Sex-specific DNA methylation changes in Alzheimer’s disease pathology

Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimers disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation changes in AD, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with AD in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated AD genes, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation changes were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Importantly, a number of drugs commonly prescribed for AD patients also targeted these genes with sex-specific DNA methylation changes. Our study implicated multiple new loci and biological processes that affected AD in a sex-specific manner and highlighted the importance of sex-specific treatment regimens for AD patients.

[1]  P. Reddy,et al.  Synaptic basis of Alzheimer’s disease: Focus on synaptic amyloid beta, P-tau and mitochondria , 2020, Ageing Research Reviews.

[2]  Juan I. Young,et al.  Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease , 2020, Nature Communications.

[3]  Yi-Sook Jung,et al.  Effect of Caffeine Consumption on the Risk for Neurological and Psychiatric Disorders: Sex Differences in Human , 2020, Nutrients.

[4]  D. Bennett,et al.  Brain Renin–Angiotensin System at the Intersect of Physical and Cognitive Frailty , 2020, Frontiers in Neuroscience.

[5]  Ying-yong Zhao,et al.  Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy , 2020, Biomarker research.

[6]  Julie A. Harris,et al.  A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease , 2020, Science Translational Medicine.

[7]  M. Conway.  Alzheimer’s disease: targeting the glutamatergic system , 2020, Biogerontology.

[8]  A. Szalay,et al.  Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex , 2019, bioRxiv.

[9]  D. Y. Lee,et al.  Coffee intake and decreased amyloid pathology in human brain , 2019, Translational Psychiatry.

[10]  Sterling C. Johnson,et al.  Sex differences in the genetic predictors of Alzheimer's pathology. , 2019, Brain : a journal of neurology.

[11]  Juan I. Young,et al.  coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes , 2019, bioRxiv.

[12]  N. Jha,et al.  Nuclear factor‐kappa β as a therapeutic target for Alzheimer's disease , 2019, Journal of neurochemistry.

[13]  Goldie Libby Sherr,et al.  Epigenetic Modifications in Alzheimer’s Neuropathology and Therapeutics , 2019, Front. Neurosci..

[14]  Chunyu Liu,et al.  Sex-differential DNA methylation and associated regulation networks in human brain implicated in the sex-biased risks of psychiatric disorders , 2019, Molecular Psychiatry.

[15]  Genetic,et al.  Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing , 2019, Nature Genetics.

[16]  B. Fiebich,et al.  Role of Microglia TLRs in Neurodegeneration , 2018, Front. Cell. Neurosci..

[17]  Christopher C. Overall,et al.  PU.1 regulates Alzheimer’s disease-associated genes in primary human microglia , 2018, Molecular Neurodegeneration.

[18]  S. Buch,et al.  PDGF/PDGFR axis in the neural systems. , 2018, Molecular aspects of medicine.

[19]  H. Leonhardt,et al.  DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex , 2018, Epigenetics & Chromatin.

[20]  Alzheimer's Disease Neuroimaging Initiative.  Sex-specific genetic predictors of Alzheimer’s disease biomarkers , 2018 .

[21]  Alexander E Dityatev,et al.  Shaping Synapses by the Neural Extracellular Matrix , 2018, Front. Neuroanat..

[22]  D. Bennett,et al.  Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer’s disease neuropathology , 2018, Alzheimer's & Dementia.

[23]  D. Gomez-Nicola,et al.  Neuroinflammation: Microglia and T Cells Get Ready to Tango , 2018, Front. Immunol..

[24]  Julian P T Higgins,et al.  A re‐evaluation of fixed effect(s) meta‐analysis , 2018 .

[25]  J. Michael Cherry,et al.  The Encyclopedia of DNA elements (ENCODE): data portal update , 2017, Nucleic Acids Res..

[26]  B. Morgan,et al.  Complement in the pathogenesis of Alzheimer’s disease , 2017, Seminars in Immunopathology.

[27]  M. Robinson,et al.  stageR: a general stage-wise method for controlling the gene-level false discovery rate in differential expression and differential transcript usage , 2017, Genome Biology.

[28]  Jisoo Park,et al.  TMEM39A and Human Diseases: A Brief Review , 2017, Toxicological research.

[29]  K. Hao,et al.  A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease , 2017, Nature Neuroscience.

[30]  J. Griffin,et al.  Amino Acid Catabolism in Alzheimer's Disease Brain: Friend or Foe? , 2017, Oxidative medicine and cellular longevity.

[31]  J. Mill,et al.  Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions , 2016, Human molecular genetics.

[32]  Timothy J. Hohman,et al.  Sex differences in the association between AD biomarkers and cognitive decline , 2017, Brain Imaging and Behavior.

