1 1946 145 EPIGENETIC ABNORMALITIES ASSOCIATED WITH A CHROMOSOME 18(Q21-Q22) INVERSION AND A GILLES DE LA TOURETTE SYNDROME PHENOTYPE. GILLES DE LA TOURETTE SYNDROME (GTS) IS A POTENTIALLY DEBILITATING NEUROPSYCHIATRIC DISORDER DEFINED BY THE PRESENCE OF BOTH VOCAL AND MOTOR TICS. DESPITE EVIDENCE THAT THIS AND A RELATED PHENOTYPIC SPECTRUM, INCLUDING CHRONIC TICS (CT) AND OBSESSIVE COMPULSIVE DISORDER (OCD), ARE GENETICALLY MEDIATED, NO GENE INVOLVED IN DISEASE ETIOLOGY HAS BEEN IDENTIFIED. CHROMOSOMAL ABNORMALITIES HAVE LONG BEEN PROPOSED TO PLAY A CAUSATIVE ROLE IN ISOLATED CASES OF GTS SPECTRUM PHENOMENA, BUT CONFIRMATION OF THIS HYPOTHESIS HAS YET TO BE FORTHCOMING. WE DESCRIBE AN I(18Q21.1-Q22.2) INVERSION IN A PATIENT WITH CT AND OCD. WE HAVE FINE MAPPED THE TELOMERIC ASPECT OF THE REARRANGEMENT TO WITHIN 1 MB OF A PREVIOUSLY REPORTED 18Q22 BREAKPOINT THAT COSEGREGATED IN A FAMILY WITH GTS AND RELATED PHENOTYPES. A COMPREHENSIVE CHARACTERIZATION OF THIS GENOMIC INTERVAL LED TO THE IDENTIFICATION OF TWO TRANSCRIPTS, NEITHER OF WHICH WAS FOUND TO BE STRUCTURALLY DISRUPTED. ANALYSIS OF THE EPIGENETIC CHARACTERISTICS OF THE REGION DEMONSTRATED A SIGNIFICANT INCREASE IN REPLICATION ASYNCHRONY IN THE PATIENT COMPARED TO CONTROLS, WITH THE INVERTED CHROMOSOME SHOWING DELAYED REPLICATION TIMING ACROSS AT LEAST A 500-KB INTERVAL. THESE FINDINGS ARE CONSISTENT WITH LONG-RANGE FUNCTIONAL DYSREGULATION OF ONE OR MORE GENES IN THE REGION. OUR DATA SUPPORT A LINK BETWEEN CHROMOSOMAL ABERRATIONS AND EPIGENETIC MECHANISMS IN GTS AND SUGGEST THAT THE STUDY OF THE FUNCTIONAL CONSEQUENCES OF BALANCED CHROMOSOMAL REARRANGEMENTS IS WARRANTED IN PATIENTS WITH PHENOTYPES OF INTEREST, IRRESPECTIVE OF THE FINDINGS REGARDING STRUCTURALLY DISRUPTED TRANSCRIPTS.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
2 5331  51 PUTTING THE PIECES TOGETHER IN GILLES DE LA TOURETTE SYNDROME: EXPLORING THE LINK BETWEEN CLINICAL OBSERVATIONS AND THE BIOLOGICAL BASIS OF DYSFUNCTION. GILLES DE LA TOURETTE SYNDROME IS A COMPLEX, IDIOPATHIC NEUROPSYCHIATRIC DISORDER WHOSE PATHOPHYSIOLOGICAL MECHANISMS HAVE YET TO BE ELUCIDATED. IT IS PHENOTYPICALLY HETEROGENEOUS AND MANIFESTS MORE OFTEN THAN NOT WITH BOTH MOTOR AND BEHAVIORAL IMPAIRMENT, ALTHOUGH TICS ARE ITS CLINICAL HALLMARK. TICS THEMSELVES PRESENT WITH A COMPLEX PROFILE AS THEY CHARACTERISTICALLY WAX AND WANE AND ARE OFTEN PRECEDED BY PREMONITORY SOMATOSENSORY SENSATIONS TO WHICH IT IS SAID A TIC IS THE RESPONSE. HIGHLY COMORBID WITH OBSESSIVE-COMPULSIVE DISORDER AND ATTENTION DEFICIT-HYPERACTIVITY DISORDER, IT IS PURPORTED TO BE AN EPIGENETIC, NEURODEVELOPMENTAL SPECTRUM DISORDER WITH A COMPLEX GENETIC PROFILE. IT HAS A CHILDHOOD ONSET, OCCURS DISPROPORTIONATELY IN MALES, AND SHOWS SPONTANEOUS SYMPTOMATIC ATTENUATION BY ADULTHOOD IN THE MAJORITY OF THOSE AFFLICTED. ALTHOUGH NOT FULLY UNDERSTOOD, ITS NEUROBIOLOGICAL BASIS IS LINKED TO DYSFUNCTION IN THE CORTICO-BASAL GANGLIA-THALAMO-CORTICAL NETWORK. TREATMENT MODALITIES FOR TOURETTE SYNDROME