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

Author

Wong, Chloe C Y, 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, Mill, Jonathan, King‘s College London, University of Exeter Medical School, University of Exeter, University of California [Los Angeles] (UCLA), University of California, Queen Mary University of London (QMUL), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), University of Essex, Genome Institute of Singapore (GIS), PsychENCODE (1R01MH094714 to D.H.G.), Medical ResearchCouncil (MR/R005176/1, MR/K013807/1, MR/M008924/1 to J.M.)., Le Bihan, Sylvie, and University of California (UC)

Subjects
Male, Genetics & Heredity, Genome, Human, [SDV]Life Sciences [q-bio], Prefrontal Cortex, DNA Methylation, Biological Sciences, Synaptic Transmission, Medical and Health Sciences, Temporal Lobe, [SDV] Life Sciences [q-bio], Epigenome, Gene Ontology, Case-Control Studies, Cerebellum, Immune System, Neural Pathways, Humans, Female, Gene Regulatory Networks, General Article, Autistic Disorder
Abstract

International audience; 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

58. List of Referees

Author

Sluyter, Frans and Schalkwyk, Leonard C.

Published
2003

59. High resolution cosmid and P1 maps spanning the 14 Mb genome of the fission yeast S. pombe

Author

Hoheisel, Jorg D., Maier, Elmar, Mott, Richard, McCarthy, Linda, Grigoriev, Andrei V., Schalkwyk, Leonard C., Nizetic, Dean, Francis, Fiona, and Lehrach, Hans

Subjects
Chromosome mapping -- Research, Biological sciences
Abstract

A P1 genomic library of 17-fold coverage and a cosmid library of eight genome equivalents were ordered by hybridizing genetic markers and individual clones from the two libraries. Both were gridded on high density filters and subdivided by yeast artificial chromosome clones covering the entire genome. Further data was provided by the hybridization of short oligonucleotides and DNA pools made from randomly selected cosmids. This approach of using parallel libraries greatly enhances the mapping and resolution of the clone order, although further improvements can be made in speed and accuracy.

Published
1993

60. Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression

Author

Malki, Karim, Tosto, Maria Grazia, Mouriño-Talín, Héctor, Rodríguez-Lorenzo, Sabela, Pain, Oliver, Jumhaboy, Irfan, Liu, Tina, Parpas, Panos, Newman, Stuart, Malykh, Arten, Carboni, Lucia, Uher, Rudolf, McGuffin, Peter, Schalkwyk, Leonard C., Bryson, Kevin, Herbster, Mark, Malki, Karim, Tosto, Maria Grazia, Mouriño-Talín, Héctor, Rodríguez-Lorenzo, Sabela, Pain, Oliver, Jumhaboy, Irfan, Liu, Tina, Parpas, Pano, Newman, Stuart, Malykh, Artem, Carboni, Lucia, Uher, Rudolf, Mcguffin, Peter, Schalkwyk, Leonard C., Bryson, Kevin, Herbster, Mark, and Engineering & Physical Science Research Council (EPSRC)

Subjects
Male, Multifactorial Inheritance, SVM, Antidepressant, Nortriptyline, Citalopram, Hippocampus, HIPPOCAMPAL NEUROGENESIS, CANDIDATE GENES, transcriptomics, Mice, Cellular and Molecular Neuroscience, Machine learning, WIDE ASSOCIATION, FACTOR CREB, Animals, SSRI, Serotonin and Noradrenaline Reuptake Inhibitors, Cyclic AMP Response Element-Binding Protein, Research Articles, Genetics (clinical), Genetics & Heredity, Psychiatry, Depressive Disorder, 0604 Genetics, Science & Technology, DRUG-TREATMENT, CONVERGENT FUNCTIONAL GENOMICS, MOLECULAR-MECHANISMS, Depression, 1103 Clinical Sciences, MAJOR DEPRESSION, ELEMENT-BINDING PROTEIN, Antidepressive Agents, FACTOR-KAPPA-B, Disease Models, Animal, Treatment Outcome, Transcriptomic, Pharmacogenetics, Psychiatry and Mental Health, antidepressants, Serotonin Uptake Inhibitors, Female, Transcriptome, 1109 Neurosciences, Life Sciences & Biomedicine, Selective Serotonin Reuptake Inhibitors, Research Article
Abstract

