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Results for “Genetic overlap”

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PubMed1996

Transient congenital hypoparathyroidism: resolution and recurrence in chromosome 22q11 deletion.

Transient congenital hypoparathyroidism (TCHP), with spontaneous resolution in infancy and subsequent recurrence in childhood, has not been associated with a specific cause. We report three patients with TCHP, initially with severe but transient neonatal hypocalcemia. During childhood, recurrence of hypoparathyroidism and recognition of phenotypic features suggested a diagnosis of velocardiofacial syndrome (VCFS). Features specific for the DiGeorge syndrome, with known clinical and genetic overlap with VCFS, were not present except for hypoparathyroidism. Genetic analysis confirmed chromosome 22q11 deletion in each patient. TCHP may be the earliest specific finding in 22q11 deletion/VCFS subgroup, with other diagnostic features emerging in later childhood. Infants with resolved TCHP need continued observation of parathyroid sufficiency, genetic analysis, and examination for anomalies associated with chromosome 22q11 deletion.

Abnormalities, Multiple↗

PubMed2001

Nested genetic algorithm for resolving overlapping spectra.

A nested genetic algorithm, including a genetic parameter level and a genetic implemented level, has been proposed and applied for resolving simulated overlapping spectra. Parameters of genetic algorithms (GA) were optimized by use of the genetic parameter level. The number of overlapping peaks was, moreover, detected simultaneously. Parameters of individual peaks in multiplets were computed by use of the genetic implemented level. It is obvious that the parameters of GA can be optimized and the number of overlapping peaks can be detected by itself. The optimization results are less affected than in traditional curve-fitting by the initial values of the parameters of the overlapping bands. Consequently, the nested genetic algorithm is superior to the curve-fitting technique for resolution of overlapping peaks.

Algorithms↗

PubMed2006

A common genetic factor explains the association between psychopathic personality and antisocial behavior.

BACKGROUND: Both psychopathic personality traits and antisocial behavior are influenced by genetic as well as environmental factors. However, little is known about how genetic and environmental factors contribute to the associations between the psychopathic personality traits and antisocial behavior. METHOD: Data were drawn from a longitudinal population-based twin sample including all 1480 twin pairs born in Sweden between May 1985 and December 1986. The twins responded to mailed self-report questionnaires at two occasions: 1999 (twins 13-14 years old), and 2002 (twins 16-17 years old). RESULTS: A common genetic factor loaded substantially on both psychopathic personality traits and antisocial behavior, whereas a common shared environmental factor loaded exclusively on antisocial behavior. CONCLUSIONS: The genetic overlap between psychopathic personality traits and antisocial behavior may reflect a genetic vulnerability to externalizing psychopathology. The finding of shared environmental influences only in antisocial behavior suggests an etiological distinction between psychopathic personality dimensions and antisocial behavior. Knowledge about temperamental correlates to antisocial behavior is important for identification of susceptibility genes, as well as for possible prevention through identification of at-risk children early in life.

Adolescent↗

PubMed2006

Complex genetic networks underlying the defensive system of rice (Oryza sativa L.) to Xanthomonas oryzae pv. oryzae.

Complete resistance (CR) and partial resistance (PR) of rice (Oryza sativa L.) to its bacterial pathogen, Xanthomonas oryzae pv. oryzae (Xoo), was genetically dissected by using 2 mapping populations and 10 Xoo races. Two CR genes, 50 quantitative resistance loci, and 60 digenic interactions were identified, which showed various degrees of race specificity to the Xoo races. The complex epistasis between these loci led us to the discovery of complex genetic networks underlying the rice defensive system to Xoo. The networks consisted of two major components: one representing interactions between alleles at the R loci of rice and alleles at the corresponding avirulence loci of Xoo for CR and the other comprising interactions between quantitative resistance loci in rice and their corresponding aggressiveness loci in Xoo for PR. The race specificity of PR and its strong genetic overlap with CR indicate that PR is essentially "weaker" CR. The genetic networks discovered are expected to maintain a high level of the allelic diversity at avirulent loci in the pathogen by stabilizing selection, which may maintain a high allelic diversity at R loci in the host by the frequency-dependent selection.