INCLUDE BEHAVIORAL, PHARMACOLOGICAL AND SURGICAL INTERVENTIONS, BUT THERE IS PRESENTLY NO CURE FOR THE DISORDER. FOR THOSE SEVERELY AFFECTED, DEEP BRAIN STIMULATION (DBS) HAS RECENTLY BECOME A VIABLE THERAPEUTIC OPTION. A KEY FACTOR TO ATTAINING OPTIMAL RESULTS FROM THIS SURGERY IS TARGET SELECTION, A TOPIC STILL UNDER DEBATE DUE TO THE COMPLEX CLINICAL PROFILE PRESENTED BY GTS PATIENTS. DEPENDING ON ITS PHENOTYPIC EXPRESSION AND THE MOST PROBLEMATIC ASPECT OF THE DISORDER FOR THE INDIVIDUAL, ONE OF THREE BRAIN REGIONS IS MOST COMMONLY CHOSEN FOR STIMULATION: THE THALAMUS, GLOBUS PALLIDUS, OR NUCLEUS ACCUMBENS. NEUROPHYSIOLOGICAL ANALYSES OF INTRA- AND POST-OPERATIVE HUMAN ELECTROPHYSIOLOGICAL RECORDINGS FROM CLINICAL DBS STUDIES SUGGEST A LINK BETWEEN TIC BEHAVIOR AND ACTIVITY IN BOTH THE THALAMUS AND GLOBUS PALLIDUS. IN PARTICULAR, CHRONIC RECORDINGS FROM THE THALAMUS HAVE SHOWN A CORRELATION BETWEEN SYMPTOMATOLOGY AND (1) SPECTRAL ACTIVITY IN GAMMA BAND POWER AND (2) THETA/GAMMA CROSS FREQUENCY COHERENCE. THESE RESULTS SUGGEST GAMMA OSCILLATIONS AND THETA/GAMMA CROSS CORRELATION DYNAMICS MAY SERVE AS BIOMARKERS FOR DYSFUNCTION. WHILE ACUTE AND CHRONIC RECORDINGS FROM HUMAN SUBJECTS UNDERGOING DBS HAVE PROVIDED BETTER INSIGHT INTO TIC GENESIS AND THE NEUROPATHOPHYSIOLOGICAL MECHANISMS UNDERLYING TOURETTE SYNDROME, THESE STUDIES ARE STILL SPARSE AND THE FIELD WOULD GREATLY BENEFIT FROM FURTHER INVESTIGATIONS. THIS REVIEW REPORTS DATA AND DISCOVERIES OF SCIENTIFIC AND CLINICAL RELEVANCE FROM A WIDE VARIETY OF METHODS AND PROVIDES UP-TO-DATE INFORMATION ABOUT OUR CURRENT UNDERSTANDING OF THE PATHOMECHANISMS UNDERLYING TOURETTE SYNDROME. IT GIVES A COMPREHENSIVE OVERVIEW OF THE CURRENT STATE OF KNOWLEDGE AND ADDRESSES OPEN QUESTIONS IN THE FIELD.	2017	
                                                             
3 2209  29 EPIGENETIC MODIFICATIONS AND OBSESSIVE-COMPULSIVE DISORDER: WHAT DO WE KNOW? OBSESSIVE-COMPULSIVE DISORDER (OCD) IS A CHRONIC, SEVERE DISABLING NEUROPSYCHIATRIC DISORDER WHOSE PATHOPHYSIOLOGY IS NOT YET WELL DEFINED. GENERALLY, THE SYMPTOM ONSET OCCURS DURING PRE-ADULT LIFE AND AFFECTS SUBJECTS IN DIFFERENT LIFE ASPECTS, INCLUDING PROFESSIONAL AND SOCIAL RELATIONSHIPS. ALTHOUGH ROBUST EVIDENCE INDICATES THE PRESENCE OF GENETIC FACTORS IN THE ETIOPATHOLOGY OF OCD, THE ENTIRELY MECHANISMS ARE NOT TOTALLY CLARIFIED. THUS, THE POSSIBLE INTERACTIONS BETWEEN GENES AND ENVIRONMENTAL RISK FACTORS MEDIATED BY EPIGENETIC MECHANISMS SHOULD BE SOUGHT. THEREFORE, WE PROVIDE A REVIEW OF GENETIC AND EPIGENETIC MECHANISMS RELATED TO OCD WITH A DEEP FOCUS ON THE REGULATION OF CRITICAL GENES OF THE CENTRAL NERVOUS SYSTEM SEEKING POSSIBLE POTENTIAL BIOMARKERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4 2105  37 EPIGENETIC EVIDENCE FOR INVOLVEMENT OF THE OXYTOCIN RECEPTOR GENE IN OBSESSIVE-COMPULSIVE DISORDER. BACKGROUND: OBSESSIVE-COMPULSIVE DISORDER (OCD) IS A CHRONIC NEURODEVELOPMENTAL DISORDER THAT AFFECTS UP TO 3% OF THE GENERAL POPULATION. ALTHOUGH