An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation

Hannon, Eilís; Dempster, Emma; Viana, Joana; Burrage, Joe; Smith, Adam R.; MacDonald, Robert C.; Clair, David St; Mustard, Colette J; Breen, Gerome; Therman, Sebastian; Kaprio, Jaakko; Toulopoulou, Timothea; Pol, Hilleke E. Hulshoff; Bohlken, Marc M.; Kahn, René S.; Nenadić, Igor; Hultman, Christina M.; Murray, Robin M.; Collier, David A.; Bass, Nick; Gurling, Hugh; McQuillin, Andrew; Schalkwyk, Leonard C.; Mill, Jonathan

doi:10.1186/s13059-016-1041-x

Cited by 291 publications

(330 citation statements)

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“…Notably, three significant associations included migraine index SNP at the YAP1, REST, and ZCCHC14 loci. This finding is consistent with previous reports of mQTL enrichment of top susceptibility variants from GWAS in whole blood (130,150,307). However, we did not find overlap between mQTLs and eQTLs or evidence for differential methylation of the associated CpG sites and therefore cannot draw conclusions on a potential functional mechanism.…”

Section: Discussionsupporting

confidence: 93%

“…Blood can be collected from a large number of individuals in a population-based setting (286), and has been used to identify replicable and biologically informative methylation loci underlying susceptibility to several traits (334). In addition, integrated analyses of SNP genotype and methylation data have found evidence for the co-localisation of existing diseaseassociated SNP loci and DNA methylation signals in blood and brain (150). These studies suggest DNA methylation patterns measured in blood may inform disease processes underlying migraine and characterise existing SNP loci identified through GWA studies.…”

Section: Discussionmentioning

confidence: 99%

“…Whole blood is a highly accessible tissue that can be collected from a large number of individuals from clinical and population-based cohorts, and has been used to identify biologically relevant pathways underlying a range of brain-related diseases (13,14,150,151), including migraine (15)(16)(17)(18). The characterisation of migraine susceptibility loci implicates likely causal genes that are both highly expressed in vascular tissues and have roles in vascular disease and the regulation of blood vessel tone, suggesting impairment of vessel wall function or pathologies.…”

Section: Chapter 8: Discussionmentioning

confidence: 99%

“…These large and well-defined methylation changes can be used to classify tumour subtypes and reliably predict survival and/or response to treatment (146,147). By comparison, the methylation landscape of non-cancer complex diseases often involves thousands of subtle changes distributed throughout the genome that regulate the activity of multiple genes and networks involved in disease pathogenesis (148)(149)(150)(151). Furthermore, many of these changes co-localise with existing risk loci identified through GWA studies, suggesting CpG methylation may mitigate the impact of DNA sequence polymorphism on gene expression and the manifestation of disease.…”

Section: Analysing and Interpreting Epigenetic Datamentioning

confidence: 99%

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Integrating Genome-Wide Association and Blood Genomic Profiling Data to Characterise Migraine Risk Loci

Gerring¹

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Migraine is a frequent, debilitating and painful headache disorder that normally affects people during their most productive years of life (25% of females and 8% of males).Genome-wide association studies have identified 44 independent single nucleotide polymorphisms associated with migraine, however the causal genes and pathogenic mechanisms underlying the disorder remain unknown. Therefore, we performed a multi-staged integrated study of gene expression and DNA methylation in a large sample of migraine cases and non-migraine controls from the Brisbane Systems Genetics Study. We identified several gene expression networks and differentially methylated regions associated with migraine, which were subsequently characterised using robust statistical and pathway-based approaches. Integration of existing genomewide association data with gene expression and methylation data prioritised migraine susceptibility genes for further functional characterisation. This study suggests the use of multiple molecular data to study existing migraine loci has the potential to provide a substantial contribution to understanding the underlying genetic architecture and biological mechanisms of migraine, and may help in the development of diagnostic tests and new targets for drug therapy.3

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Chapter 8: Discussionmentioning

confidence: 99%

Section: Analysing and Interpreting Epigenetic Datamentioning

confidence: 99%

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Integrating Genome-Wide Association and Blood Genomic Profiling Data to Characterise Migraine Risk Loci

Gerring¹

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“…LD relationships were inferred from a reference GWAS dataset (Phase 1) from another study 67 . Neighbouring regions located within 250kb…”

