Genetic comorbidities in parkinson's disease

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 forSNPsnear 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. Weexamine brain methylation andexpression signatures proximal to schizophreniaandCrohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity.Wecompare 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.

Original languageEnglish
Article numberddt465
Pages (from-to)831-841
Number of pages11
JournalHuman Molecular Genetics
Volume23
Issue number3
DOIs
Publication statusPublished - 1 Feb 2014
Externally publishedYes

Fingerprint

Parkinson Disease
Comorbidity
Crohn Disease
Schizophrenia
Genome-Wide Association Study
Brain
Methylation
Epidemiologic Studies
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Nalls, M. A., Saad, M., Noyce, A. J., Keller, M. F., Schrag, A., Bestwick, J. P., ... Singleton, A. B. (2014). Genetic comorbidities in parkinson's disease. Human Molecular Genetics, 23(3), 831-841. [ddt465]. https://doi.org/10.1093/hmg/ddt465

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.; Raphael Gibbs, J.; Hernandez, Dena G.; Cookson, Mark R.; Morris, Huw R.; Williams, Nigel; Gasser, Thomas; Heutink, Peter; Wood, Nick; Hardy, John; Martinez, Maria; Singleton, Andrew B.

In: Human Molecular Genetics, Vol. 23, No. 3, ddt465, 01.02.2014, p. 831-841.

Research output: Contribution to journalArticle

Nalls, MA, Saad, M, Noyce, AJ, Keller, MF, Schrag, A, Bestwick, JP, Traynor, BJ, Raphael Gibbs, J, Hernandez, DG, Cookson, MR, Morris, HR, Williams, N, Gasser, T, Heutink, P, Wood, N, Hardy, J, Martinez, M & Singleton, AB 2014, 'Genetic comorbidities in parkinson's disease', Human Molecular Genetics, vol. 23, no. 3, ddt465, pp. 831-841. https://doi.org/10.1093/hmg/ddt465
Nalls MA, Saad M, Noyce AJ, Keller MF, Schrag A, Bestwick JP et al. Genetic comorbidities in parkinson's disease. Human Molecular Genetics. 2014 Feb 1;23(3):831-841. ddt465. https://doi.org/10.1093/hmg/ddt465
Nalls, Mike A. ; Saad, Mohamad ; Noyce, Alastair J. ; Keller, Margaux F. ; Schrag, Anette ; Bestwick, Jonathan P. ; Traynor, Bryan J. ; Raphael Gibbs, J. ; Hernandez, Dena G. ; Cookson, Mark R. ; Morris, Huw R. ; Williams, Nigel ; Gasser, Thomas ; Heutink, Peter ; Wood, Nick ; Hardy, John ; Martinez, Maria ; Singleton, Andrew B. / Genetic comorbidities in parkinson's disease. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 3. pp. 831-841.
@article{3846979fdc214cec9ec5473db9f12eb0,
title = "Genetic comorbidities in parkinson's disease",
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 forSNPsnear 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. Weexamine brain methylation andexpression signatures proximal to schizophreniaandCrohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity.Wecompare 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.",
author = "Nalls, {Mike A.} and Mohamad Saad and Noyce, {Alastair J.} and Keller, {Margaux F.} and Anette Schrag and Bestwick, {Jonathan P.} and Traynor, {Bryan J.} and {Raphael Gibbs}, J. and Hernandez, {Dena G.} and Cookson, {Mark R.} and Morris, {Huw R.} and Nigel Williams and Thomas Gasser and Peter Heutink and Nick Wood and John Hardy and Maria Martinez and Singleton, {Andrew B.}",
year = "2014",
month = "2",
day = "1",
doi = "10.1093/hmg/ddt465",
language = "English",
volume = "23",
pages = "831--841",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "3",

}

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 - Raphael Gibbs, J.

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.

PY - 2014/2/1

Y1 - 2014/2/1

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 forSNPsnear 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. Weexamine brain methylation andexpression signatures proximal to schizophreniaandCrohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity.Wecompare 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 forSNPsnear 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. Weexamine brain methylation andexpression signatures proximal to schizophreniaandCrohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity.Wecompare 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.

UR - http://www.scopus.com/inward/record.url?scp=84892453822&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892453822&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddt465

DO - 10.1093/hmg/ddt465

M3 - Article

C2 - 24057672

AN - SCOPUS:84892453822

VL - 23

SP - 831

EP - 841

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 3

M1 - ddt465

ER -