EPIGENETIC MECHANISMS PLAY A ROLE IN NEURODEVELOPMENT DISORDERS, EPIGENETIC PATHWAYS ASSOCIATED WITH OCD HAVE RARELY BEEN INVESTIGATED. OXYTOCIN IS A NEUROPEPTIDE INVOLVED IN NEUROBEHAVIORAL FUNCTIONS. OXYTOCIN HAS BEEN SHOWN TO BE ASSOCIATED WITH THE REGULATION OF COMPLEX SOCIO-COGNITIVE PROCESSES SUCH AS ATTACHMENT, SOCIAL EXPLORATION, AND SOCIAL RECOGNITION, AS WELL AS ANXIETY AND OTHER STRESS-RELATED BEHAVIORS. OXYTOCIN HAS ALSO BEEN LINKED TO THE PATHOPHYSIOLOGY OF OCD, ALBEIT INCONSISTENTLY. THE AIM OF THIS STUDY WAS TO INVESTIGATE METHYLATION IN TWO TARGETS SEQUENCES LOCATED IN THE EXON III OF THE OXYTOCIN RECEPTOR GENE (OXTR), IN OCD PATIENTS AND HEALTHY CONTROLS. WE USED BISULFITE SEQUENCING TO QUANTIFY DNA METHYLATION IN PERIPHERAL BLOOD SAMPLES COLLECTED FROM 42 OCD PATIENTS AND 31 HEALTHY CONTROLS. RESULTS: WE FOUND THAT THE LEVEL OF METHYLATION OF THE CYTOSINE-PHOSPHATE-GUANINE SITES IN TWO TARGETS SEQUENCES ANALYZED WAS GREATER IN THE OCD PATIENTS THAN IN THE CONTROLS. THE HIGHER METHYLATION IN THE OCD PATIENTS CORRELATED WITH OCD SEVERITY. WE MEASURED DNA METHYLATION IN THE PERIPHERAL BLOOD, WHICH PREVENTED US FROM DRAWING ANY CONCLUSIONS ABOUT PROCESSES IN THE CENTRAL NERVOUS SYSTEM. CONCLUSION: TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY INVESTIGATING DNA METHYLATION OF THE OXTR IN OCD. FURTHER STUDIES ARE NEEDED TO EVALUATE THE ROLES THAT DNA METHYLATION AND OXYTOCIN PLAY IN OCD.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5 4370  34 MIRNAS AND THEIR ROLE IN THE CORRELATION BETWEEN SCHIZOPHRENIA AND CANCER (REVIEW). SCHIZOPHRENIA (SZ) AND CANCER (CA) HAVE A BROAD SPECTRUM OF CLINICAL PHENOTYPES AND A COMPLEX BIOLOGICAL BACKGROUND, IMPLICATING A LARGE NUMBER OF GENETIC AND EPIGENETIC FACTORS. SZ IS A CHRONIC NEURODEVELOPMENTAL DISORDER SIGNIFIED BY AN INCREASE IN THE EXPRESSION OF APOPTOTIC MOLECULAR SIGNALS, WHEREAS CA IS CONVERSELY CHARACTERIZED BY AN INCREASE IN APPROPRIATE MOLECULAR SIGNALING THAT STIMULATES UNCONTROLLED CELL PROLIFERATION. THE RATHER LOW RISK OF DEVELOPING CA IN PATIENTS SUFFERING FROM SZ IS A HYPOTHESIS THAT IS STILL UNDER DEBATE. RECENT EVIDENCE HAS INDICATED THAT MICRORNAS (MIRNAS OR MIRS), A LARGE GROUP OF SMALL NON?CODING OLIGONOUCLEOTIDES, MAY PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF CA AND MAJOR PSYCHIATRIC DISORDERS, SUCH AS SZ, BIPOLAR DISORDER, AUTISM SPECTRUM DISORDERS, SUICIDALITY AND DEPRESSION, THROUGH THEIR INTERFERENCE WITH THE EXPRESSION OF MULTIPLE GENES. FOR INSTANCE, THE POSSIBLE ROLE OF LET?7, MIR?98 AND MIR?183 AS BIOMARKERS FOR CA AND SZ WAS INVESTIGATED IN OUR PREVIOUS RESEARCH STUDIES. THEREFORE, FURTHER INVESTIGATIONS ON THE EXPRESSION PROFILES OF THESE REGULATORY, SMALL RNA MOLECULES AND THE MOLECULAR PATHWAYS THROUGH WHICH THEY EXERT THEIR CONTROL MAY PROVIDE A PLAUSIBLE EXPLANATION AS TO WHETHER THERE IS A CORRELATION BETWEEN PSYCHIATRIC DISORDERS AND LOW RISK OF DEVELOPING CA.