A histone acetylome-wide association study of Alzheimer's disease:
Neuropathology-associated regulatory variation in the human entorhinal cortex
|Sarah J. Marzi, Szi Kay Leung, Teodora Ribarska, Eilis Hannon, Adam R. Smith, Ehsan Pishva, Jeremie Poschmann, Karen Moore, Claire Troakes, Safa Al-Sarraj, Stephan Beck, Stuart Newman, Katie Lunnon, Leonard C. Schalkwyk, Jonathan Mill|
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks were enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, and MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly-significant enrichment of AD risk variants in entrohinal cortex H3K27ac peak regions. Finally, targeted gene expression analysis showed that variable H3K27ac is associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1 and RGCC. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.
Currently available as a preprint on bioRχiv.
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Figure 2 (The top-ranked AD-associated hyperacetylated peak annotated to SOX1 and TEX29 on chromosome 13)
Figure 3 (The top-ranked AD-associated hypoacetylated peak located in intron 1 of ZNF680 on chromosome 7)
Figure 5 (A region annotated to MAPT spanning six H3K27ac peaks characterized by significant hyperacetylation in AD)
Figure 6 (A region annotated to PSEN2 spanning nine H3K27ac peaks characterized by significant hyperacetylation in AD)