Alleles↗

PubMed2024

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981-2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%-100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Humans↗

PubMed2004

Enhancement of the stability of genetic switches by overlapping upstream regulatory domains.

We study genetic switches formed from pairs of mutually repressing operons. The switch stability is characterized by a well-defined lifetime, which grows very rapidly, albeit subexponentially, with the number of copies of the most-expressed transcription factor. The switch stability can be drastically enhanced by overlapping the upstream regulatory domains such that competing regulatory molecules mutually exclude each other. Our results suggest that robustness against biochemical noise can provide a selection pressure that drives operons together in the course of evolution.

Computer Simulation↗

PubMed2026

Multilevel Exploration of Shared Genetic Architecture Between Primary Biliary Cholangitis and Four Autoimmune Diseases.

INTRODUCTION: Primary Biliary Cholangitis (PBC) frequently coexists with various autoimmune diseases, such as Multiple Sclerosis (MS), Psoriasis (PS), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). Understanding the genetic associations between these diseases is crucial for providing deeper insights into their shared pathogenic mechanisms and comorbidity patterns. METHODS: This study utilized genome-wide association study summary data of PBC and four autoimmune diseases (MS, PS, RA, and SS). A multi-stage analytical pipeline was employed to systematically investigate the genetic associations between the diseases. The analytical approach consisted of three stages: first, linkage disequilibrium score regression and high-definition likelihood methods were applied to estimate overall genetic correlations between the diseases; second, local genetic correlation analysis was conducted to pinpoint genetic signals in specific chromosomal regions; third, conditional/conjunctional false discovery rate (cond/conjFDR) algorithms were used to quantitatively assess genetic overlap and identify shared susceptibility loci. RESULTS: Genome-wide analysis revealed significant genetic associations between PBC and the four autoimmune diseases (MS, PS, RA, and SS). Regional analysis showed local genetic correlations across various chromosomal segments. cond/conjFDR analysis confirmed genetic intersections among the diseases and identified several critical genetic polymorphic loci that influence disease susceptibility. DISCUSSION: This study comprehensively delineates the shared genetic architecture underlying PBC and four autoimmune diseases through integrative analyses of multiple genome-wide approaches. The results highlight strong genetic correlations, particularly between PBC and MS, PS, RA, and SS, and identify key shared susceptibility genes, including CLEC16A, CD58, CD86, STAT4, IRF5, TYK2, and TNFAIP3, which collectively mediate immune dysregulation through autophagy, cytokine signaling, and NF-κB pathways. These findings not only extend current understanding of the molecular mechanisms driving autoimmune comorbidity but also provide potential genetic targets for future functional validation and therapeutic exploration. CONCLUSION: This study provides comprehensive genomic evidence for the genetic connections between PBC and the four autoimmune diseases (MS, PS, RA, and SS), offering valuable insights into the shared pathological mechanisms underlying their comorbidities.

Humans↗

PubMed1997

Smoking and intoxication after alcohol challenge in women and men: genetic influences.

In an earlier analysis, men and women who were current or former smokers were found to report feeling less intoxicated on average than nonsmokers after ingestion of a challenge dose of alcohol. Here, we examine whether differences in subjective response to alcohol and a tendency to smoke cigarettes are transmitted together in families; and, if so, whether this association might be entirely explained by the same heritable factors that influence alcohol intake (as we might expect if both smoking and subjective intoxication are influenced by some general susceptibility for substance use). Alcohol challenge data on 388 Australian male and female twins (194 complete pairs) were reanalyzed using multivariate genetic analysis to evaluate the association between cigarette smoking and self-report intoxication after a standard dose of alcohol. In women, we could not reject the hypothesis of complete genetic overlap between effects on intoxication rating and history of smoking, and a significant residual genetic correlation between smoking and postalcohol intoxication persisted even when genetic influences on alcohol consumption were controlled for. In men, the familial association seemed to be largely environmentally mediated and associated with differences in drinking history. These findings prompt the question of whether, in some individuals, cigarette smoking may contribute to the development of tolerance to the effects of alcohol.