Response to antidepressant (AD) treatment may be a more polygenic trait than previously hypothesized, with many genetic variants interacting in yet unclear ways. In this study we used methods that can automatically learn to detect patterns of statistical regularity from a sparsely distributed signal across hippocampal transcriptome measurements in a large‐scale animal pharmacogenomic study to uncover genomic variations associated with AD. The study used four inbred mouse strains of both sexes, two drug treatments, and a control group (escitalopram, nortriptyline, and saline). Multi‐class and binary classification using Machine Learning (ML) and regularization algorithms using iterative and univariate feature selection methods, including InfoGain, mRMR, ANOVA, and Chi Square, were used to uncover genomic markers associated with AD response. Relevant genes were selected based on Jaccard distance and carried forward for gene‐network analysis. Linear association methods uncovered only one gene associated with drug treatment response. The implementation of ML algorithms, together with feature reduction methods, revealed a set of 204 genes associated with SSRI and 241 genes associated with NRI response. Although only 10% of genes overlapped across the two drugs, network analysis shows that both drugs modulated the CREB pathway, through different molecular mechanisms. Through careful implementation and optimisations, the algorithms detected a weak signal used to predict whether an animal was treated with nortriptyline (77%) or escitalopram (67%) on an independent testing set. The results from this study indicate that the molecular signature of AD treatment may include a much broader range of genomic markers than previously hypothesized, suggesting that response to medication may be as complex as the pathology. The search for biomarkers of antidepressant treatment response could therefore consider a higher number of genetic markers and their interactions. Through predominately different molecular targets and mechanisms of action, the two drugs modulate the same Creb1 pathway which plays a key role in neurotrophic responses and in inflammatory processes. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Published
2017

61. DNA methylation at the Igf2/H19 imprinting control region is associated with cerebellum mass in outbred mice

Author

Pidsley Ruth, Fernandes Cathy, Viana Joana, Paya-Cano Jose L, Liu Lin, Smith Rebecca G, Schalkwyk Leonard C, and Mill Jonathan

Subjects
Igf2, H19, Epigenetics, DNA methylation, Cerebellum, Brain, Mouse, Genotype, Genomic imprinting, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Insulin-like growth factor 2 (Igf2) is a paternally expressed imprinted gene regulating fetal growth, playing an integral role in the development of many tissues including the brain. The parent-of-origin specific expression of Igf2 is largely controlled by allele-specific DNA methylation at CTCF-binding sites in the imprinting control region (ICR), located immediately upstream of the neighboring H19 gene. Previously we reported evidence of a negative correlation between DNA methylation in this region and cerebellum weight in humans. Results We quantified cerebellar DNA methylation across all four CTCF binding sites spanning the murine Igf2/H19 ICR in an outbred population of Heterogeneous Stock (HS) mice (n = 48). We observe that DNA methylation at the second and third CTCF binding sites in the Igf2/H19 ICR shows a negative relationship with cerebellar mass, reflecting the association observed in human post-mortem cerebellum tissue. Conclusions Given the important role of the cerebellum in motor control and cognition, and the link between structural cerebellar abnormalities and neuropsychiatric phenotypes, the identification of epigenetic factors associated with cerebellum growth and development may provide important insights about the etiology of psychiatric disorders.

Published
2012
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62. Genetic variation in hippocampal microRNA expression differences in C57BL/6 J X DBA/2 J (BXD) recombinant inbred mouse strains

Author

Parsons Michael J, Grimm Christina, Paya-Cano Jose L, Fernandes Cathy, Liu Lin, Philip Vivek M, Chesler Elissa J, Nietfeld Wilfried, Lehrach Hans, and Schalkwyk Leonard C

