TY - JOUR
T1 - Genetic comorbidities in Parkinson's disease
AU - Nalls, Mike A.
AU - Saad, Mohamad
AU - Noyce, Alastair J.
AU - Keller, Margaux F.
AU - Schrag, Anette
AU - Bestwick, Jonathan P.
AU - Traynor, Bryan J.
AU - Gibbs, J. Raphael
AU - Hernandez, Dena G.
AU - Cookson, Mark R.
AU - Morris, Huw R.
AU - Williams, Nigel
AU - Gasser, Thomas
AU - Heutink, Peter
AU - Wood, Nick
AU - Hardy, John
AU - Martinez, Maria
AU - Singleton, Andrew B.
AU - AUTHOR GROUP
AU - Nalls, Mike
AU - Plagnol, Vincent
AU - Sharma, Manu
AU - Sheerin, Una-Marie
AU - Simón-Sánchez, Javier
AU - Schulte, Claudia
AU - Lesage, Suzanne
AU - Sveinbjörnsdóttir, Sigurlaug
AU - Arepalli, Sampath
AU - Barker, Roger
AU - Ben-Shlomo, Yoav
AU - Berendse, Henk W.
AU - Berg, Daniela
AU - Bhatia, Kailash
AU - de Bie, Rob M. A.
AU - Biffi, Alessandro
AU - Bloem, Bas
AU - Bochdanovits, Zoltan
AU - Bonin, Michael
AU - Bras, Jose M.
AU - Brockmann, Kathrin
AU - Brooks, Janet
AU - Burn, David J.
AU - Charlesworth, Gavin
AU - Chen, Honglei
AU - Chinnery, Patrick F.
AU - Chong, Sean
AU - Clarke, Carl E.
AU - Cooper, J. Mark
AU - Corvol, Jean Christophe
AU - Post, Bart
AU - Velseboer, Daan
PY - 2014
Y1 - 2014
N2 - Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain
AB - Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain
U2 - https://doi.org/10.1093/hmg/ddt465
DO - https://doi.org/10.1093/hmg/ddt465
M3 - Article
C2 - 24057672
SN - 0964-6906
VL - 23
SP - 831
EP - 841
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 3
ER -