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      Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer’s disease neuropathology

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          Abstract

          Introduction:

          Alzheimer’s disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain.

          Methods:

          We performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740).

          Results:

          We identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts ( P = 3.11 × 10 −18).

          Discussion:

          We present robust evidence for elevated DNA methylation associated with Alzheimer’s disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer’s disease, implicating the HOX gene family as a target for future investigation.

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          Most cited references9

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          Alzheimer's disease.

          Alzheimer's disease is the most common cause of dementia. Research advances have enabled detailed understanding of the molecular pathogenesis of the hallmarks of the disease--ie, plaques, composed of amyloid beta (Abeta), and tangles, composed of hyperphosphorylated tau. However, as our knowledge increases so does our appreciation for the pathogenic complexity of the disorder. Familial Alzheimer's disease is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to Abeta metabolism. By contrast with familial disease, sporadic Alzheimer's disease is very common with more than 15 million people affected worldwide. The cause of the sporadic form of the disease is unknown, probably because the disease is heterogeneous, caused by ageing in concert with a complex interaction of both genetic and environmental risk factors. This seminar reviews the key aspects of the disease, including epidemiology, genetics, pathogenesis, diagnosis, and treatment, as well as recent developments and controversies.
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            Comb-p: software for combining, analyzing, grouping and correcting spatially correlated P-values.

            comb-p is a command-line tool and a python library that manipulates BED files of possibly irregularly spaced P-values and (1) calculates auto-correlation, (2) combines adjacent P-values, (3) performs false discovery adjustment, (4) finds regions of enrichment (i.e. series of adjacent low P-values) and (5) assigns significance to those regions. In addition, tools are provided for visualization and assessment. We provide validation and example uses on bisulfite-seq with P-values from Fisher's exact test, tiled methylation probes using a linear model and Dam-ID for chromatin binding using moderated t-statistics. Because the library accepts input in a simple, standardized format and is unaffected by the origin of the P-values, it can be used for a wide variety of applications. comb-p is maintained under the BSD license. The documentation and implementation are available at https://github.com/brentp/combined-pvalues. bpederse@gmail.com
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              An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation

              Background Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1041-x) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                101231978
                33173
                Alzheimers Dement
                Alzheimers Dement
                Alzheimer's & dementia : the journal of the Alzheimer's Association
                1552-5260
                1552-5279
                31 December 2018
                15 March 2018
                December 2018
                28 March 2019
                : 14
                : 12
                : 1580-1588
                Affiliations
                [a ]Institute of Clinical and Biomedical Science, University of Exeter Medical School, RILD Building, Royal Devon & Exeter Hospital Campus, Exeter, Devon, UK
                [b ]Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women’s Hospital, Boston, MA, USA
                [c ]Harvard Medical School, Boston, MA, USA
                [d ]Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA
                [e ]Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
                [f ]Queen Mary University of London, London, UK
                [g ]Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, USA
                [h ]Department of Neuroscience, The Icahn School of Medicine at Mount Sinai, New York, NY, USA
                [i ]JJ Peters VA Medical Center, Bronx, NY, USA
                [j ]Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
                [k ]Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
                [l ]University of Essex, Colchester, UK
                Author notes
                [* ]Corresponding author. Tel.: +44 1392 408 501.
                [** ]Corresponding author. Tel.: + 44 1392 408 298.
                Article
                NIHMS1516805
                10.1016/j.jalz.2018.01.017
                6438205
                29550519
                3f91f344-f818-468b-9e35-406e37dbb978

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Article

                alzheimer’s disease (ad),braak stage,dna methylation,epigenetics,epigenome-wide association study (ewas),hoxa,illumina infinium 450k beadchip (450k array),meta-analysis,neuropathology,prefrontal cortex (pfc),superior temporal gyrus (stg)

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