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background miRNAs are short single-stranded non-coding RNAs involved in post-transcriptional gene regulation that play a major role in normal biological functions and diseases. Little is currently known about how expression of miRNAs is regulated. We surveyed variation in miRNA abundance in the hippocampus of mouse inbred strains, allowing us to take a genetic approach to the study of miRNA regulation, which is novel for miRNAs. The BXD recombinant inbred panel is a very well characterized genetic reference panel which allows quantitative trait locus (QTL) analysis of miRNA abundance and detection of correlates in a large store of brain and behavioural phenotypes. Results We found five suggestive trans QTLs for the regulation of miRNAs investigated. Further analysis of these QTLs revealed two genes, Tnik and Phf17, under the miR-212 regulatory QTLs, whose expression levels were significantly correlated with miR-212 expression. We found that miR-212 expression is correlated with cocaine-related behaviour, consistent with a reported role for this miRNA in the control of cocaine consumption. miR-31 is correlated with anxiety and alcohol related behaviours. KEGG pathway analysis of each miRNA’s expression correlates revealed enrichment of pathways including MAP kinase, cancer, long-term potentiation, axonal guidance and WNT signalling. Conclusions The BXD reference panel allowed us to establish genetic regulation and characterize biological function of specific miRNAs. QTL analysis enabled detection of genetic loci that regulate the expression of these miRNAs. eQTLs that regulate miRNA abundance are a new mechanism by which genetic variation influences brain and behaviour. Analysis of one of these QTLs revealed a gene, Tnik, which may regulate the expression of a miRNA, a molecular pathway and a behavioural phenotype. Evidence of genetic covariation of miR-212 abundance and cocaine related behaviours is strongly supported by previous functional studies, demonstrating the value of this approach for discovery of new functional roles and downstream processes regulated by miRNA.

Published
2012
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63. O4-10-06: INTEGRATED GENETIC-EPIGENETIC ANALYSES OF ALZHEIMER'S DISEASE

Author

Smith, Rebecca G., primary, Pishva, Ehsan, additional, Shireby, Gemma, additional, Smith, Adam R., additional, Hannon, Eilis, additional, Sharp, Andrew J., additional, f Mastroeni, Diego, additional, Schalkwyk, Leonard C., additional, Haroutunian, Vahram, additional, Coleman, Paul D., additional, Bennett, David A., additional, van den Hove, Daniel L.A., additional, De Jager, Philip L., additional, Mill, Jonathan, additional, and Lunnon, Katie, additional

Published
2019
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65. Utility of the pooling approach as applied to whole genome association scans with high-density Affymetrix microarrays

Author

Gray Joanna, Gunasinghe Cerisse, Korszun Ania, Elkin Amanda, Schalkwyk Leonard C, Cohen-Woods Sarah, Gaysina Darya, Pirlo Katrina, Schosser Alexandra, Jones Lisa, Meaburn Emma, Farmer Anne E, Craig Ian W, and McGuffin Peter

Subjects
Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract

Abstract Background We report an attempt to extend the previously successful approach of combining SNP (single nucleotide polymorphism) microarrays and DNA pooling (SNP-MaP) employing high-density microarrays. Whereas earlier studies employed a range of Affymetrix SNP microarrays comprising from 10 K to 500 K SNPs, this most recent investigation used the 6.0 chip which displays 906,600 SNP probes and 946,000 probes for the interrogation of CNVs (copy number variations). The genotyping assay using the Affymetrix SNP 6.0 array is highly demanding on sample quality due to the small feature size, low redundancy, and lack of mismatch probes. Findings In the first study published so far using this microarray on pooled DNA, we found that pooled cheek swab DNA could not accurately predict real allele frequencies of the samples that comprised the pools. In contrast, the allele frequency estimates using blood DNA pools were reasonable, although inferior compared to those obtained with previously employed Affymetrix microarrays. However, it might be possible to improve performance by developing improved analysis methods. Conclusions Despite the decreasing costs of genome-wide individual genotyping, the pooling approach may have applications in very large-scale case-control association studies. In such cases, our study suggests that high-quality DNA preparations and lower density platforms should be preferred.

Published
2010
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66. Applicability of DNA pools on 500 K SNP microarrays for cost-effective initial screens in genomewide association studies

Author

Schalkwyk Leonard C, Butcher Lee M, Docherty Sophia J, and Plomin Robert

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Genetic influences underpinning complex traits are thought to involve multiple quantitative trait loci (QTLs) of small effect size. Detection of such QTL associations requires systematic screening of large numbers of DNA markers within large sample populations. Using pooled DNA on SNP microarrays to screen for allelic frequency differences between groups such as cases and controls (called SNP Microarray and Pooling, or SNP-MaP) has been validated as an efficient solution on both 10 k and 100 k platforms. We demonstrate that this approach can be effectively applied to the truly genomewide Affymetrix GeneChip® Mapping 500 K Array. Results In comparisons between five independent DNA pools (N ~200 per pool) on separate Affymetrix GeneChip® Mapping 500 K Array sets, we show that, for SNPs with minor allele frequencies > 0.05, the reliability of the rank order of estimated allele frequencies, assessed as the average correlation between allele frequency estimates across the DNA pools, was 0.948 (average mean difference across the five pools = 0.069). Similarly, validity of the SNP-MaP approach was demonstrated by a rank-order correlation of 0.937 (average mean difference = 0.095) between the average DNA pool allele frequency estimates and the allele frequencies of an independent (CEPH) sample of 60 unrelated individually genotyped subjects. Conclusion We conclude that SNP-MaP can be extended for use on the Affymetrix GeneChip® Mapping 500 K Array, providing a cost-effective, reliable and valid initial screen of 500 K SNP microarrays in genomewide association scans.

