A Systems Biology Approach for Hypothesizing the Effect of Genetic Variants on Neuroimaging Features in Alzheimer’s Disease

Background: Neuroimaging markers provide quantitative insight into brain structure and function in neurodegenerative diseases, such as Alzheimer’s disease, where we lack mechanistic insights to explain pathophysiology. These mechanisms are often mediated by genes and genetic variations and are often studied through the lens of genome-wide association studies. Linking these two disparate layers (i.e., imaging and genetic variation) through causal relationships between biological entities involved in the disease’s etiology would pave the way to large-scale mechanistic reasoning and interpretation. Objective: We explore how genetic variants may lead to functional alterations of intermediate molecular traits, which can further impact neuroimaging hallmarks over a series of biological processes across multiple scales. Methods: We present an approach in which knowledge pertaining to single nucleotide polymorphisms and imaging readouts is extracted from the literature, encoded in Biological Expression Language, and used in a novel workflow to assist in the functional interpretation of SNPs in a clinical context. Results: We demonstrate our approach in a case scenario which proposes KANSL1 as a candidate gene that accounts for the clinically reported correlation between the incidence of the genetic variants and hippocampal atrophy. We find that the workflow prioritizes multiple mechanisms reported in the literature through which KANSL1 may have an impact on hippocampal atrophy such as through the dysregulation of cell proliferation, synaptic plasticity, and metabolic processes. Conclusion: We have presented an approach that enables pinpointing relevant genetic variants as well as investigating their functional role in biological processes spanning across several, diverse biological scales.

[1]  G. Cenini,et al.  Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update , 2019, Front. Pharmacol..

[2]  Mohammad Asif Emon,et al.  PS4DR: a multimodal workflow for identification and prioritization of drugs based on pathway signatures , 2019, BMC Bioinformatics.

[3]  Andreas Spiegler,et al.  Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease , 2019, bioRxiv.

[4]  C. Wahlestedt,et al.  HDAC Inhibitors Induce BDNF Expression and Promote Neurite Outgrowth in Human Neural Progenitor Cells-Derived Neurons , 2019, International journal of molecular sciences.

[5]  Andrew J. Saykin,et al.  A Longitudinal Imaging Genetics Study of Neuroanatomical Asymmetry in Alzheimer’s Disease , 2018, Biological Psychiatry.

[6]  Aron K Barbey,et al.  Small sample sizes reduce the replicability of task-based fMRI studies , 2018, Communications Biology.

[7]  Sorin Draghici,et al.  A novel computational approach for drug repurposing using systems biology , 2018, Bioinform..

[8]  I. Scheffer,et al.  KANSL1 variation is not a major contributing factor in self-limited focal epilepsy syndromes of childhood , 2018, PloS one.

[9]  Thawfeek M. Varusai,et al.  The Reactome Pathway Knowledgebase , 2017, Nucleic Acids Res..

[10]  Ryan Miller,et al.  WikiPathways: a multifaceted pathway database bridging metabolomics to other omics research , 2017, Nucleic Acids Res..

[11]  N. Greig,et al.  Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview. , 2017, Current Alzheimer research.

[12]  Charles Tapley Hoyt,et al.  PyBEL: a computational framework for Biological Expression Language , 2017, Bioinform..

[13]  Martin Hofmann-Apitius,et al.  Neuroimaging Feature Terminology: A Controlled Terminology for the Annotation of Brain Imaging Features , 2017, Journal of Alzheimer's disease : JAD.

[14]  S. Rankin,et al.  Evidence of Oxidative Stress and Secondary Mitochondrial Dysfunction in Metabolic and Non-Metabolic Disorders , 2017, Journal of clinical medicine.

[15]  Mohammad Asif Emon,et al.  Multimodal mechanistic signatures for neurodegenerative diseases (NeuroMMSig): a web server for mechanism enrichment , 2017, Bioinform..

[16]  B. Kaang,et al.  Epigenetic regulation and chromatin remodeling in learning and memory , 2017, Experimental & Molecular Medicine.

