorders Institute, Sheba Medical Center, Tel Hashomer, Israel.
⁹ Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA.
¹⁰ Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada.
¹¹ Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
¹² Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address: ziv.gan-or@mcgill.ca.

PMID: 33239198
PMCID: PMC7940813
DOI: 10.1016/j.neurobiolaging.2020.10.019

Abstract

Rare mutations in genes originally discovered in multigenerational families have been associated with increased risk of Parkinson's disease (PD). The involvement of rare variants in DNAJC13, UCHL1, HTRA2, GIGYF2, and EIF4G1 loci has been poorly studied or has produced conflicting results across cohorts. However, they are still being often referred to as "PD genes" and used in different models. To further elucidate the role of these 5 genes in PD, we fully sequenced them using molecular inversion probes in 2408 patients with PD and 3444 controls from 3 different cohorts. A total of 788 rare variants were identified across the 5 genes and 3 cohorts. Burden analyses and optimized sequence Kernel association tests revealed no significant association between any of the genes and PD after correction for multiple comparisons. Our results do not support an association of the 5 tested genes with PD. Combined with previous studies, it is unlikely that any of these genes plays an important role in PD. Their designation as "PARK" genes should be reconsidered.

Keywords: Ashkenazi-Jewish; DNAJC13; EIF4G1; French-Canadian; GIGYF2; HTRA2; Parkinson's disease; SKAT-O; UCHL1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Carrier Proteins*
Cohort Studies
Eukaryotic Initiation Factor-4G*
Female
Genetic Association Studies / methods*
High-Temperature Requirement A Serine Peptidase 2*
Humans
Male
Molecular Chaperones*
Negative Results*
Parkinson Disease / genetics*
Ubiquitin Thiolesterase*
White People / genetics

Substances

Carrier Proteins
DNAJC13 protein, human
EIF4G1 protein, human
Eukaryotic Initiation Factor-4G
GIGYF2 protein, human
Molecular Chaperones
UCHL1 protein, human
Ubiquitin Thiolesterase
HTRA2 protein, human
High-Temperature Requirement A Serine Peptidase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding