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.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Mike A
MA
Nalls
Mohamad
M
Saad
Alastair J
AJ
Noyce
Margaux F
MF
Keller
Anette
A
Schrag
Jonathan P
JP
Bestwick
Bryan J
BJ
Traynor
J Raphael
JR
Gibbs
Dena G
DG
Hernandez
Mark R
MR
Cookson
Huw R
HR
Morris
Nigel
N
Williams
Thomas
T
Gasser
Peter
P
Heutink
Nick
N
Wood
John
J
Hardy
Maria
M
Martinez
Andrew B
AB
Singleton
D015897:Comorbidity; D018899:CpG Islands; D003424:Crohn Disease / Q000453:epidemiology* / Q000235:genetics; D019175:DNA Methylation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D010300:Parkinson Disease / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology* / Q000235:genetics