[17]  Minoru Kanehisa,et al.  KEGG: new perspectives on genomes, pathways, diseases and drugs , 2016, Nucleic Acids Res..

[18]  Marie-Thérèse Heemels,et al.  Neurodegenerative diseases , 2016, Nature.

[19]  O. Kretz,et al.  MOF Acetyl Transferase Regulates Transcription and Respiration in Mitochondria , 2016, Cell.

[20]  Núria Queralt-Rosinach,et al.  DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants , 2016, Nucleic Acids Res..

[21]  Peter Veselcic,et al.  Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology , 2016, Neurobiology of Disease.

[22]  D. Hanger,et al.  Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons , 2016, Neurobiology of Disease.

[23]  Desheng Wang,et al.  Dietary cholesterol concentration affects synaptic plasticity and dendrite spine morphology of rabbit hippocampal neurons , 2015, Brain Research.

[24]  M. Moreno-Igoa,et al.  KANSL1 gene disruption associated with the full clinical spectrum of 17q21.31 microdeletion syndrome , 2015, BMC Medical Genetics.

[25]  Magda Tsolaki,et al.  A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN , 2015, Molecular Psychiatry.

[26]  A. Fischer,et al.  Histone-acetylation: a link between Alzheimer's disease and post-traumatic stress disorder? , 2014, Front. Neurosci..

[27]  H. Ostrer,et al.  Genome-wide mapping of IBD segments in an Ashkenazi PD cohort identifies associated haplotypes. , 2014, Human molecular genetics.

[28]  Ted Slater,et al.  Recent advances in modeling languages for pathway maps and computable biological networks. , 2014, Drug discovery today.

[29]  M. Nöthen,et al.  Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene , 2014, Translational Psychiatry.

[30]  Elke Edelmann,et al.  Pre- and postsynaptic twists in BDNF secretion and action in synaptic plasticity , 2014, Neuropharmacology.

[31]  F. Catalá-López,et al.  Alzheimer's Disease and Cancer: Current Epidemiological Evidence for a Mutual Protection , 2014, Neuroepidemiology.

[32]  Nick C Fox,et al.  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease , 2013, Nature Genetics.

[33]  Z. Fišar,et al.  Control mechanisms in mitochondrial oxidative phosphorylation☆ , 2013, Neural regeneration research.

[34]  J. Moscat,et al.  TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor , 2012, Neurochemistry International.

[35]  Sang Hong Lee,et al.  Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood , 2012, Bioinform..

[36]  Eurie L. Hong,et al.  Annotation of functional variation in personal genomes using RegulomeDB , 2012, Genome research.

[37]  S. Bhatta,et al.  Transcriptional signatures mediated by acetylation overlap with early-stage Alzheimer’s disease , 2012, Experimental Brain Research.

[38]  P. Scheltens,et al.  Atrophy of medial temporal lobes on MRI in “probable” Alzheimer's disease and normal ageing: diagnostic value and neuropsychological correlates , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[39]  M. Lei,et al.  Structural insight into the regulation of MOF in the male-specific lethal complex and the non-specific lethal complex , 2012, Cell Research.

[40]  T. A. Rosenberger,et al.  Acetate supplementation modulates brain histone acetylation and decreases interleukin-1β expression in a rat model of neuroinflammation , 2012, Journal of Neuroinflammation.

[41]  Chuong B. Do,et al.  Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database , 2012, PLoS genetics.

[42]  Jo Knight,et al.  Introduction to genetic association studies. , 2012, Cold Spring Harbor protocols.

[43]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[44]  Paul M. Thompson,et al.  Neuroimaging Measures as Endophenotypes in Alzheimer's Disease , 2011, International journal of Alzheimer's disease.

[45]  R. Desikan,et al.  Genetic variation and neuroimaging measures in Alzheimer disease. , 2010, Archives of neurology.

[46]  Fatima Soliman,et al.  Imaging genetics and development: Challenges and promises , 2010, Human brain mapping.

[47]  Joseph V. Hajnal,et al.  A robust method to estimate the intracranial volume across MRI field strengths (1.5T and 3T) , 2010, NeuroImage.

