Imputation of DNA Methylation Levels in the Brain Implicates a Risk Factor for Parkinson’s Disease

Abstract

Understanding how genetic variation affects intermediate phenotypes, like DNA methylation or gene expression, and how these in turn vary with complex human disease provides valuable insight into disease etiology. However, intermediate phenotypes are typically tissue and developmental stage specific, making relevant phenotypes difficult to assay. Assembling large case–control cohorts, necessary to achieve sufficient statistical power to assess associations between complex traits and relevant intermediate phenotypes, has therefore remained challenging. Imputation of such intermediate phenotypes represents a practical alternative in this context. We used a mixed linear model to impute DNA methylation (DNAm) levels of four brain tissues at up to 1826 methylome-wide sites in 6259 patients with Parkinson’s disease and 9452 controls from across five genome-wide association studies (GWAS). Six sites, in two regions, were found to associate with Parkinson’s disease for at least one tissue. While a majority of identified sites were within an established risk region for Parkinson’s disease, suggesting a role of DNAm in mediating previously observed genetic effects at this locus, we also identify an association with four CpG sites in chromosome 16p11.2. Direct measures of DNAm in the substantia nigra of 39 cases and 13 control samples were used to independently replicate these four associations. Only the association at cg10917602 replicated with a concordant direction of effect (P = 0.02). cg10917602 is 87 kb away from the closest reported GWAS hit. The employed imputation methodology implies that variation of DNAm levels at cg10917602 is predictive for Parkinson’s disease risk, suggesting a possible causal role for methylation at this locus. More generally this study demonstrates the feasibility of identifying predictive epigenetic markers of disease risk from readily available data sets.

Nicotinamide-N-methyltransferase controls behavior, neurodegeneration and lifespan by regulating neuronal autophagy

“…Several studies have implicated NNMT in PD, schizophrenia, and other neurological disorders such as bipolar disorder and epilepsy [ 23 – 28 ]. Notably, both PD and schizophrenia are associated with methylation disturbances in the cell [ 29 , 30 ]. Although some in vitro studies have found potential mechanisms that contribute to NNMT action in neurons [ 31 , 32 ], no mechanism of action has been described in vivo so far.…”

Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk

“…This suggests that both DNA methylation and gene expression could reside along the causal pathway between genetic variation and disease, although thus far, uncovering evidence of a mediated effect between mQTLs and traits has been more limited than using eQTLs 11, 12, 13, 14. Identifying epigenetic markers for disease risk should prove valuable in understanding the underlying biological mechanisms for trait-associated variants 15 . Indeed, the value of this approach was demonstrated in a recent study that applied the SMR 2 method to uncover pleiotropic effects between methylation levels and a range of complex traits 16 …”

The association of DAT gene methylation with striatal DAT availability in healthy subjects

“…The dopamine transporter (DAT) is a sodium chloride-dependent transmembrane protein on the presynaptic dopaminergic nerve terminal [ 1 ], regulating levels of dopamine by reuptake [ 2 , 3 ]. As DAT binding is correlated with the density of dopaminergic neurons [ 4 ], decreased DAT uptake represents dopaminergic neurodegeneration such as PD [ 4 ], a neurodegenerative disease with death of dopaminergic neurons in the substantia nigra pars compacta [ 5 , 6 ]. The most sensitive imaging techniques for the diagnosis of neurodegeneration are positron emission tomography (PET) and single photon emission computed tomography (SPECT) by using ligands that report nigrostriatal dopaminergic function [ 3 ], which allow quantifying dopaminergic system in human brain [ 7 ].…”