Adolescent↗

PubMed2026

Shared Genetic Basis, Biological Function and Causal Relationship Between Sleep Traits and Hypothyroidism: Evidence from a Comprehensive Genetic Analysis.

BACKGROUND: This research attempts to clarify whether there are any genetic similarities between sleep traits and hypothyroidism based on publicly accessible large-scale genomewide association studies. METHODS: The methodology included colocalization analysis, cross-phenotype association analysis, and linkage disequilibrium score regression analysis to find common genetic overlap. Through tissue function specificity and functional mapping, we were able to identify the shared genetic level. Genetic instrumental factors were used for causal inference in two-sample univariate and multivariable Mendelian randomization analyses. RESULTS: A hereditary correlation between hypothyroidism and napping during the day and getting up in the morning (rg= -0.0982, P= 0.0007; rg= -0.101, P= 0.0001). MAGI3, and HLA-DRB1 BX296568.1 may be potential targets for shared treatments. Colocalization and tissue-specific analysis demonstrated that the common genes and SNPs were identified in the thyroid, lung, brain, and lymphatic tissues. Functional analysis emphasized the importance of these common genes in processes like as protein transport, inflammatory response, and MHC class II protein synthesis. Furthermore, an association has been established between hypothyroidism and sleep duration (IVW, OR 1.5208; 95% CI 1.1142-2.0758, P=0.0082) and getting up in the morning (IVW, OR 1.8375; 95%CI: 1.4502-2.3284, P=4.73E-07). Furthermore, the reverse MR analysis revealed no causal connection between aberrant sleep traits and hypothyroidism. The enduring impact of insomnia on hypothyroidism persists despite controlling for alcohol consumption and smoking habits. CONCLUSION: Certain genetic correlations between sleep traits and hypothyroidism have been emphasized. These findings may elucidate the origin of comorbidity and have implications for future clinical trials.

Humans↗

PubMed2004

Statistical genetics of molar cusp patterning in pedigreed baboons: implications for primate dental development and evolution.

Gene expression and knock-out studies provide considerable information about the genetic mechanisms required for tooth organogenesis. Quantitative genetic studies of normal phenotypic variation are complementary to these developmental studies and may help elucidate the genes and mechanisms that contribute to the normal population-level phenotypic variation upon which selection acts. Here we present the first quantitative genetic analysis of molar cusp positioning in mammals. We analyzed quantitative measures of molar cusp position in a captive pedigreed baboon breeding colony housed at the Southwest National Primate Research Center in San Antonio, Texas. Our results reveal complete pleiotropy between antimeric pairs of traits--i.e., they are influenced by the same gene or suite of genes. Mandibular morphological homologues in the molar series also exhibit complete pleiotropy. In contrast, morphological homologues in maxillary molar series appear to be influenced by partial, incomplete pleiotropic effects. Variation in the mandibular mesial and distal molar loph orientation on the same molar crown is estimated to be genetically independent, whereas the maxillary molar mesial and distal loph orientation is estimated to have partially overlapping genetic affects. The differences between the maxillary and mandibular molar patterning, and the degree of genetic independence found between lophs on the same molar crown, may be indicative of previously unrecognized levels of modularity in the primate dentition.

Animals↗

PubMed2004

Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3.

