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

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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

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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., Traynor, B. J., Raphael Gibbs, J., Hernandez, D. G., Cookson, M. R., Morris, H. R., Williams, N., Gasser, T., Heutink, P., Wood, N., Hardy, J., Martinez, M., & 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