Published
2007
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67. Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

Author

Min, Josine L., Hemani, Gibran, Hannon, Eilis, Dekkers, Koen F., Castillo-Fernandez, Juan, Luijk, René, Carnero-Montoro, Elena, Lawson, Daniel J., Burrows, Kimberley, Suderman, Matthew, Bretherick, Andrew D., Richardson, Tom G., Klughammer, Johanna, Iotchkova, Valentina, Sharp, Gemma, Al Khleifat, Ahmad, Shatunov, Aleksey, Iacoangeli, Alfredo, McArdle, Wendy L., Ho, Karen M., Kumar, Ashish, Söderhäll, Cilla, Soriano-Tárraga, Carolina, Giralt-Steinhauer, Eva, Kazmi, Nabila, Mason, Dan, McRae, Allan F., Corcoran, David L., Sugden, Karen, Kasela, Silva, Cardona, Alexia, Day, Felix R., Cugliari, Giovanni, Viberti, Clara, Guarrera, Simonetta, Lerro, Michael, Gupta, Richa, Bollepalli, Sailalitha, Mandaviya, Pooja, Zeng, Yanni, Clarke, Toni-Kim, Walker, Rosie M., Schmoll, Vanessa, Czamara, Darina, Ruiz-Arenas, Carlos, Rezwan, Faisal I., Marioni, Riccardo E., Lin, Tian, Awaloff, Yvonne, Germain, Marine, Aïssi, Dylan, Zwamborn, Ramona, van Eijk, Kristel, Dekker, Annelot, van Dongen, Jenny, Hottenga, Jouke-Jan, Willemsen, Gonneke, Xu, Cheng-Jian, Barturen, Guillermo, Català-Moll, Francesc, Kerick, Martin, Wang, Carol, Melton, Phillip, Elliott, Hannah R., Shin, Jean, Bernard, Manon, Yet, Idil, Smart, Melissa, Gorrie-Stone, Tyler, Shaw, Chris, Al Chalabi, Ammar, Ring, Susan M., Pershagen, Göran, Melén, Erik, Jiménez-Conde, Jordi, Roquer, Jaume, Lawlor, Deborah A., Wright, John, Martin, Nicholas G., Montgomery, Grant W., Moffitt, Terrie E., Poulton, Richie, Esko, Tõnu, Milani, Lili, Metspalu, Andres, Perry, John R. B., Ong, Ken K., Wareham, Nicholas J., Matullo, Giuseppe, Sacerdote, Carlotta, Panico, Salvatore, Caspi, Avshalom, Arseneault, Louise, Gagnon, France, Ollikainen, Miina, Kaprio, Jaakko, Felix, Janine F., Rivadeneira, Fernando, Tiemeier, Henning, van IJzendoorn, Marinus H., Uitterlinden, André G., Jaddoe, Vincent W. V., Haley, Chris, McIntosh, Andrew M., Evans, Kathryn L., Murray, Alison, Räikkönen, Katri, Lahti, Jari, Nohr, Ellen A., Sørensen, Thorkild I. A., Hansen, Torben, Morgen, Camilla S., Binder, Elisabeth B., Lucae, Susanne, Gonzalez, Juan Ramon, Bustamante, Mariona, Sunyer, Jordi, Holloway, John W., Karmaus, Wilfried, Zhang, Hongmei, Deary, Ian J., Wray, Naomi R., Starr, John M., Beekman, Marian, van Heemst, Diana, Slagboom, P. Eline, Morange, Pierre-Emmanuel, Trégouët, David-Alexandre, Veldink, Jan H., Davies, Gareth E., de Geus, Eco J. C., Boomsma, Dorret I., Vonk, Judith M., Brunekreef, Bert, Koppelman, Gerard H., Alarcón-Riquelme, Marta E., Huang, Rae-Chi, Pennell, Craig E., van Meurs, Joyce, Ikram, M. Arfan, Hughes, Alun D., Tillin, Therese, Chaturvedi, Nish, Pausova, Zdenka, Paus, Tomas, Spector, Timothy D., Kumari, Meena, Schalkwyk, Leonard C., Visscher, Peter M., Davey Smith, George, Bock, Christoph, Gaunt, Tom R., Bell, Jordana T., Heijmans, Bastiaan T., Mill, Jonathan, and Relton, Caroline L.

