A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the 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

doi:10.1038/s41593-018-0253-7

A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the 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^*

^*Corresponding author for this work

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Abstract

We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-beta and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.

Original language	English
Pages (from-to)	1618-1627
Number of pages	17
Journal	Nature Neuroscience
Volume	21
Issue number	11
DOIs	https://doi.org/10.1038/s41593-018-0253-7
Publication status	Published - 1 Nov 2018

Keywords

AMYLOID PRECURSOR PROTEIN
DNA METHYLATION
GENE-EXPRESSION
BRAIN
NEURODEGENERATION
QUANTIFICATION
PRESENILIN-1
ACETYLATION
PROGRESSION
HYPOTHESIS

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10.1038/s41593-018-0253-7

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Marzi, S. J., Leung, S. K., Ribarska, T., Hannon, E., Smith, A. R., Pishva, E., Poschmann, J., Moore, K., Troakes, C., Al-Sarraj, S., Beck, S., Newman, S., Lunnon, K., Schalkwyk, L. C., & Mill, J. (2018). A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex. Nature Neuroscience, 21(11), 1618-1627. https://doi.org/10.1038/s41593-018-0253-7

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title = "A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex",

abstract = "We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-beta and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.",

keywords = "AMYLOID PRECURSOR PROTEIN, DNA METHYLATION, GENE-EXPRESSION, BRAIN, NEURODEGENERATION, QUANTIFICATION, PRESENILIN-1, ACETYLATION, PROGRESSION, HYPOTHESIS",

author = "Marzi, {Sarah J.} and Leung, {Szi Kay} and Teodora Ribarska and Eilis Hannon and Smith, {Adam R.} and Ehsan Pishva and Jeremie Poschmann and Karen Moore and Claire Troakes and Safa Al-Sarraj and Stephan Beck and Stuart Newman and Katie Lunnon and Schalkwyk, {Leonard C.} and Jonathan Mill",

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Marzi, SJ, Leung, SK, Ribarska, T, Hannon, E, Smith, AR, Pishva, E, Poschmann, J, Moore, K, Troakes, C, Al-Sarraj, S, Beck, S, Newman, S, Lunnon, K, Schalkwyk, LC & Mill, J 2018, 'A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex', Nature Neuroscience, vol. 21, no. 11, pp. 1618-1627. https://doi.org/10.1038/s41593-018-0253-7

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T1 - A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex

AU - Marzi, Sarah J.

AU - Leung, Szi Kay

AU - Ribarska, Teodora

AU - Hannon, Eilis

AU - Smith, Adam R.

AU - Pishva, Ehsan

AU - Poschmann, Jeremie

AU - Moore, Karen

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Beck, Stephan

AU - Newman, Stuart

AU - Lunnon, Katie

AU - Schalkwyk, Leonard C.

AU - Mill, Jonathan

PY - 2018/11/1

Y1 - 2018/11/1

N2 - We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-beta and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.

AB - We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-beta and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.

KW - AMYLOID PRECURSOR PROTEIN

KW - DNA METHYLATION

KW - GENE-EXPRESSION

KW - BRAIN

KW - NEURODEGENERATION

KW - QUANTIFICATION

KW - PRESENILIN-1

KW - ACETYLATION

KW - PROGRESSION

KW - HYPOTHESIS

U2 - 10.1038/s41593-018-0253-7

DO - 10.1038/s41593-018-0253-7

M3 - Article

C2 - 30349106

SN - 1097-6256

VL - 21

SP - 1618

EP - 1627

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 11

ER -