Michael G Heckman1, Koji Kasanuki2, Nancy N Diehl3, Shunsuke Koga4, Alexandra Soto5, Melissa E Murray6, Dennis W Dickson7, Owen A Ross8. 1. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: heckman.michael@mayo.edu. 2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Kasanuki.Koji@mayo.edu. 3. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Diehl.Nancy@mayo.edu. 4. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Koga.Shunsuke@mayo.edu. 5. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Soto.Alexandra@mayo.edu. 6. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Murray.Melissa@mayo.edu. 7. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: dickson.dennis@mayo.edu. 8. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA; Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Ross.Owen@mayo.edu.
Abstract
INTRODUCTION: Meta-analyses of genome-wide association studies (GWAS) have established common genetic risk factors for clinical Parkinson's disease (PD); however, associations between these risk factors and quantitative neuropathologic markers of disease severity have not been well-studied. This study evaluated associations of nominated variants from the most recent PD GWAS meta-analysis with Lewy body disease (LBD) subtype (brainstem, transitional, or diffuse) and pathologic burden of LB pathology as measured by LB counts in five cortical regions in a series of LBD cases. METHODS: 547 autopsy-confirmed cases of LBD were included and genotyped for 29 different GWAS-nominated PD risk variants. LB counts were measured in middle frontal (MF), superior temporal (ST), inferior parietal (IP), cingulate (CG), and parahippocampal (PH) gyri. RESULTS: None of the variants examined were significantly associated with LB counts in any brain region or with LBD subtype after correcting for multiple testing. Nominally significant (P < 0.05) associations with LB counts where the direction of association was in agreement with that observed in the PD GWAS meta-analysis were observed for variants in BCKDK/STX1B (MF, ST, IP) and SNCA (ST). Additionally, MIR4697 and BCKDK/STX1B variants were nominally associated with LBD subtype. CONCLUSION: The lack of a significant association between PD GWAS variants and severity of LB pathology is consistent with the generally subtle association odds ratios that have been observed in disease-risk analysis. These results also suggest that genetic factors other than the susceptibility loci may determine quantitative neuropathologic outcomes in patients with LBD.
INTRODUCTION: Meta-analyses of genome-wide association studies (GWAS) have established common genetic risk factors for clinical Parkinson's disease (PD); however, associations between these risk factors and quantitative neuropathologic markers of disease severity have not been well-studied. This study evaluated associations of nominated variants from the most recent PD GWAS meta-analysis with Lewy body disease (LBD) subtype (brainstem, transitional, or diffuse) and pathologic burden of LB pathology as measured by LB counts in five cortical regions in a series of LBD cases. METHODS: 547 autopsy-confirmed cases of LBD were included and genotyped for 29 different GWAS-nominated PD risk variants. LB counts were measured in middle frontal (MF), superior temporal (ST), inferior parietal (IP), cingulate (CG), and parahippocampal (PH) gyri. RESULTS: None of the variants examined were significantly associated with LB counts in any brain region or with LBD subtype after correcting for multiple testing. Nominally significant (P < 0.05) associations with LB counts where the direction of association was in agreement with that observed in the PD GWAS meta-analysis were observed for variants in BCKDK/STX1B (MF, ST, IP) and SNCA (ST). Additionally, MIR4697 and BCKDK/STX1B variants were nominally associated with LBD subtype. CONCLUSION: The lack of a significant association between PD GWAS variants and severity of LB pathology is consistent with the generally subtle association odds ratios that have been observed in disease-risk analysis. These results also suggest that genetic factors other than the susceptibility loci may determine quantitative neuropathologic outcomes in patients with LBD.
Authors: Owen A Ross; Adam T Braithwaite; Lisa M Skipper; Jennifer Kachergus; Mary M Hulihan; Frank A Middleton; Kenya Nishioka; Julia Fuchs; Thomas Gasser; Demetrius M Maraganore; Charles H Adler; Lydie Larvor; Marie-Christine Chartier-Harlin; Christer Nilsson; J William Langston; Katrina Gwinn; Nobutaka Hattori; Matthew J Farrer Journal: Ann Neurol Date: 2008-06 Impact factor: 10.422