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6 1524  29 DNA METHYLATION CHANGES IN CYSTIC FIBROSIS: CAUSE OR CONSEQUENCE? TWIN AND SIBLING STUDIES HAVE SHOWN THAT LUNG DISEASE SEVERITY IS VARIABLE AMONG CYSTIC FIBROSIS (CF) PATIENTS AND AFFECTED TO THE SAME EXTENT BY GENETIC AND NONHERITABLE FACTORS. GENETIC FACTORS HAVE BEEN THOROUGHLY ASSESSED, WHEREAS THE MOLECULAR MECHANISMS WHEREBY NONHERITABLE FACTORS CONTRIBUTE TO THE PHENOTYPIC VARIABILITY OF CF PATIENTS ARE STILL UNKNOWN. EPIGENETIC MODIFICATIONS MAY REPRESENT THE MISSING LINK BETWEEN NONHERITABLE FACTORS AND PHENOTYPIC VARIATION IN CF. HEREIN, WE REVIEW RECENT STUDIES SHOWING THAT DNA METHYLATION IS ALTERED IN CF AND WE ADDRESS THREE POSSIBLE FACTORS RESPONSIBLE FOR THESE VARIATIONS: (I) OVERPRODUCTION OF REACTIVE OXYGEN SPECIES, (II) DEPLETION OF DNA METHYLATION COFACTORS AND (III) SUSCEPTIBILITY TO ACUTE AND CHRONIC BACTERIAL INFECTIONS. ALSO, WE HYPOTHESIZE THAT THE UNIQUE DNA METHYLATION PROFILE OF EACH PATIENT CAN MODULATE THE PHENOTYPE AND DISCUSS THE INTEREST OF IMPLEMENTING INTEGRATED GENOMIC, EPIGENOMIC AND TRANSCRIPTOMIC STUDIES TO FURTHER UNDERSTAND THE CLINICAL DIVERSITY OF CF PATIENTS (GRAPHICAL ABSTRACT).	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 2815  34 FIBROMYALGIA: GENETICS AND EPIGENETICS INSIGHTS MAY PROVIDE THE BASIS FOR THE DEVELOPMENT OF DIAGNOSTIC BIOMARKERS. FIBROMYALGIA IS A DISEASE CHARACTERIZED BY CHRONIC WIDESPREAD PAIN WITH ADDITIONAL SYMPTOMS, SUCH AS JOINT STIFFNESS, FATIGUE, SLEEP DISTURBANCE, COGNITIVE DYSFUNCTION, AND DEPRESSION. CURRENTLY, FIBROMYALGIA DIAGNOSIS IS BASED EXCLUSIVELY ON A COMPREHENSIVE CLINICAL ASSESSMENT, ACCORDING TO 2016 ACR CRITERIA, BUT VALIDATED BIOLOGICAL BIOMARKERS ASSOCIATED WITH FIBROMYALGIA HAVE NOT YET BEEN IDENTIFIED. GENOME-WIDE ASSOCIATION STUDIES INVESTIGATED GENES POTENTIALLY INVOLVED IN FIBROMYALGIA PATHOGENESIS HIGHLIGHTING THAT GENETIC FACTORS ARE POSSIBLY RESPONSIBLE FOR UP TO 50% OF THE DISEASE SUSCEPTIBILITY. POTENTIAL CANDIDATE GENES FOUND ASSOCIATED TO FIBROMYALGIA ARE SLC64A4, TRPV2, MYT1L, AND NRXN3. FURTHERMORE, A GENE-ENVIRONMENTAL INTERACTION HAS BEEN PROPOSED AS TRIGGERING MECHANISM, THROUGH EPIGENETIC ALTERATIONS: IN PARTICULAR, FIBROMYALGIA APPEARS TO BE CHARACTERIZED BY A HYPOMETHYLATED DNA PATTERN, IN GENES IMPLICATED IN STRESS RESPONSE, DNA REPAIR, AUTONOMIC SYSTEM RESPONSE, AND SUBCORTICAL NEURONAL ABNORMALITIES. DIFFERENCES IN THE GENOME-WIDE EXPRESSION PROFILE OF MICRORNAS WERE FOUND AMONG MULTIPLE TISSUES, INDICATING THE INVOLVEMENT OF DISTINCT PROCESSES IN FIBROMYALGIA PATHOGENESIS. FURTHER STUDIES SHOULD BE DEDICATED TO STRENGTH THESE PRELIMINARY FINDINGS, IN LARGER MULTICENTER COHORTS, TO IDENTIFY RELIABLE DIRECTIONS FOR BIOMARKER RESEARCH AND CLINICAL PRACTICE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8 1050  33 CLINICAL FEATURES ASSOCIATED TO REFRACTORY OBSESSIVE-COMPULSIVE DISORDER. SOME PATIENTS WITH OBSESSIVE-COMPULSIVE DISORDER (OCD) EXHIBIT AN UNSATISFACTORY REDUCTION IN SYMPTOM SEVERITY DESPITE BEING TREATED WITH ALL THE AVAILABLE THERAPEUTIC