Objective: To gain potential mechanistic insight into the pathogenesis of Parkinson’s disease (PD), a map of DNA methylation in normal human brain assessing 486,428 CpG sites was used to integrate 20,615 proximal CpG sites with 28 definitively identified PD risk alleles.

Background: One approach to assess the biological consequences of genetic variation is to integrate genotype with a quantitative trait, such as DNA methylation, in a manner in which biological meaning can be derived from the association between the two datasets. Studies have shown a close interplay between allele load and DNA methylation levels including descriptions of natural human variation and neurological disorders; thus, emphasizing the significance of DNA methylation patterns for diverse phenotypes, including those related to diseases.

Methods: We evaluated the association of PD risk loci with CpG methylation levels in the frontal cortex region of approx. 400 normal human brain samples. CpG methylation levels within 1Mb of 28 reported PD risk variants were examined as potential methylation QTLs. Genotyping for the 28 SNPs with known genome-wide significance in PD GWA studies was performed using the Illumina NeuroX genotyping array. CpG methylation status of 485,577 CpG sites was determined using the Illumina Infinium HumanMethylation450 BeadChip.

Results: Significant DNA methylation QTL are shown for 19 of 28 PD risk loci. The most associated probes within each of the 19 SNPs ranged in significance from p=0.0009 on chromosome 16 to p=3.4×10-79 at the MAPT locus. Our results show two independent risk alleles within SNCA to be associated with methylation of a CpG island and CpG Shore close to the promoter region. The two risk alleles also confer independent effects on CpG methylation in normal human brain, increasing DNA methylation.

Conclusions: The work identifies significant methylation QTLs for 19 of 28 identified PD risk loci, demonstrating correlation of risk alleles for PD with a biologically relevant trait in human brain tissue. Two independent risk alleles within SNCA show significant association with increased DNA methylation. These variants, which confer independent risk effects for PD, also confer independent effects on CpG methylation. Previous studies have suggested an association between SNCA risk alleles and increased SNCA expression. The current data suggests a mechanism for how expression may be modulated at SNCA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/assessment-of-parkinsons-disease-risk-loci-as-dna-methylation-quantitative-trait-loci/