[48]  M. Costanzi,et al.  Impaired Terminal Differentiation of Hippocampal Granule Neurons and Defective Contextual Memory in PC3/Tis21 Knockout Mice , 2009, PloS one.

[49]  M. Cole,et al.  Subunit Composition and Substrate Specificity of a MOF-containing Histone Acetyltransferase Distinct from the Male-specific Lethal (MSL) Complex* , 2009, The Journal of Biological Chemistry.

[50]  A. Simmons,et al.  AddNeuroMed—The European Collaboration for the Discovery of Novel Biomarkers for Alzheimer's Disease , 2009, Annals of the New York Academy of Sciences.

[51]  A. Hill,et al.  ATP‐binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro , 2008, Journal of neurochemistry.

[52]  F. Tagliavini,et al.  A new function of microtubule-associated protein tau: Involvement in chromosome stability , 2008, Cell cycle.

[53]  Andreas Meyer-Lindenberg,et al.  False positives in imaging genetics , 2008, NeuroImage.

[54]  Hongyu Luo,et al.  Tissue-specific expression of B-cell translocation gene 2 (BTG2) and its function in T-cell immune responses in a transgenic mouse model. , 2008, International immunology.

[55]  Jose C Florez,et al.  Introduction to genetic association studies. , 2007, The Journal of investigative dermatology.

[56]  A. Levey,et al.  Evidence of shared risk for Alzheimer’s disease and Parkinson’s disease using family history , 2007, Neurogenetics.

[57]  Rachael L Neve,et al.  The cell cycle as a therapeutic target for Alzheimer's disease. , 2006, Pharmacology & therapeutics.

[58]  Mu-ming Poo,et al.  Shrinkage of Dendritic Spines Associated with Long-Term Depression of Hippocampal Synapses , 2004, Neuron.

[59]  Hongye Li,et al.  Genetic Bottlenecks Reduce Population Variation in an Experimental RNA Virus Population , 2004, Journal of Virology.

[60]  M. Bear,et al.  LTP and LTD An Embarrassment of Riches , 2004, Neuron.

[61]  M. Mattson,et al.  Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[62]  A. Koudinov,et al.  Cholesterol, synaptic function and Alzheimer's disease. , 2003, Pharmacopsychiatry.

[63]  R. Nussbaum,et al.  Alzheimer's disease and Parkinson's disease. , 2003, The New England journal of medicine.

[64]  P. Gregory,et al.  Histone acetylation and chromatin remodeling. , 2001, Experimental cell research.

[65]  J. Magaud,et al.  Interaction of BTG1 and p53-regulatedBTG2 Gene Products with mCaf1, the Murine Homolog of a Component of the Yeast CCR4 Transcriptional Regulatory Complex* , 1998, The Journal of Biological Chemistry.

[66]  R. Weichselbaum,et al.  p53 Expression Induces Apoptosis in Hippocampal Pyramidal Neuron Cultures , 1997, The Journal of Neuroscience.

[67]  R. Berger,et al.  Identification of BTG2, an antiproliferative p53–dependent component of the DNA damage cellular response pathway , 1996, Nature Genetics.

[68]  A. Rajput,et al.  Alzheimer's Disease and Idiopathic Parkinson's Disease Coexistence , 1993, Journal of geriatric psychiatry and neurology.

[69]  A. Boyle,et al.  Human Mutation , 2019 .

[70]  C. Bramham,et al.  BDNF and Hippocampal Synaptic Plasticity. , 2017, Vitamins and hormones.

[71]  Dana C. Crawford,et al.  The detection and characterization of pleiotropy: discovery, progress, and promise , 2016, Briefings Bioinform..

[72]  T. Abel,et al.  The Role of Histone Acetylation in Memory Formation and Cognitive Impairments , 2013, Neuropsychopharmacology.

[73]  M. Mattson,et al.  Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders , 2002, NeuroMolecular Medicine.

[74]  The FASEB Journal express article 10.1096/fj.00-0815fje. Published online June 27, 2001. Essential role for cholesterol in synaptic plasticity and neuronal degeneration , 2022 .