[33]  Gilles J Guillemin,et al.  The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease: A Mini Review , 2016, Oxidative medicine and cellular longevity.

[34]  Paolo Vineis,et al.  Epigenetic Signatures of Cigarette Smoking , 2016, Circulation. Cardiovascular genetics.

[35]  J. Manson,et al.  Relationships Between Caffeine Intake and Risk for Probable Dementia or Global Cognitive Impairment: The Women's Health Initiative Memory Study. , 2016, The journals of gerontology. Series A, Biological sciences and medical sciences.

[36]  P. Zhou,et al.  Interleukin-8 gene polymorphism –251T>A contributes to Alzheimer's disease susceptibility , 2016, Medicine.

[37]  Robin M. Murray,et al.  An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation , 2016, Genome Biology.

[38]  S. Bilbo,et al.  Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development , 2016, The Journal of Steroid Biochemistry and Molecular Biology.

[39]  P. Eline Slagboom,et al.  Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution , 2016, bioRxiv.

[40]  R. Malinow,et al.  Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer’s disease , 2016, Science Signaling.

[41]  R. Straub,et al.  Chronic inflammatory systemic diseases , 2016, Evolution, medicine, and public health.

[42]  Nathan C. Sheffield,et al.  LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor , 2015, Bioinform..

[43]  Babak A Ardekani,et al.  Analysis of the MIRIAD Data Shows Sex Differences in Hippocampal Atrophy Progression. , 2016, Journal of Alzheimer's disease : JAD.

[44]  A. Sharp,et al.  Genome-wide12 DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer’s disease , 2016, Genome Medicine.

[45]  M. McCarthy,et al.  At the frontier of epigenetics of brain sex differences , 2015, Front. Behav. Neurosci..

[46]  Manolis Kellis,et al.  Systematic chromatin state comparison of epigenomes associated with diverse properties including sex and tissue type , 2015, Nature Communications.

[47]  P. Murali Doraiswamy,et al.  Marked gender differences in progression of mild cognitive impairment over 8 years , 2015, Alzheimer's & dementia.

[48]  Wei Chen,et al.  A systematic study of normalization methods for Infinium 450K methylation data using whole-genome bisulfite sequencing data , 2015, Epigenetics.

[49]  Bethany L Peterson,et al.  Sex-related differences in effects of progesterone following neonatal hypoxic brain injury , 2015, Behavioural Brain Research.

[50]  George Papadatos,et al.  ChEMBL web services: streamlining access to drug discovery data and utilities , 2015, Nucleic Acids Res..

[51]  Michael C O'Donovan,et al.  Methylomic trajectories across human fetal brain development , 2015, Genome research.

[52]  Patrick Lombard,et al.  CODEX: a next-generation sequencing experiment database for the haematopoietic and embryonic stem cell communities , 2014, Nucleic Acids Res..

[53]  L. Tan,et al.  TYROBP in Alzheimer’s Disease , 2015, Molecular Neurobiology.

[54]  D. Bennett,et al.  Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease , 2014, Nature Neuroscience.

[55]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[56]  Manolis Kellis,et al.  Alzheimery's disease pathology is associated with early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci , 2014, Nature Neuroscience.

[57]  G. Gambina,et al.  Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer's disease , 2014, International journal of geriatric psychiatry.

[58]  Rena Li,et al.  Brain sex matters: Estrogen in cognition and Alzheimer’s disease , 2014, Molecular and Cellular Endocrinology.

[59]  Yaqin Yu,et al.  Sex-biased methylome and transcriptome in human prefrontal cortex. , 2014, Human molecular genetics.

[60]  A. Dale,et al.  Higher Rates of Decline for Women and Apolipoprotein E ε4 Carriers , 2013, American Journal of Neuroradiology.

[61]  G. Pigino,et al.  Axonal degeneration in Alzheimer's disease: When signaling abnormalities meet the axonal transport system , 2013, Experimental Neurology.

[62]  Hartmut Derendorf,et al.  Sex related differences on valproic acid pharmacokinetics after oral single dose , 2013, Journal of Pharmacokinetics and Pharmacodynamics.

[63]  J. Weuve,et al.  Alzheimer disease in the United States (2010–2050) estimated using the 2010 census , 2013, Neurology.

[64]  L. Tran,et al.  Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease , 2013, Cell.

[65]  Paco Martorell,et al.  Monetary costs of dementia in the United States. , 2013, The New England journal of medicine.

[66]  Martin J. Aryee,et al.  A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression , 2013, Epigenetics.