Authors: Lorraine N Clark; Lykourgos A Kartsaklis; Rebecca Wolf Gilbert; Beatriz Dorado; Barbara M Ross; Sergey Kisselev; Miguel Verbitsky; Helen Mejia-Santana; Lucien J Cote; Howard Andrews; Jean-Paul Vonsattel; Stanley Fahn; Richard Mayeux; Lawrence S Honig; Karen Marder Journal: Arch Neurol Date: 2009-05
Authors: Yaroslau Compta; Laura Parkkinen; Sean S O'Sullivan; Jana Vandrovcova; Janice L Holton; Catherine Collins; Tammaryn Lashley; Constantinos Kallis; David R Williams; Rohan de Silva; Andrew J Lees; Tamas Revesz Journal: Brain Date: 2011-05 Impact factor: 13.501
Authors: Mike A Nalls; Nathan Pankratz; Christina M Lill; Chuong B Do; Dena G Hernandez; Mohamad Saad; Anita L DeStefano; Eleanna Kara; Jose Bras; Manu Sharma; Claudia Schulte; Margaux F Keller; Sampath Arepalli; Christopher Letson; Connor Edsall; Hreinn Stefansson; Xinmin Liu; Hannah Pliner; Joseph H Lee; Rong Cheng; M Arfan Ikram; John P A Ioannidis; Georgios M Hadjigeorgiou; Joshua C Bis; Maria Martinez; Joel S Perlmutter; Alison Goate; Karen Marder; Brian Fiske; Margaret Sutherland; Georgia Xiromerisiou; Richard H Myers; Lorraine N Clark; Kari Stefansson; John A Hardy; Peter Heutink; Honglei Chen; Nicholas W Wood; Henry Houlden; Haydeh Payami; Alexis Brice; William K Scott; Thomas Gasser; Lars Bertram; Nicholas Eriksson; Tatiana Foroud; Andrew B Singleton Journal: Nat Genet Date: 2014-07-27 Impact factor: 38.330
Authors: Valentina Escott-Price; Mike A Nalls; Huw R Morris; Steven Lubbe; Alexis Brice; Thomas Gasser; Peter Heutink; Nicholas W Wood; John Hardy; Andrew B Singleton; Nigel M Williams Journal: Ann Neurol Date: 2015-03-13 Impact factor: 10.422
Authors: Michael A Nalls; Raquel Duran; Grisel Lopez; Marzena Kurzawa-Akanbi; Ian G McKeith; Patrick F Chinnery; Christopher M Morris; Jessie Theuns; David Crosiers; Patrick Cras; Sebastiaan Engelborghs; Peter Paul De Deyn; Christine Van Broeckhoven; David M A Mann; Julie Snowden; Stuart Pickering-Brown; Nicola Halliwell; Yvonne Davidson; Linda Gibbons; Jenny Harris; Una-Marie Sheerin; Jose Bras; John Hardy; Lorraine Clark; Karen Marder; Lawrence S Honig; Daniela Berg; Walter Maetzler; Kathrin Brockmann; Thomas Gasser; Fabiana Novellino; Aldo Quattrone; Grazia Annesi; Elvira Valeria De Marco; Ekaterina Rogaeva; Mario Masellis; Sandra E Black; Juan M Bilbao; Tatiana Foroud; Bernardino Ghetti; William C Nichols; Nathan Pankratz; Glenda Halliday; Suzanne Lesage; Stephan Klebe; Alexandra Durr; Charles Duyckaerts; Alexis Brice; Benoit I Giasson; John Q Trojanowski; Howard I Hurtig; Nahid Tayebi; Claudia Landazabal; Melanie A Knight; Margaux Keller; Andrew B Singleton; Tyra G Wolfsberg; Ellen Sidransky Journal: JAMA Neurol Date: 2013-06 Impact factor: 18.302
Authors: Jose Bras; Rita Guerreiro; Lee Darwent; Laura Parkkinen; Olaf Ansorge; Valentina Escott-Price; Dena G Hernandez; Michael A Nalls; Lorraine N Clark; Lawrence S Honig; Karen Marder; Wiesje M Van Der Flier; Afina Lemstra; Philip Scheltens; Ekaterina Rogaeva; Peter St George-Hyslop; Elisabet Londos; Henrik Zetterberg; Sara Ortega-Cubero; Pau Pastor; Tanis J Ferman; Neill R Graff-Radford; Owen A Ross; Imelda Barber; Anne Braae; Kristelle Brown; Kevin Morgan; Walter Maetzler; Daniela Berg; Claire Troakes; Safa Al-Sarraj; Tammaryn Lashley; Yaroslau Compta; Tamas Revesz; Andrew Lees; Nigel Cairns; Glenda M Halliday; David Mann; Stuart Pickering-Brown; Dennis W Dickson; Andrew Singleton; John Hardy Journal: Hum Mol Genet Date: 2014-06-27 Impact factor: 6.150
Authors: Michael G Heckman; Koji Kasanuki; Rebecca R Brennan; Catherine Labbé; Emily R Vargas; Alexandra I Soto; Melissa E Murray; Shunsuke Koga; Dennis W Dickson; Owen A Ross Journal: Mov Disord Date: 2019-06-24 Impact factor: 10.338
Authors: Matthias Höllerhage; Markus Stepath; Michael Kohl; Kathy Pfeiffer; Oscar Wing Ho Chua; Linghan Duan; Franziska Hopfner; Martin Eisenacher; Katrin Marcus; Günter U Höglinger Journal: Front Neurol Date: 2022-04-11 Impact factor: 4.003
Authors: Youngduk Seo; Kyoungjune Pak; Hyun Yeol Nam; Ju Won Seok; Myung Jun Lee; Eun Joo Kim; Jae Meen Lee; Seong Jang Kim; In Joo Kim Journal: Yonsei Med J Date: 2018-08 Impact factor: 2.759
Authors: Elisabeth J van Bree; Rita L F P Guimarães; Mischa Lundberg; Elena R Blujdea; Jimi L Rosenkrantz; Fred T G White; Josse Poppinga; Paula Ferrer-Raventós; Anne-Fleur E Schneider; Isabella Clayton; David Haussler; Marcel J T Reinders; Henne Holstege; Adam D Ewing; Colette Moses; Frank M J Jacobs Journal: Genome Res Date: 2022-03-24 Impact factor: 9.438