Autism is a common neurodevelopmental disorder of complex genetic etiology. Rett syndrome, an X-linked dominant disorder caused by MECP2 mutations, and Angelman syndrome, an imprinted disorder caused by maternal 15q11-q13 or UBE3A deficiency, have phenotypic and genetic overlap with autism. MECP2 encodes methyl-CpG-binding protein 2 that acts as a transcriptional repressor for methylated gene constructs but is surprisingly not required for maintaining imprinted gene expression. Here, we test the hypothesis that MECP2 deficiency may affect the level of expression of UBE3A and neighboring autism candidate gene GABRB3 without necessarily affecting imprinted expression. Multiple quantitative methods were used including automated quantitation of immunofluorescence and in situ hybridization by laser scanning cytometry on tissue microarrays, immunoblot and TaqMan PCR. The results demonstrated significant defects in UBE3A/E6AP expression in two different Mecp2 deficient mouse strains and human Rett, Angelman and autism brains compared with controls. Although no difference was observed in the allelic expression of several imprinted transcripts in Mecp2-null brain, Ube3a sense expression was significantly reduced, consistent with the decrease in protein. A non-imprinted gene from 15q11-q13, GABRB3, encoding the beta3 subunit of the GABAA receptor, also showed significantly reduced expression in multiple Rett, Angelman and autism brain samples, and Mecp2 deficient mice by quantitative immunoblot. These results suggest an overlapping pathway of gene dysregulation within 15q11-q13 in Rett, Angelman and autism and implicate MeCP2 in the regulation of UBE3A and GABRB3 expressions in the postnatal mammalian brain.

Angelman Syndrome↗

PubMed2005

Comparison of array-based comparative genomic hybridization with gene expression-based regional expression biases to identify genetic abnormalities in hepatocellular carcinoma.

BACKGROUND: Regional expression biases (REBs) are genetic intervals where gene expression is coordinately changed. For example, if a region of the genome is amplified, often the majority of genes that map within the amplified region show increased expression when compared to genes located in cytogenetically normal regions. As such, REBs have the potential to act as surrogates for cytogenetic data traditionally obtained using molecular technologies such as comparative genomic hybridization. However as REBs are identified using transcriptional information, detection of REBs may also identify local transcriptional abnormalities produced by both genetic and epigenetic mechanisms. RESULTS: REBs were identified from a set of hepatocellular carcinoma (HCC) gene expression profiles using a multiple span moving binomial test and compared to genetic abnormalities identified using array-based comparative genomic hybridization (aCGH). In the majority of cases, REBs overlapped genetic abnormalities as determined by aCGH. For example, both methods identified narrow regions of frequent amplification on chromosome 1p and narrow regions of frequent deletion on 17q. In a minority of cases, REBs were identified in regions not determined to be abnormal via other cytogenetic technologies. Specifically, expression biases reflective of cell proliferation were frequently identified on chromosome 6p21-23. CONCLUSION: Identification of REBs using a multiple span moving binomial test produced reasonable approximations of underlying cytogenetic abnormalities. However, caution should be used when attributing REBs identified on chromosome 6p to cytogenetic events in rapidly proliferating cells.

Carcinoma, Hepatocellular↗

PubMed2024

Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients' neurons.

Autism spectrum disorders (ASDs) are highly heritable and result in abnormal repetitive behaviors and impairment in communication and cognitive skills. Previous studies have focused on the genetic correlation between ASDs and other neuropsychiatric disorders, but an in-depth understanding of the correlation to other disorders is required. We conducted an extensive meta-analysis of common variants identified in ASDs by genome-wide association studies (GWAS) and compared it to the consensus genes and single nucleotide polymorphisms (SNPs) of Schizophrenia (SCZ). We found approximately 75% of the GWAS genes that are associated with ASD are also associated with SCZ. We further investigated the cellular phenotypes of neurons derived from induced pluripotent stem cell (iPSC) models in ASD and SCZ. Our findings revealed that ASD and SCZ neurons initially follow divergent developmental trajectories compared to control neurons. However, despite these early diametrical differences, both ASD and SCZ neurons ultimately display similar deficits in synaptic activity as they mature. This significant genetic overlap between ASD and SCZ, coupled with the convergence towards similar synaptic deficits, highlights the intricate interplay of genetic and developmental factors in shaping the shared underlying mechanisms of these complex neurodevelopmental and neuropsychiatric disorders.