[67]  R. Pacchiana,et al.  Alzheimer's disease: an update of the roles of receptors, astrocytes and primary cilia (review). , 2013, International journal of molecular medicine.

[68]  Wendy A Bickmore,et al.  Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes , 2013, Genome Biology.

[69]  A. Alcina,et al.  Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CLBL genes , 2012, Multiple sclerosis.

[70]  J. R. Pilsner,et al.  DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences. , 2012, Epigenomics.

[71]  Lisa Helbling Chadwick,et al.  The NIH Roadmap Epigenomics Program data resource. , 2012, Epigenomics.

[72]  Christoph Bock,et al.  Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk , 2012, Genome research.

[73]  F. Herrmann.  34 Cognitive reserve and survival , 2012, Neurobiology of Aging.

[74]  K. Ono,et al.  Vitamin A and Alzheimer's disease , 2012, Geriatrics & gerontology international.

[75]  Manolis Kellis,et al.  ChromHMM: automating chromatin-state discovery and characterization , 2012, Nature Methods.

[76]  Mattias Ohlsson,et al.  Evaluation of a Previously Suggested Plasma Biomarker Panel to Identify Alzheimer's Disease , 2012, PloS one.

[77]  Howard Hu,et al.  Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex. , 2012, Journal of Alzheimer's disease : JAD.

[78]  R. Green,et al.  Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study. , 2011, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[79]  J. Valero,et al.  The role of CREB signaling in Alzheimer’s disease and other cognitive disorders , 2011, Reviews in the neurosciences.

[80]  T. Bale,et al.  Sex-specificity in transgenerational epigenetic programming , 2011, Hormones and Behavior.

[81]  Richard D Riley,et al.  Interpretation of random effects meta-analyses , 2011, BMJ : British Medical Journal.

[82]  D. Spengler,et al.  Sex differences in brain epigenetics. , 2010, Epigenomics.

[83]  M. Anker,et al.  The impact of sex, gender and pregnancy on 2009 H1N1 disease , 2010, Biology of Sex Differences.

[84]  Michael W. Weiner,et al.  Sex and age differences in atrophic rates: an ADNI study with n=1368 MRI scans , 2010, Neurobiology of Aging.

[85]  G. Remuzzi,et al.  Angiotensin II revisited: new roles in inflammation, immunology and aging , 2010, EMBO molecular medicine.

[86]  N. Schupf,et al.  Hormonal Influences on Cognition and Risk for Alzheimer’s Disease , 2010, Current neurology and neuroscience reports.

[87]  Cory Y. McLean,et al.  GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[88]  F. Jessen,et al.  The Role of Macrophage Migration Inhibitory Factor in Alzheimer’s Disease , 2010, Molecular medicine.

[89]  Margaret A. Pericak-Vance,et al.  Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci , 2009, Human molecular genetics.

[90]  Rongling Li,et al.  Estrogen receptor genotype and risk of cognitive impairment in elders: Findings from the Health ABC study , 2009, Neurobiology of Aging.

[91]  R. Brinton.  Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. , 2009, Trends in pharmacological sciences.

[92]  Yoav Gilad,et al.  Sex-specific genetic architecture of human disease , 2008, Nature Reviews Genetics.

[93]  M. Shimabukuro,et al.  Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia. , 2007, Journal of psychiatric research.

[94]  R. Tibshirani,et al.  Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins , 2007, Nature Medicine.

[95]  F. Schmitt,et al.  Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment , 2007, Neurology.

[96]  M. Shimabukuro,et al.  Behavioral and Brain Functions , 2006 .

[97]  T. Hansen,et al.  Estrogen receptor alpha and risk for cognitive impairment in postmenopausal women , 2006, Psychiatric genetics.

[98]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[99]  R. Spreafico,et al.  Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia , 2004, The European journal of neuroscience.

[100]  Sara T Brookes,et al.  Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. , 2004, Journal of clinical epidemiology.

[101]  L. Peltonen,et al.  Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. , 2002, American journal of human genetics.

[102]  S. Thompson,et al.  Quantifying heterogeneity in a meta‐analysis , 2002, Statistics in medicine.

[103]  K. Yaffe,et al.  Estrogen receptor 1 polymorphisms and risk of cognitive impairment in older women , 2002, Biological Psychiatry.

[104]  V. Mor,et al.  Gender differences in predictors of mortality in nursing home residents with AD , 2001, Neurology.

[105]  E. Masliah,et al.  Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease , 2001, Neurology.

[106]  M. Albert,et al.  Predicting time to nursing home care and death in individuals with Alzheimer disease. , 1997, JAMA.

[107]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[108]  S. DeKosky,et al.  Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity , 1990, Annals of neurology.