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Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes.

Abstract Genome-wide association studies (GWAS) have linked dozens of single nucleotide polymorphisms (SNPs) with Parkinson's disease (PD) risk. Ascertaining the functional and eventual causal mechanisms underlying these relationships has proven difficult. The majority of risk SNPs, and nearby SNPs in linkage disequilibrium (LD), are found in intergenic or intronic regions and confer risk through allele-dependent expression of multiple unknown target genes. Combining GWAS results with publicly available GTEx data, generated through eQTL (expression quantitative trait loci) identification studies, enables a direct association of SNPs to gene expression levels and aids in narrowing the large population of potential genetic targets for hypothesis-driven experimental cell biology. Separately, overlapping of SNPs with putative enhancer segmentations can strengthen target filtering. We report here the results of analyzing 7,607 PD risk SNPs along with an additional 23,759 high linkage disequilibrium-associated variants paired with eQTL gene expression. We found that enrichment analysis on the set of genes following target filtering pointed to a single large LD block at 6p21 that contained multiple HLA-MHC-II genes. These MHC-II genes remain associated with PD when the genes were filtered for correlation between GWAS significance and eQTL levels, strongly indicating a direct effect on PD etiology.
PMID
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Authors

Mayor MeshTerms

Polymorphism, Single Nucleotide

Keywords
Journal Title plos one
Publication Year Start




PMID- 28407015
OWN - NLM
STAT- MEDLINE
DA  - 20170413
DCOM- 20170420
LR  - 20170420
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Parkinson's disease-associated genetic variation is linked to quantitative
      expression of inflammatory genes.
PG  - e0175882
LID - 10.1371/journal.pone.0175882 [doi]
AB  - Genome-wide association studies (GWAS) have linked dozens of single nucleotide
      polymorphisms (SNPs) with Parkinson's disease (PD) risk. Ascertaining the
      functional and eventual causal mechanisms underlying these relationships has
      proven difficult. The majority of risk SNPs, and nearby SNPs in linkage
      disequilibrium (LD), are found in intergenic or intronic regions and confer risk 
      through allele-dependent expression of multiple unknown target genes. Combining
      GWAS results with publicly available GTEx data, generated through eQTL
      (expression quantitative trait loci) identification studies, enables a direct
      association of SNPs to gene expression levels and aids in narrowing the large
      population of potential genetic targets for hypothesis-driven experimental cell
      biology. Separately, overlapping of SNPs with putative enhancer segmentations can
      strengthen target filtering. We report here the results of analyzing 7,607 PD
      risk SNPs along with an additional 23,759 high linkage disequilibrium-associated 
      variants paired with eQTL gene expression. We found that enrichment analysis on
      the set of genes following target filtering pointed to a single large LD block at
      6p21 that contained multiple HLA-MHC-II genes. These MHC-II genes remain
      associated with PD when the genes were filtered for correlation between GWAS
      significance and eQTL levels, strongly indicating a direct effect on PD etiology.
FAU - Pierce, Steven
AU  - Pierce S
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI, United States.
FAU - Coetzee, Gerhard A
AU  - Coetzee GA
AD  - Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids,
      MI, United States.
LA  - eng
PT  - Journal Article
DEP - 20170413
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Histocompatibility Antigens Class II)
SB  - IM
MH  - Gene Expression
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - Histocompatibility Antigens Class II/*genetics
MH  - Humans
MH  - Linkage Disequilibrium
MH  - Parkinson Disease/*genetics
MH  - *Polymorphism, Single Nucleotide
MH  - Quantitative Trait Loci
EDAT- 2017/04/14 06:00
MHDA- 2017/04/21 06:00
CRDT- 2017/04/14 06:00
PHST- 2016/12/30 [received]
PHST- 2017/03/31 [accepted]
AID - 10.1371/journal.pone.0175882 [doi]
AID - PONE-D-16-50794 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 13;12(4):e0175882. doi: 10.1371/journal.pone.0175882.
      eCollection 2017.

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