Section: Analysis Of Differential H3k27ac Across Ad Regions From Genomentioning

confidence: 99%

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Marzi

Ribarska

Smith

et al. 2017

Preprint

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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 (n = 47) 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 are 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, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. 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.. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/183541 doi: bioRxiv preprint first posted online 3 Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and memory loss that contributes substantially to the global burden of disease, affecting in excess of 26 million people worldwide 1 . The symptoms of AD are associated with progressive neuropathology in the neocortex, with regions surrounding the entorhinal cortex being particularly affected early in the disease 2 . These neuropathological hallmarks of AD include the extracellular deposition of neurotoxic amyloid-β (Aβ) in the form of amyloid plaques and an accumulation of intracellular neurofibrillary tangles composed of hyperphosphorylated tau 3 . Despite progress in understanding risk factors contributing to AD progression, the mechanisms involved in disease progression are not fully understood and long-term treatments, reversing the cellular disease process in the cortex, are elusive.The...

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Association of a Reproducible Epigenetic Risk Profile for Schizophrenia With Brain Methylation and Function

et al. 2020

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IMPORTANCE Schizophrenia is a severe mental disorder in which epigenetic mechanisms may contribute to illness risk. Epigenetic profiles can be derived from blood cells, but to our knowledge, it is unknown whether these predict established brain alterations associated with schizophrenia.OBJECTIVE To identify an epigenetic signature (quantified as polymethylation score [PMS]) of schizophrenia using machine learning applied to genome-wide blood DNA-methylation data; evaluate whether differences in blood-derived PMS are mirrored in data from postmortem brain samples; test whether the PMS is associated with alterations of dorsolateral prefrontal cortex hippocampal (DLPFC-HC) connectivity during working memory in healthy controls (HC); explore the association between interactions between polygenic and epigenetic risk with DLPFC-HC connectivity; and test the specificity of the signature compared with other serious psychiatric disorders. DESIGN, SETTING, AND PARTICIPANTS In this case-control study conducted from 2008 to 2018 in sites in Germany, the United Kingdom, the United States, and Australia, blood DNA-methylation data from 2230 whole-blood samples from 6 independent cohorts comprising HC (1238 [55.5%]) and participants with schizophrenia (803 [36.0%]), bipolar disorder (39 [1.7%]), major depressive disorder 35 [1.6%]), and autism (27 [1.2%]), and first-degree relatives of all patient groups (88 [3.9%]) were analyzed. DNA-methylation data were further explored from 244 postmortem DLPFC samples from 136 HC and 108 patients with schizophrenia. Neuroimaging and genome-wide association data were available for 393 HC. The latter data was used to calculate a polygenic risk score (PRS) for schizophrenia. The data were analyzed in 2019. MAIN OUTCOMES AND MEASURESThe accuracy of schizophrenia control classification based on machine learning using epigenetic data; association of schizophrenia PMS scores with DLPFC-HC connectivity; and association of the interaction between PRS and PMS with DLPFC-HC connectivity. RESULTSThis study included 7488 participants (4395 men [58.7%]), of whom 3158 (2230 men [70.6%]) received a diagnosis of schizophrenia. The PMS signature was associated with schizophrenia across 3 independent data sets (area under the curve [AUC] from 0.69 to 0.78; P value from 0.049 to 1.24 × 10 −7 ) and data from postmortem DLPFC samples (AUC = 0.63; P = 1.42 × 10 −4 ), but not with major depressive disorder (AUC = 0.51; P = .16), autism (AUC = 0.53; P = .66), or bipolar disorder (AUC = 0.58; P = .21). Pathways contributing most to the classification included synaptic processes. Healthy controls with schizophrenia-like PMS showed significantly altered DLPFC-HC connectivity (validation methylation/magnetic resonance imaging, t < −3.81; P for familywise error, <.04; validation magnetic resonance imaging, t < −3.54; P for familywise error, <.02), mirroring the lack of functional decoupling in schizophrenia. There was no significant association of the interaction between PMS and PRS with DLPFC-HC connectivity (P > .19)...

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An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation

Cited by 291 publications

References 62 publications

Integrating Genome-Wide Association and Blood Genomic Profiling Data to Characterise Migraine Risk Loci

Integrating Genome-Wide Association and Blood Genomic Profiling Data to Characterise Migraine Risk Loci

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Association of a Reproducible Epigenetic Risk Profile for Schizophrenia With Brain Methylation and Function

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