ALTERNATIVES. THE CLINICAL VARIABLES ASSOCIATED WITH TREATMENT-REFRACTORINESS IN OCD ARE INCONSISTENTLY DESCRIBED IN THE LITERATURE. METHODS: TO INVESTIGATE FACTORS ASSOCIATED WITH TREATMENT-REFRACTORINESS OF PATIENTS WITH OCD, WE CONDUCTED A CASE-CONTROL STUDY, COMPARING 23 PATIENTS WITH TREATMENT-REFRACTORY OCD TO 26 PATIENTS WITH TREATMENT-RESPONDING OCD. RESULTS: THE FACTORS ASSOCIATED WITH REFRACTORINESS OF OCD WERE HIGHER SEVERITY OF SYMPTOMS SINCE THE ONSET OF OCD (P<0.001), CHRONIC COURSE (P=0.003), LACK OF A PARTNER (P=0.037), UNEMPLOYMENT (P=0.025), LOW ECONOMIC STATUS (P=0.015), PRESENCE OF OBSESSIVE-COMPULSIVE SYMPTOMS OF SEXUAL/RELIGIOUS CONTENT (P=0.043), AND HIGHER SCORES ON FAMILY ACCOMMODATION (P<0.001). ONLY THE THREE LATTER VARIABLES REMAINED SIGNIFICANTLY ASSOCIATED WITH TREATMENT-REFRACTORINESS AFTER REGRESSION ANALYSES. LIMITATIONS: SMALL SAMPLE SIZE, THE BIASES AND DRAWBACKS INHERENT TO A CASE-CONTROL STUDY, AND THE INCLUSION CRITERIA USED TO DEFINE THE STUDY GROUPS MAY HAVE LIMITED THE GENERALISATION OF THE RESULTS. CONCLUSION: A MAJOR STRENGTH OF THIS STUDY IS THE SYSTEMATIC AND STRUCTURED EVALUATION OF A VAST ARRAY OF VARIABLES RELATED TO THE CLINICAL EXPRESSION OF OCD, INCLUDING EPIGENETIC FACTORS AND RATINGS DERIVED FROM INSTRUMENTS EVALUATING FAMILY ACCOMMODATION. THE PRESENCE OF SEXUAL/RELIGIOUS SYMPTOMS, LOW ECONOMIC STATUS AND HIGH MODIFICATION ON FAMILY FUNCTION DUE TO OCD WERE INDEPENDENTLY ASSOCIATED WITH TREATMENT-REFRACTORINESS. FUTURE LONGITUDINAL STUDIES ARE WARRANTED TO VERIFY IF THESE VARIABLES REPRESENT PREDICTIVE FACTORS OF TREATMENT NON-RESPONSE.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9 6137  27 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10 6159  40 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11 2507  33 EPIGENETICS AND OBESITY: THE DEVIL IS IN THE DETAILS. OBESITY IS A COMPLEX DISEASE WITH MULTIPLE WELL-DEFINED RISK FACTORS. NEVERTHELESS, SUSCEPTIBILITY TO OBESITY AND ITS SEQUELAE WITHIN OBESOGENIC ENVIRONMENTS VARIES GREATLY FROM ONE PERSON TO THE NEXT, SUGGESTING A ROLE FOR GENE X ENVIRONMENT INTERACTIONS IN THE ETIOLOGY OF THE DISORDER. EPIGENETIC REGULATION OF THE HUMAN GENOME PROVIDES A PUTATIVE MECHANISM BY WHICH SPECIFIC ENVIRONMENTAL EXPOSURES CONVEY RISK FOR OBESITY AND OTHER HUMAN DISEASES AND IS ONE POSSIBLE MECHANISM THAT UNDERLIES THE GENE X ENVIRONMENT/TREATMENT INTERACTIONS OBSERVED IN EPIDEMIOLOGICAL STUDIES AND CLINICAL TRIALS. A STUDY PUBLISHED IN BMC MEDICINE THIS MONTH BY WANG ET AL. REPORTS ON AN EXAMINATION OF DNA METHYLATION IN PERIPHERAL BLOOD LEUKOCYTES OF LEAN AND OBESE ADOLESCENTS, COMPARING METHYLATION PATTERNS BETWEEN THE TWO GROUPS. THE AUTHORS IDENTIFIED TWO GENES THAT WERE DIFFERENTIALLY METHYLATED, BOTH OF WHICH HAVE ROLES IN IMMUNE FUNCTION. HERE WE OVERVIEW THE FINDINGS FROM THIS STUDY IN THE CONTEXT OF THOSE EMERGING FROM OTHER RECENT GENETIC AND EPIGENETIC STUDIES, DISCUSS THE STRENGTHS AND WEAKNESSES OF THE STUDY AND SPECULATE ON THE FUTURE OF EPIGENETICS IN CHRONIC DISEASE RESEARCH.