Abstract

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15–17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype–phenotype map than previously anticipated.

Published
2021
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68. Genotyping DNA pools on microarrays: Tackling the QTL problem of large samples and large numbers of SNPs

Author

Plomin Robert, Al-Chalabi Ammar, Hansen Valerie, Fernandes Cathy, Liu Lin, Butcher Lee M, Meaburn Emma, Craig Ian, and Schalkwyk Leonard C

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Quantitative trait locus (QTL) theory predicts that genetic influence on complex traits involves multiple genes of small effect size. To detect QTL associations of small effect size, large samples and systematic screens of thousands of DNA markers are required. An efficient solution is to genotype case and control DNA pools using SNP microarrays. We demonstrate that this is practical using DNA pools of 100 individuals. Results Using standard microarray protocols for the Affymetrix GeneChip® Mapping 10 K Array Xba 131, we show that relative allele signal (RAS) values provide a quantitative index of allele frequencies in pooled DNA that correlate 0.986 with allele frequencies for 104 SNPs that were genotyped individually for 100 individuals. The sensitivity of the assay was demonstrated empirically in a spiking experiment in which 15% and 20% of one individual's DNA was added to a DNA pool. Conclusion We conclude that this approach, which we call SNP-MaP (SNP microarrays and pooling), is rapid, cost effective and promises to be a valuable initial screening method in the hunt for QTLs.

Published
2005
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70. Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic forms of autism in post-mortem human brain tissue

Author

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

Published
2018
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71. Properties of the epigenetic clock and age acceleration

Author

Khoury, Louis El, primary, Gorrie-Stone, Tyler, additional, Smart, Melissa, additional, Hughes, Amanda, additional, Bao, Yanchun, additional, Andrayas, Alexandria, additional, Burrage, Joe, additional, Hannon, Eilis, additional, Kumari, Meena, additional, Mill, Jonathan, additional, and Schalkwyk, Leonard C, additional

Published
2018
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75. A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Author

Marzi, Sarah J., primary, Ribarska, Teodora, additional, Smith, Adam R., additional, Hannon, Eilis, additional, Poschmann, Jeremie, additional, Moore, Karen, additional, Troakes, Claire, additional, Al-Sarraj, Safa, additional, Beck, Stephan, additional, Newman, Stuart, additional, Lunnon, Katie, additional, Schalkwyk, Leonard C., additional, and Mill, Jonathan, additional

Published
2017
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77. The mouse homeobox gene Not is required for caudal notochord development and affected by the truncate mutation

Author

Abdelkhalek, Hanaa Ben, Schuster-Gossler, Karin, Beckers, Anja, Pavlova, Maria N., Lickert, Heiko, Burkhardt, Hannelore, Rossant, Janet, Schalkwyk, Leonard C., Reinhardt, Richard, Miller, Ines, Ceolin, Marcelo, Herrmann, Bernhard G., Rivera-Pomar, Rolando, and Gossler, Achim

Subjects
Gene mutations -- Research, Nucleotide sequence -- Research, Genetic research, Gene expression, Notochord, Biological sciences
Abstract

A homeobox gene is identified on the basis of sequence and expression pattern, to represent a murine member of the vertebrate Not gene family. It is shown that this gene is affected by the mouse truncate mutation by complementation test with a targeted null allele and is essential for development of the entire notochord.

Published
2004

78. Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions

Author

Viana, Joana, primary, Hannon, Eilis, additional, Dempster, Emma, additional, Pidsley, Ruth, additional, Macdonald, Ruby, additional, Knox, Olivia, additional, Spiers, Helen, additional, Troakes, Claire, additional, Al-Saraj, Safa, additional, Turecki, Gustavo, additional, Schalkwyk, Leonard C, additional, and Mill, Jonathan, additional

Published
2016
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79. Highly polygenic architecture of antidepressant treatment response: Comparative analysis of SSRI and NRI treatment in an animal model of depression

Author

Malki, Karim, primary, Tosto, Maria Grazia, additional, Mouriño-Talín, Héctor, additional, Rodríguez-Lorenzo, Sabela, additional, Pain, Oliver, additional, Jumhaboy, Irfan, additional, Liu, Tina, additional, Parpas, Panos, additional, Newman, Stuart, additional, Malykh, Artem, additional, Carboni, Lucia, additional, Uher, Rudolf, additional, McGuffin, Peter, additional, Schalkwyk, Leonard C., additional, Bryson, Kevin, additional, and Herbster, Mark, additional

Published
2016
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80. Bigmelon: tools for analysing large DNA methylation datasets.

