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Genetic comorbidities in Parkinson's disease

Genetic comorbidities in Parkinson's disease
Genetic comorbidities in Parkinson's disease
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.
831-841
Nalls, M.A.
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Saad, M.
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Noyce, A.J.
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Keller, M.F.
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Schrag, A.
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Bestwick, J.P.
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Traynor, B.J.
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Gibbs, J.R.
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Hernandez, D.G.
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Cookson, M.R.
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Morris, H.R.
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Williams, N.
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Gasser, T.
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Heutink, P.
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Wood, N.
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Hardy, J.
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Martinez, M.
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Singleton, A. B.
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Morrison, Karen
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Nalls, M.A.
f952a2fe-c78a-492d-8df0-4277a6ab06e9
Saad, M.
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Noyce, A.J.
1b7ed04d-c0d8-49ab-ad0a-502e0a560bc8
Keller, M.F.
b464ef8b-1007-4bba-99ba-a14865041124
Schrag, A.
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Bestwick, J.P.
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Traynor, B.J.
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Gibbs, J.R.
b7533129-25bd-4e2e-9331-dae5e8d564b4
Hernandez, D.G.
204bb8de-a24d-47d8-952a-00795bf4c426
Cookson, M.R.
391ea80d-0ffa-40b6-9ee7-6ec73645dcc4
Morris, H.R.
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Williams, N.
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Gasser, T.
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Heutink, P.
4eeb2fe2-a362-4bd3-9a72-67b7ebce65a6
Wood, N.
6860682a-f3e3-4711-9e3d-cdf3fa633cc5
Hardy, J.
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Martinez, M.
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Singleton, A. B.
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Morrison, Karen
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Nalls, M.A., Saad, M. and Noyce, A.J. et al. (2014) Genetic comorbidities in Parkinson's disease. Human Molecular Genetics, 23 (3), 831-841. (doi:10.1093/hmg/ddt465). (PMID:24057672)

Record type: Article

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.

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Accepted/In Press date: 17 September 2013
Published date: 2014
Organisations: Medical Education

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Local EPrints ID: 398326
URI: http://eprints.soton.ac.uk/id/eprint/398326
PURE UUID: b5784809-b7fa-4419-af9e-fa3a8da18821
ORCID for Karen Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 21 Jul 2016 14:04
Last modified: 29 Oct 2019 01:34

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Contributors

Author: M.A. Nalls
Author: M. Saad
Author: A.J. Noyce
Author: M.F. Keller
Author: A. Schrag
Author: J.P. Bestwick
Author: B.J. Traynor
Author: J.R. Gibbs
Author: D.G. Hernandez
Author: M.R. Cookson
Author: H.R. Morris
Author: N. Williams
Author: T. Gasser
Author: P. Heutink
Author: N. Wood
Author: J. Hardy
Author: M. Martinez
Author: A. B. Singleton
Author: Karen Morrison ORCID iD

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