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12 6457  55 TIC DISORDERS: WHEN HABIT FORMING NEURAL SYSTEMS FORM HABITS OF THEIR OWN? TOURETTE SYNDROME (TS), OBSESSIVE-COMPULSIVE DISORDER (OCD) AND RELATED CONDITIONS ARE PREVALENT DISORDERS AFFECTING AS MANY AS 0.3-3% OF THE POPULATION. THEY ARE FREQUENTLY CHRONIC AND CAN BE ASSOCIATED WITH MARKED IMPAIRMENT AND DISABILITY. ALTHOUGH CLINICAL CARE HAS IMPROVED OVER THE PAST DECADE, A SIGNIFICANT NUMBER OF PATIENTS FAIL TO RESPOND ADEQUATELY OR EXPERIENCE INTOLERABLE SIDE EFFECTS. THE ETIOLOGY OF THESE DISORDERS IS UNKNOWN. COMPELLING EVIDENCE SUGGESTS THAT THE VULNERABILITY TO DEVELOP TS AND OCD IS MEDIATED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS, AND THAT NEURAL SYSTEMS LOCATED IN THE BASAL GANGLIA AND FUNCTIONALLY RELATED BRAIN STRUCTURES ARE INVOLVED IN THEIR PATHOGENESIS. BASED ON EXPLICIT MODELS OF PATHOGENESIS FOR TS AND OCD AND BUILDING ON WORK ACCOMPLISHED OVER THE PAST TWO DECADES, AN ARRAY OF CLINICAL, NEUROPSYCHOLOGICAL, GENETIC, NEUROIMAGING, EPIDEMIOLOGICAL NEUROBIOLOGICAL, AND TREATMENT STUDIES HAVE BEEN COMPLETED OR ARE UNDERWAY AT THE CHILD STUDY CENTER AT YALE UNIVERSITY. A MULTIDISCIPLINARY TEAM OF INVESTIGATORS HAS JOINED FORCES TO TEST SPECIFIC HYPOTHESES THROUGH THE INTEGRATION AND TRANSLATION OF BASIC AND CLINICAL NEUROSCIENCE RESEARCH. ALL SUBJECTS HAVE BEEN STUDIED USING IDENTICAL CLINICAL, NEUROPSYCHOLOGICAL, GENETIC, NEUROBIOLOGICAL, AND PHARMACOLOGICAL TECHNIQUES. CURRENT CONCEPTUALIZATIONS OF TS HAVE BEEN SHAPED BY ADVANCES IN CLINICAL PHENOMENOLOGY, GENETICS, SYSTEMS NEUROSCIENCE AND THE EMERGING UNDERSTANDING OF THE ROLE OF THE BASAL GANGLIA IN IMPLICIT LEARNING AND HABIT FORMATION, NEUROIMMUNOLOGY AND PSYCHOPHARMACOLOGY. AN APPRECIATION OF THE PREMONITORY URGES THAT PRECEDE TICS AND TEMPORAL DYNAMICS OF TICS HAVE PROVIDED USEFUL VIEWPOINTS FROM WHICH TO REGARD THE NATURAL HISTORY OF TS. WHILE THE LONG-TERM OUTCOME OF TS CAN BE RELATIVELY BENIGN, THE PRESENCE OF COMORBID CONDITIONS SUCH AS ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD), OCD OR A MAJOR AFFECTIVE DISORDER CAN HAVE LASTING UNTOWARD CONSEQUENCES. THE IDENTIFICATION OF SUSCEPTIBILITY GENES IN TS WILL DOUBTLESS POINT IN NEW THERAPEUTIC DIRECTIONS FOR TREATMENT, AS WILL THE CHARACTERIZATION OF THE PUTATIVE AUTOIMMUNE MECHANISMS ACTIVE IN SUBGROUP OF PATIENTS. CONTINUED SUCCESS IN FUNCTIONAL IN VIVO NEUROIMAGING STUDIES WILL LEAD TO THE TARGETING OF SPECIFIC BRAIN CIRCUITS FOR MORE INTENSIVE STUDY. ALTHOUGH IDEAL ANTI-TIC THERAPIES ARE NOT AVAILABLE, RECENTLY COMPLETED CLINICAL TRIALS WITH ALPHA-ADRENERGIC AGENTS AND ATYPICAL NEUROLEPTICS ARE ENCOURAGING. GIVEN THESE DEVELOPMENTS, TS CAN BE CONSIDERED A MODEL DISORDER TO STUDY THE DYNAMIC INTERPLAY OF GENETIC VULNERABILITIES, EPIGENETIC EVENTS, AND NEUROBIOLOGICAL SYSTEMS ACTIVE DURING EARLY BRAIN DEVELOPMENT. IT IS LIKELY THAT THE RESEARCH PARADIGMS UTILIZED IN THESE STUDIES AND MANY OF THE EMPIRICAL FINDINGS RESULTING FROM THEM, WILL BE RELEVANT TO OTHER DISORDERS OF CHILDHOOD ONSET AND TO OUR UNDERSTANDING OF NORMAL DEVELOPMENT.	2001	

