Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Lai, Dongbing; Alipanahi, Babak; Fontanillas, Pierre; Schwantes‐An, Tae‐Hwi; Aasly, Jan; Alcalay, Roy N.; Beecham, Gary W.; Berg, Daniela; Bressman, Susan; Brice, Alexis; Brockman, Kathrin; Clark, Lorraine; Cookson, Mark; Das, Sayantan; Van Deerlin, Vivianna; Follett, Jordan; Farrer, Matthew J.; Trinh, Joanne; Gasser, Thomas; Goldwurm, Stefano; Gustavsson, Emil; Klein, Christine; Lang, Anthony E.; Langston, J. William; Latourelle, Jeanne; Lynch, Timothy; Marder, Karen; Marras, Connie; Martin, Eden R.; McLean, Cory Y.; Mejia‐Santana, Helen; Molho, Eric; Myers, Richard H.; Nuytemans, Karen; Ozelius, Laurie; Payami, Haydeh; Raymond, Deborah; Rogaeva, Ekaterina; Rogers, Michael P.; Ross, Owen A.; Samii, Ali; Saunders‐Pullman, Rachel; Schüle, Birgitt; Schulte, Claudia; Scott, William K.; Tanner, Caroline; Tolosa, Eduardo; Tomkins, James E.; Vilas, Dolores; Trojanowski, John Q.; Uitti, Ryan; Vance, Jeffery M.; Visanji, Naomi P.; Wszolek, Zbigniew K.; Zabetian, Cyrus P.; Mirelman, Anat; Giladi, Nir; Orr Urtreger, Avi; Cannon, Paul; Fiske, Brian; Foroud, Tatiana

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Documentdetail

ID kaart

oai:pubmedcentral.nih.gov:8252...

Onderwerp

Research Articles

Auteur

Lai, Dongbing Alipanahi, Babak Fontanillas, Pierre Schwantes‐An, Tae‐Hwi Aasly, Jan Alcalay, Roy N. Beecham, Gary W. Berg, Daniela Bressman, Susan Brice, Alexis Brockman, Kathrin Clark, Lorraine Cookson, Mark Das, Sayantan Van Deerlin, Vivianna Follett, Jordan Farrer, Matthew J. Trinh, Joanne Gasser, Thomas Goldwurm, Stefano Gustavsson, Emil Klein, Christine Lang, Anthony E. Langston, J. William Latourelle, Jeanne Lynch, Timothy Marder, Karen Marras, Connie Martin, Eden R. McLean, Cory Y. Mejia‐Santana, Helen Molho, Eric Myers, Richard H. Nuytemans, Karen Ozelius, Laurie Payami, Haydeh Raymond, Deborah Rogaeva, Ekaterina Rogers, Michael P. Ross, Owen A. Samii, Ali Saunders‐Pullman, Rachel Schüle, Birgitt Schulte, Claudia Scott, William K. Tanner, Caroline Tolosa, Eduardo Tomkins, James E. Vilas, Dolores Trojanowski, John Q. Uitti, Ryan Vance, Jeffery M. Visanji, Naomi P. Wszolek, Zbigniew K. Zabetian, Cyrus P. Mirelman, Anat Giladi, Nir Orr Urtreger, Avi Cannon, Paul Fiske, Brian Foroud, Tatiana

Langue

Editor

John Wiley & Sons, Inc.

Categorie

Wiley-Blackwell Online Open

Jaar

2021

vermelding datum

01-12-2023

Trefwoorden

variant risk coro1c association lrrk2 disease parkinson study mutations genomewide age‐at‐onset

Metriek

Beschrijving

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age‐at‐onset of Parkinson's disease.

METHODS: We performed the first genomewide association study of penetrance and age‐at‐onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non‐cases at their last evaluation).

Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age‐at‐onset of LRRK2 mutations, respectively.

We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age‐at‐onset in LRRK2 mutation carriers.

RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E‐08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model.

Co‐immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins.

A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E‐07; age‐at‐onset top variant: p value = 9.3E‐07).

A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age‐at‐onset.

INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations.

In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.

ANN NEUROL 2021;90:82–94

Lai, Dongbing,Alipanahi, Babak,Fontanillas, Pierre,Schwantes‐An, Tae‐Hwi,Aasly, Jan,Alcalay, Roy N.,Beecham, Gary W.,Berg, Daniela,Bressman, Susan,Brice, Alexis,Brockman, Kathrin,Clark, Lorraine,Cookson, Mark,Das, Sayantan,Van Deerlin, Vivianna,Follett, Jordan,Farrer, Matthew J.,Trinh, Joanne,Gasser, Thomas,Goldwurm, Stefano,Gustavsson, Emil,Klein, Christine,Lang, Anthony E.,Langston, J. William,Latourelle, Jeanne,Lynch, Timothy,Marder, Karen,Marras, Connie,Martin, Eden R.,McLean, Cory Y.,Mejia‐Santana, Helen,Molho, Eric,Myers, Richard H.,Nuytemans, Karen,Ozelius, Laurie,Payami, Haydeh,Raymond, Deborah,Rogaeva, Ekaterina,Rogers, Michael P.,Ross, Owen A.,Samii, Ali,Saunders‐Pullman, Rachel,Schüle, Birgitt,Schulte, Claudia,Scott, William K.,Tanner, Caroline,Tolosa, Eduardo,Tomkins, James E.,Vilas, Dolores,Trojanowski, John Q.,,Uitti, Ryan,Vance, Jeffery M.,Visanji, Naomi P.,Wszolek, Zbigniew K.,Zabetian, Cyrus P.,Mirelman, Anat,Giladi, Nir,Orr Urtreger, Avi,Cannon, Paul,Fiske, Brian,Foroud, Tatiana, 2021, Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease, John Wiley & Sons, Inc.