Author

Gorrie-Stone, Tyler J, Smart, Melissa C, Saffari, Ayden, Malki, Karim, Hannon, Eilis, Burrage, Joe, Mill, Jonathan, Kumari, Meena, and Schalkwyk, Leonard C

Subjects
DNA methylation, EPIGENETICS, BIOINFORMATICS, DATA mining, BIG data
Abstract

Motivation The datasets generated by DNA methylation analyses are getting bigger. With the release of the HumanMethylationEPIC micro-array and datasets containing thousands of samples, analyses of these large datasets using R are becoming impractical due to large memory requirements. As a result there is an increasing need for computationally efficient methodologies to perform meaningful analysis on high dimensional data. Results Here we introduce the bigmelon R package, which provides a memory efficient workflow that enables users to perform the complex, large scale analyses required in epigenome wide association studies (EWAS) without the need for large RAM. Building on top of the CoreArray Genomic Data Structure file format and libraries packaged in the gdsfmt package, we provide a practical workflow that facilitates the reading-in, preprocessing, quality control and statistical analysis of DNA methylation data. We demonstrate the capabilities of the bigmelon package using a large dataset consisting of 1193 human blood samples from the Understanding Society: UK Household Longitudinal Study, assayed on the EPIC micro-array platform. Availability and implementation The bigmelon package is available on Bioconductor (http://bioconductor.org/packages/bigmelon/). The Understanding Society dataset is available at https://www.understandingsociety.ac.uk/about/health/data upon request. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Published
2019
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81. INTEGRATED GENETIC-EPIGENETIC ANALYSES OF ALZHEIMER'S DISEASE

Author

Smith, Rebecca G., Pishva, Ehsan, Shireby, Gemma, Smith, Adam R., Hannon, Eilis, Sharp, Andrew J., Mastroeni, Diego f, Schalkwyk, Leonard C., Haroutunian, Vahram, Coleman, Paul D., Bennett, David A., van den Hove, Daniel L.A., De Jager, Philip L., Mill, Jonathan, and Lunnon, Katie

Published
2019
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82. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Author

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

Subjects
Male, Aging, Genome-wide association study, Neurodegenerative, Alzheimer's Disease, 80 and over, 2.1 Biological and endogenous factors, Psychology, Protein Interaction Maps, Aetiology, Epigenomics, Genetics, Aged, 80 and over, General Neuroscience, Intracellular Signaling Peptides and Proteins, Brain, Adaptor Proteins, Nuclear Proteins, Methylation, Amyloidosis, Middle Aged, 3. Good health, CpG site, Neurological, DNA methylation, Female, Cognitive Sciences, Alzheimer's disease, Ankyrins, and over, Biology, Article, Alzheimer Disease, Acquired Cognitive Impairment, medicine, Humans, Genetic Predisposition to Disease, Gene, Adaptor Proteins, Signal Transducing, Aged, Neurology & Neurosurgery, Tumor Suppressor Proteins, Human Genome, Signal Transducing, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), DNA Methylation, medicine.disease, Brain Disorders, Differentially methylated regions, Dementia, CpG Islands, Carrier Proteins, Genome-Wide Association Study
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., National Institutes of Health (U.S.) (Grant R01 AG036042), National Institutes of Health (U.S.) (Grant R01AG036836), National Institutes of Health (U.S.) (Grant R01 AG17917), National Institutes of Health (U.S.) (Grant R01AG15819), National Institutes of Health (U.S.) (Grant R01 AG032990), National Institutes of Health (U.S.) (Grant R01 AG18023), National Institutes of Health (U.S.) (Grant RC2 AG036547), National Institutes of Health (U.S.) (Grant P30 AG10161), National Institutes of Health (U.S.) (Grant P50 AG016574), National Institutes of Health (U.S.) (Grant U01 ES017155), National Institutes of Health (U.S.) (Grant KL2 RR024151), National Institutes of Health (U.S.) (Grant K25 AG041906-01)