13 2909  38 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14 6827  29 [GILLES DE LA TOURETTE'S DISEASE. SYMPTOMS, ETIOPATHOGENESIS AND THERAPEUTIC APPROACHES]. THE GILLES DE LA TOURETTE SYNDROME IS A USUALLY CHRONIC NEUROPSYCHIATRIC DISORDER WITH AN EARLY CHILDHOOD ONSET FEATURING MAINLY MOTOR AND VOCAL TICS. IT SEEMS THAT STRONG GENETIC FACTORS MAKE A MAJOR CONTRIBUTION TO THE ETIOLOGY OF THIS DISORDER, BUT THERE ARE ALSO CLUES THAT EPIGENETIC FACTORS ARE INVOLVED IN THE PATHOGENESIS OF TOURETTE'S SYNDROME, SUCH AS MATERNAL STRESS DURING PREGNANCY, BIRTH COMPLICATIONS AND HORMONAL INFLUENCES. FIRST IN LINE FOR ADEQUATE TREATMENT ARE NEUROLEPTIC COMPOUNDS OF HIGH POTENCY, BESIDES, SEVERAL OTHER PSYCHOACTIVE DRUGS HAVE SHOWN SOME THERAPEUTIC EFFECTS. LESS EVIDENT IS THE EFFICACY OF NEUROSURGICAL AND PSYCHOTHERAPEUTIC INTERVENTIONS.	1997	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15 1279  33 DE NOVO MUTATIONS IDENTIFIED BY WHOLE-GENOME SEQUENCING IMPLICATE CHROMATIN MODIFICATIONS IN OBSESSIVE-COMPULSIVE DISORDER. OBSESSIVE-COMPULSIVE DISORDER (OCD) IS A CHRONIC ANXIETY DISORDER WITH A SUBSTANTIAL GENETIC BASIS AND A BROADLY UNDISCOVERED ETIOLOGY. RECENT STUDIES OF DE NOVO MUTATION (DNM) EXOME-SEQUENCING STUDIES FOR OCD HAVE REINFORCED THE HYPOTHESIS THAT RARE VARIATION CONTRIBUTES TO THE RISK. WE PERFORMED, TO OUR KNOWLEDGE, THE FIRST WHOLE-GENOME SEQUENCING ON 53 PARENT-OFFSPRING FAMILIES WITH OFFSPRING AFFECTED WITH OCD TO INVESTIGATE ALL RARE DE NOVO VARIANTS AND INSERTIONS/DELETIONS. WE OBSERVED HIGHER MUTATION RATES IN PROMOTER-ANCHORED CHROMATIN LOOPS (EMPIRICAL P = 0.0015) AND REGIONS WITH HIGH FREQUENCIES OF HISTONE MARKS (EMPIRICAL P = 0.0001). MUTATIONS AFFECTING CODING REGIONS WERE SIGNIFICANTLY ENRICHED WITHIN COEXPRESSION MODULES OF GENES INVOLVED IN CHROMATIN MODIFICATION DURING HUMAN BRAIN DEVELOPMENT. FOUR GENES-SETD5, KDM3B, ASXL3, AND FBL-HAD STRONG AGGREGATED EVIDENCE AND FUNCTIONALLY CONVERGED ON TRANSCRIPTION'S EPIGENETIC REGULATION, SUGGESTING AN IMPORTANT OCD RISK MECHANISM. OUR DATA CHARACTERIZED DIFFERENT GENOME-WIDE DNMS AND HIGHLIGHTED THE CONTRIBUTION OF CHROMATIN MODIFICATION IN THE ETIOLOGY OF OCD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 5696  33 SIMILARITIES AND DIFFERENCES IN PERIPHERAL BLOOD GENE-EXPRESSION SIGNATURES OF INDIVIDUALS WITH SCHIZOPHRENIA AND THEIR FIRST-DEGREE BIOLOGICAL RELATIVES. SEVERAL STUDIES HAVE EVALUATED THE POTENTIAL UTILITY OF BLOOD-BASED WHOLE-TRANSCRIPTOME SIGNATURES AS A SOURCE OF BIOMARKERS FOR SCHIZOPHRENIA. THIS ENDEAVOR HAS BEEN COMPLICATED BY THE FACT THAT INDIVIDUALS WITH SCHIZOPHRENIA TYPICALLY DIFFER FROM APPROPRIATE COMPARISON SUBJECTS ON MORE THAN JUST THE PRESENCE OF THE DISORDER; FOR EXAMPLE, INDIVIDUALS WITH SCHIZOPHRENIA TYPICALLY RECEIVE ANTIPSYCHOTIC MEDICATIONS, AND HAVE BEEN DEALING WITH THE SEQUELAE OF THIS CHRONIC ILLNESS FOR YEARS. THE