Inferring the shared noncoding regulatory mechanisms underlying genetic susceptibility to Alzheimer’s and Parkinson’s Diseases
Date:
Alexandre Amlie-Wolf, Yuk Yee Leung, Gerard Schellenberg, Li-San Wang
Objectives
Genome-wide association studies (GWAS) have identified genetic variants associated with Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), but the majority are noncoding and may affect transcriptional regulatory elements such as enhancers. We set out to characterize the regulatory mechanisms underlying these genetic associations and identify common mechanisms between AD and PD.
Methods
We applied INFERNO (http://inferno.lisanwanglab.org) to GWAS summary statistics for AD (Lambert et al., Nature Genetics 2013) and for PD (Nalls et al., Nature Genetics 2014). INFERNO integrates GWAS data with hundreds of functional genomics datasets to infer the regulatory mechanisms affected by noncoding genetic variants.
Results
In 19 tag regions for AD and 22 for PD, INFERNO identified 1,044 and 3,997 potentially causal variants, respectively. Overall, only 1.6% of these variants were localized in coding exons, while 65% overlapped enhancers in at least one tissue and 46% overlapped transcription factor binding sites. GWAS-eQTL co-localization analysis identified tissue-specific effects on 71 target genes in AD and 103 in PD, with no shared target genes. However, several long noncoding RNAs (lncRNAs) were affected in each disease, and INFERNO identified 61 lncRNA-regulated pathways shared between AD and PD. These pathways were related to mRNA processing and splicing, histone modification, and the immune response.
Conclusions
The principled integration of hundreds of functional genomics datasets revealed lncRNA-mediated biological mechanisms affected in both AD and PD. INFERNO identified the regulatory mechanisms underlying genetic susceptibility to these diseases and prioritized shared biological processes that may be a hallmark of general neurodegeneration.