Published
2014

83. Transcriptome analysis of genes and gene networks involved in aggressive behavior in mouse and zebrafish

Author

Malki, Karim, primary, Du Rietz, Ebba, additional, Crusio, Wim E., additional, Pain, Oliver, additional, Paya-Cano, Jose, additional, Karadaghi, Rezhaw L., additional, Sluyter, Frans, additional, de Boer, Sietse F., additional, Sandnabba, Kenneth, additional, Schalkwyk, Leonard C., additional, Asherson, Philip, additional, and Tosto, Maria Grazia, additional

Published
2016
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84. Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

Author

Houtepen, Lotte C., primary, Vinkers, Christiaan H., additional, Carrillo-Roa, Tania, additional, Hiemstra, Marieke, additional, van Lier, Pol A., additional, Meeus, Wim, additional, Branje, Susan, additional, Heim, Christine M., additional, Nemeroff, Charles B., additional, Mill, Jonathan, additional, Schalkwyk, Leonard C., additional, Creyghton, Menno P., additional, Kahn, René S., additional, Joëls, Marian, additional, Binder, Elisabeth B., additional, and Boks, Marco P. M., additional

Published
2016
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85. Tissue-specific patterns of allelically-skewed DNA methylation

Author

Marzi, Sarah J., primary, Meaburn, Emma L., additional, Dempster, Emma L., additional, Lunnon, Katie, additional, Paya-Cano, Jose L., additional, Smith, Rebecca G., additional, Volta, Manuela, additional, Troakes, Claire, additional, Schalkwyk, Leonard C., additional, and Mill, Jonathan, additional

Published
2016
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89. Intermediate DNA methylation is a conserved signature of genome regulation

Author

Elliott, GiNell, primary, Hong, Chibo, additional, Xing, Xiaoyun, additional, Zhou, Xin, additional, Li, Daofeng, additional, Coarfa, Cristian, additional, Bell, Robert J.A., additional, Maire, Cecile L., additional, Ligon, Keith L., additional, Sigaroudinia, Mahvash, additional, Gascard, Philippe, additional, Tlsty, Thea D., additional, Harris, R. Alan, additional, Schalkwyk, Leonard C., additional, Bilenky, Misha, additional, Mill, Jonathan, additional, Farnham, Peggy J., additional, Kellis, Manolis, additional, Marra, Marco A., additional, Milosavljevic, Aleksandar, additional, Hirst, Martin, additional, Stormo, Gary D., additional, Wang, Ting, additional, and Costello, Joseph F., additional

Published
2015
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94. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease

Author

Lunnon, Katie, primary, Smith, Rebecca, additional, Hannon, Eilis, additional, De Jager, Philip L, additional, Srivastava, Gyan, additional, Volta, Manuela, additional, Troakes, Claire, additional, Al-Sarraj, Safa, additional, Burrage, Joe, additional, Macdonald, Ruby, additional, Condliffe, Daniel, additional, Harries, Lorna W, additional, Katsel, Pavel, additional, Haroutunian, Vahram, additional, Kaminsky, Zachary, additional, Joachim, Catharine, additional, Powell, John, additional, Lovestone, Simon, additional, Bennett, David A, additional, Schalkwyk, Leonard C, additional, and Mill, Jonathan, additional

Published
2014
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95. The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder

Author

Malki, Karim, primary, Keers, Robert, additional, Tosto, Maria Grazia, additional, Lourdusamy, Anbarasu, additional, Carboni, Lucia, additional, Domenici, Enrico, additional, Uher, Rudolf, additional, McGuffin, Peter, additional, and Schalkwyk, Leonard C, additional

Published
2014
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97. Putative Transcriptomic Biomarkers in the Inflammatory Cytokine Pathway Differentiate Major Depressive Disorder Patients from Control Subjects and Bipolar Disorder Patients

Author

Powell, Timothy R., primary, McGuffin, Peter, additional, D'Souza, Ursula M., additional, Cohen-Woods, Sarah, additional, Hosang, Georgina M., additional, Martin, Charlotte, additional, Matthews, Keith, additional, Day, Richard K., additional, Farmer, Anne E., additional, Tansey, Katherine E., additional, and Schalkwyk, Leonard C., additional

Published
2014
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