INABILITY TO CONTROL SUCH FACTORS INTRODUCES A CONSIDERABLE DEGREE OF UNCERTAINTY IN THE RESULTS TO DATE. TO OVERCOME THIS, WE PERFORMED A BLOOD-BASED GENE-EXPRESSION PROFILING STUDY OF SCHIZOPHRENIA PATIENTS (N = 9) AS WELL AS THEIR UNMEDICATED, NONPSYCHOTIC, BIOLOGICAL SIBLINGS (N = 9) AND UNAFFECTED COMPARISON SUBJECTS (N = 12). THE UNAFFECTED BIOLOGICAL SIBLINGS, WHO MAY HARBOR SOME OF THE GENETIC PREDISPOSITION TO SCHIZOPHRENIA, EXHIBITED A HOST OF GENE-EXPRESSION DIFFERENCES FROM UNAFFECTED COMPARISON SUBJECTS, MANY OF WHICH WERE SHARED BY THEIR SCHIZOPHRENIC SIBLINGS, PERHAPS INDICATIVE OF UNDERLYING RISK FACTORS FOR THE DISORDER. SEVERAL GENES THAT WERE DYSREGULATED IN BOTH INDIVIDUALS WITH SCHIZOPHRENIA AND THEIR SIBLINGS RELATED TO NUCLEOSOME AND HISTONE STRUCTURE AND FUNCTION, SUGGESTING A POTENTIAL EPIGENETIC MECHANISM UNDERLYING THE RISK STATE FOR THE DISORDER. NONPSYCHOTIC SIBLINGS ALSO DISPLAYED SOME DIFFERENCES FROM COMPARISON SUBJECTS THAT WERE NOT FOUND IN THEIR AFFECTED SIBLINGS, SUGGESTING THAT THE DYSREGULATION OF SOME GENES IN PERIPHERAL BLOOD MAY BE INDICATIVE OF UNDERLYING PROTECTIVE FACTORS. THIS STUDY, WHILE EXPLORATORY, ILLUSTRATED THE POTENTIAL UTILITY AND INCREASED INFORMATIVENESS OF INCLUDING UNAFFECTED FIRST-DEGREE RELATIVES IN RESEARCH IN PURSUIT OF PERIPHERAL BIOMARKERS FOR SCHIZOPHRENIA.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17 1508  46 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18 1736  30 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19   36  28 A CHROMATIN ASSAY FOR HUMAN BRAIN TISSUE. CHRONIC NEUROPSYCHIATRIC ILLNESSES SUCH AS SCHIZOPHRENIA, BIPOLAR DISEASE AND AUTISM ARE THOUGHT TO RESULT FROM A COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS THAT MIGHT RESULT IN EPIGENETIC ALTERATIONS OF GENE EXPRESSION AND OTHER MOLECULAR PATHOLOGY. TRADITIONALLY, HOWEVER, EXPRESSION STUDIES IN POSTMORTEM BRAIN WERE CONFINED TO QUANTIFICATION OF MRNA OR PROTEIN. THE LIMITATIONS ENCOUNTERED IN POSTMORTEM BRAIN RESEARCH SUCH AS VARIABILITIES IN AUTOLYSIS TIME AND TISSUE INTEGRITIES ARE ALSO LIKELY TO IMPACT ANY STUDIES OF HIGHER ORDER CHROMATIN STRUCTURES. HOWEVER, THE NUCLEOSOMAL ORGANIZATION OF GENOMIC DNA INCLUDING DNA:CORE HISTONE BINDING - APPEARS TO BE LARGELY PRESERVED IN REPRESENTATIVE SAMPLES PROVIDED BY VARIOUS BRAIN BANKS. THEREFORE, IT IS POSSIBLE TO STUDY THE METHYLATION PATTERN AND OTHER COVALENT MODIFICATIONS OF THE CORE HISTONES AT DEFINED GENOMIC LOCI IN POSTMORTEM BRAIN. HERE, WE PRESENT A SIMPLIFIED NATIVE CHROMATIN IMMUNOPRECIPITATION (NCHIP) PROTOCOL FOR FROZEN (NEVER-FIXED) HUMAN BRAIN SPECIMENS. STARTING WITH MICROCOCCAL NUCLEASE DIGESTION OF BRAIN HOMOGENATES, NCHIP FOLLOWED BY QPCR CAN BE COMPLETED WITHIN THREE DAYS. THE METHODOLOGY PRESENTED HERE SHOULD BE USEFUL TO ELUCIDATE EPIGENETIC MECHANISMS OF GENE EXPRESSION IN NORMAL AND DISEASED HUMAN BRAIN.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20 1796  39 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA.	2023