Genetic comorbidities in Parkinson's disease.

Nalls, Mike A; Saad, Mohamad; Noyce, Alastair J; Keller, Margaux F; Schrag, Anette; Bestwick, Jonathan P; Traynor, Bryan J; Gibbs, J Raphael; Hernandez, Dena G; Cookson, Mark R; Morris, Huw R; Williams, Nigel; Gasser, Thomas; Heutink, Peter; Wood, Nick; Hardy, John; Martinez, Maria; Singleton, Andrew B

dc.contributor.author	Nalls, Mike A
dc.contributor.author	Saad, Mohamad
dc.contributor.author	Noyce, Alastair J
dc.contributor.author	Keller, Margaux F
dc.contributor.author	Schrag, Anette
dc.contributor.author	Bestwick, Jonathan P
dc.contributor.author	Traynor, Bryan J
dc.contributor.author	Gibbs, J Raphael
dc.contributor.author	Hernandez, Dena G
dc.contributor.author	Cookson, Mark R
dc.contributor.author	Morris, Huw R
dc.contributor.author	Williams, Nigel
dc.contributor.author	Gasser, Thomas
dc.contributor.author	Heutink, Peter
dc.contributor.author	Wood, Nick
dc.contributor.author	Hardy, John
dc.contributor.author	Martinez, Maria
dc.contributor.author	Singleton, Andrew B
dc.date.accessioned	2015-05-07T15:36:33Z	en
dc.date.available	2015-05-07T15:36:33Z	en
dc.date.issued	2014-02-01	en
dc.date.submitted	2015	en
dc.identifier.citation	Hum. Mol. Genet. 2014, 23 (3):831-41	en
dc.identifier.issn	1460-2083	en
dc.identifier.pmid	24057672	en
dc.identifier.doi	10.1093/hmg/ddt465	en
dc.identifier.uri	http://hdl.handle.net/2336/552462	en
dc.description	To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.	en
dc.description.abstract	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.
dc.language.iso	en	en
dc.publisher	Oxford Univ Press	en
dc.relation.url	http://dx.doi.org/ 10.1093/hmg/ddt465	en
dc.relation.url	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888265/	en
dc.rights	Archived with thanks to Human molecular genetics	en
dc.subject	Parkinsonsveiki	en
dc.subject	Crohns-sjúkdómur	en
dc.subject	Geðklofi	en
dc.subject	Arfgengi	en
dc.subject.mesh	Comorbidity	en
dc.subject.mesh	CpG Islands	en
dc.subject.mesh	Crohn Disease	en
dc.subject.mesh	DNA Methylation	en
dc.subject.mesh	Genetic Predisposition to Disease	en
dc.subject.mesh	Genome-Wide Association Study	en
dc.subject.mesh	Humans	en
dc.subject.mesh	Parkinson Disease	en
dc.subject.mesh	Polymorphism, Single Nucleotide	en
dc.subject.mesh	Risk Factors	en
dc.subject.mesh	Schizophrenia	en
dc.title	Genetic comorbidities in Parkinson's disease.	en
dc.type	Article	en
dc.contributor.department	[ 1 ] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA [ 2 ] Ctr Physiopathol Toulouse Purpan, Inst Natl Sante & Rech Med, UMR 1043, Toulouse, France [ 3 ] Univ Toulouse 3, F-31062 Toulouse, France [ 4 ] UCL Inst Neurol, Reta Lila Weston Inst Neurol Studies, London, England [ 5 ] UCL Inst Neurol, Dept Clin Neurosci, London, England [ 6 ] Temple Univ, Dept Biol Anthropol, Philadelphia, PA 19122 USA [ 7 ] Queen Mary Univ London, Wolfson Inst Prevent Med, Barts & London Sch Med & Dent, London, England [ 8 ] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Sch Med, Cardiff CF10 3AX, S Glam, Wales [ 9 ] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany [ 10 ] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany [ 11 ] UCL, Inst Neurol, Dept Mol Neurosci, London, England [ 12 ] UCL, UCL Genet Inst, London, England	en
dc.identifier.journal	Human molecular genetics	en
dc.rights.access	Open Access	en
refterms.dateFOA	2018-09-12T15:11:28Z
html.description.abstract	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.