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2. DNA methylation aging clocks: challenges and recommendations

Author

Bell, Christopher G, Lowe, Robert, Adams, Peter D, Baccarelli, Andrea A, Beck, Stephan, Bell, Jordana T, Christensen, Brock C, Gladyshev, Vadim N, Heijmans, Bastiaan T, Horvath, Steve, Ideker, Trey, Issa, Jean-Pierre J, Kelsey, Karl T, Marioni, Riccardo E, Reik, Wolf, Relton, Caroline L, Schalkwyk, Leonard C, Teschendorff, Andrew E, Wagner, Wolfgang, Zhang, Kang, and Rakyan, Vardhman K

Subjects
Human Genome, Genetics, Aging, Generic health relevance, Animals, Biological Clocks, DNA Methylation, Epigenesis, Genetic, Genome, Human, Genome-Wide Association Study, Humans, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Bioinformatics
Abstract

Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.

Published
2019

3. Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

Author

Wong, Chloe CY, Smith, Rebecca G, Hannon, Eilis, Ramaswami, Gokul, Parikshak, Neelroop N, Assary, Elham, Troakes, Claire, Poschmann, Jeremie, Schalkwyk, Leonard C, Sun, Wenjie, Prabhakar, Shyam, Geschwind, Daniel H, and Mill, Jonathan

Subjects
Human Genome, Neurosciences, Intellectual and Developmental Disabilities (IDD), Autism, Genetics, Pediatric, Mental Health, Brain Disorders, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Mental health, Neurological, Autistic Disorder, Case-Control Studies, Cerebellum, DNA Methylation, Epigenome, Female, Gene Ontology, Gene Regulatory Networks, Genome, Human, Humans, Immune System, Male, Neural Pathways, Prefrontal Cortex, Synaptic Transmission, Temporal Lobe, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

Published
2019

5. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Author

De Jager, Philip L, Srivastava, Gyan, Lunnon, Katie, Burgess, Jeremy, Schalkwyk, Leonard C, Yu, Lei, Eaton, Matthew L, Keenan, Brendan T, Ernst, Jason, McCabe, Cristin, Tang, Anna, Raj, Towfique, Replogle, Joseph, Brodeur, Wendy, Gabriel, Stacey, Chai, High S, Younkin, Curtis, Younkin, Steven G, Zou, Fanggeng, Szyf, Moshe, Epstein, Charles B, Schneider, Julie A, Bernstein, Bradley E, Meissner, Alex, Ertekin-Taner, Nilufer, Chibnik, Lori B, Kellis, Manolis, Mill, Jonathan, and Bennett, David A

Subjects
Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Alzheimer's Disease, Human Genome, Genetics, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Alzheimer Disease, Amyloidosis, Ankyrins, Brain, Carrier Proteins, CpG Islands, DNA Methylation, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, Nuclear Proteins, Protein Interaction Maps, Tumor Suppressor Proteins, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

Published
2014

17. Microarrays

Author

Plomin, Robert and Schalkwyk, Leonard C.

Abstract

Microarrays are revolutionizing genetics by making it possible to genotype hundreds of thousands of DNA markers and to assess the expression (RNA transcripts) of all of the genes in the genome. Microarrays are slides the size of a postage stamp that contain millions of DNA sequences to which single-stranded DNA or RNA can hybridize. This miniaturization requires little DNA or RNA and makes the method fast and inexpensive; multiple assays of each target make the method highly accurate. DNA microarrays with hundreds of thousands of DNA markers have made it possible to conduct systematic scans of the entire genome to identify genetic associations with complex disorders or dimensions likely to be influenced by many genes of small effect size. RNA microarrays can provide snapshots of gene expression across all of the genes in the genome at any time in any tissue, which has far-reaching applications such as structural and functional "genetic neuroimaging" and providing a biological basis for understanding environmental influence.

Published
2007
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23. Leveraging DNA-Methylation Quantitative-Trait Loci to Characterize the Relationship between Methylomic Variation, Gene Expression, and Complex Traits

Author

Hannon, Eilis, Gorrie-Stone, Tyler J., Smart, Melissa C., Burrage, Joe, Hughes, Amanda, Bao, Yanchun, Kumari, Meena, Schalkwyk, Leonard C., and Mill, Jonathan

Subjects
summary-data-based Mendelian randomization, genome-wide association study, DNA methylation, quantitative-trait loci, Transcription, Genetic, QTL, Quantitative Trait Loci, Genetic Variation, SNP, Gene Expression, DNA, SMR, single-nucleotide polymorphism, Article, Epigenesis, Genetic, complex traits, Phenotype, Quantitative Trait, Heritable, pleiotropy, GWAS, Humans, Longitudinal Studies, Transcriptome
Abstract

Characterizing the complex relationship between genetic, epigenetic, and transcriptomic variation has the potential to increase understanding about the mechanisms underpinning health and disease phenotypes. We undertook a comprehensive analysis of common genetic variation on DNA methylation (DNAm) by using the Illumina EPIC array to profile samples from the UK Household Longitudinal study. We identified 12,689,548 significant DNA methylation quantitative trait loci (mQTL) associations (p < 6.52 × 10−14) occurring between 2,907,234 genetic variants and 93,268 DNAm sites, including a large number not identified by previous DNAm-profiling methods. We demonstrate the utility of these data for interpreting the functional consequences of common genetic variation associated with > 60 human traits by using summary-data-based Mendelian randomization (SMR) to identify 1,662 pleiotropic associations between 36 complex traits and 1,246 DNAm sites. We also use SMR to characterize the relationship between DNAm and gene expression and thereby identify 6,798 pleiotropic associations between 5,420 DNAm sites and the transcription of 1,702 genes. Our mQTL database and SMR results are available via a searchable online database as a resource to the research community.

Published
2018

27. Allelic skewing of DNA methylation is widespread across the genome

Author

Schalkwyk, Leonard C., Meaburn, Emma L., Smith, Rebecca, Dempster, Emma L., Jeffries, Aaron R., Davies, Matthew N., Plomin, Robert, and Mill, Jonathan

Subjects
Methylation -- Research, Nucleotide sequence -- Research, Allelomorphism -- Research, Biological sciences
Abstract

A genome-wide survey investigates the level of allelic skewing of DNA methylation in order to identify previously unknown differentially methylated regions (DMRs) mainly associated with DNA sequence variation acting in cis or genomic imprinting. A quantitative assessment of allele-specific DNA methylation (ASM) using SNP microarrays reveals that allelic skewing of DNA methylation is widespread across the genome, with likely heterogeneity between individuals and across tissues.

Published
2010

34. Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex

Author

Shireby, Gemma L, primary, Davies, Jonathan P, additional, Francis, Paul T, additional, Burrage, Joe, additional, Walker, Emma M, additional, Neilson, Grant W A, additional, Dahir, Aisha, additional, Thomas, Alan J, additional, Love, Seth, additional, Smith, Rebecca G, additional, Lunnon, Katie, additional, Kumari, Meena, additional, Schalkwyk, Leonard C, additional, Morgan, Kevin, additional, Brookes, Keeley, additional, Hannon, Eilis, additional, and Mill, Jonathan, additional

Published
2020
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46. Response to comment by Stuart Macgregor

Author

Ronald, Angelica, Butcher, Lee M., Docherty, Sophia J., Davis, Oliver S.P., Schalkwyk, Leonard C., Craig, Ian W., and Plomin, Robert

Published
2010

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