Humans↗

PubMed2005

Spatial working memory function in twins with schizophrenia and bipolar disorder.

BACKGROUND: Family studies are in conflict as to whether schizophrenia and bipolar disorder have independent genetic etiologies. Given the relatively low prevalence (approximately 1%) of these disorders, the use of quantitative endophenotypic markers of genetic liability might provide a more sensitive strategy for evaluating their genetic overlap. We have previously demonstrated that spatial working memory deficits increase in a dose-dependent fashion with increasing genetic proximity to a proband among the unaffected co-twins of schizophrenic patients. Here, we evaluated whether such deficits might also mark genetic susceptibility to bipolar disorder. METHODS: The Wechsler Memory Scale-Revised Visual Memory Span and Digit Span subtests were administered to 46 schizophrenic patients, 32 of their unaffected co-twins, 22 bipolar patients, 16 of their unaffected co-twins, and 100 control twins, representing unselectively nationwide twin samples. RESULTS: Schizophrenic patients and their unaffected co-twins performed significantly worse than control subjects on the spatial working memory task, whereas only the schizophrenic patients performed significantly below the control subjects on the verbal working memory task. Neither bipolar patients nor their unaffected co-twins differed from control subjects on these measures. CONCLUSIONS: Our findings support the hypothesis that impairment in spatial working memory might effectively reflect an expression of genetic liability to schizophrenia but less clearly to bipolar disorder.

Aged↗

PubMed2026

Multilevel genomic, transcriptomic, and epidemiologic evidence linking diabetic retinopathy to Alzheimer disease.

BACKGROUND: Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD. METHODS: We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD. RESULTS: With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses. CONCLUSIONS: Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.

Humans↗

PubMed1998

Genes on mouse chromosomes 2 and 9 determine variation in ethanol consumption.

Quantitative trait locus (QTL) mapping efforts in alcohol (ethanol) research are beginning to generate promising data that may ultimately lead to the identification of genes influencing alcohol addiction. Rodents have been extensively utilized to study ethanol's rewarding and aversive effects, and to demonstrate the existence of genetic influences on traits such as free-choice ethanol-consumption, ethanol-conditioned place preference and ethanol-conditioned taste aversion. The purpose of the current investigation was to verify or eliminate from further consideration putative QTLs for free-choice ethanol consumption originally identified in BXD Recombinant Inbred (RI) strains and other informative genetic crosses. B6D2F2 mice were utilized in a verification testing strategy to evaluate the viability of putative ethanol consumption QTLs. When data were combined from BXD RI, B6D2F2 and short-term selected line (STSL) mapping studies, verification was obtained for two QTLs, one on Chromosome (Chr) 9 (proximal-mid) and another on Chr 2 (distal), and suggestive verification was obtained for QTLs on Chrs 2 (proximal), 3, 4, 7, and 15. In addition, the possible genetic association of ethanol consumption with conditioned place preference was evaluated. Genetic correlations were estimated from BXD RI strain means, and QTL maps for these traits were compared to evaluate the possibility of a genetic association. The correlational analysis yielded a trend (r = 0.34, p = 0.09), but no statistically significant results. However, comparisons of QTL mapping results between phenotypes suggested some possible genetic overlap for these traits, both putative measures of ethanol reward. These data suggest that the determinants of these two measures are genetically diverse, but may share some common genetic elements.

Alcohol Drinking↗

PubMed2002

Effect of forward and reverse selection for ethanol-induced locomotor response on other measures of ethanol sensitivity.

BACKGROUND: Ethanol sensitivity may be a predictor of genetic predisposition to ethanol abuse. To examine ethanol sensitivity in rodents, two lines of mice were bred in replicate for high (FAST-1 and -2) and low (SLOW-1 and -2) locomotor stimulant responses to ethanol. After large differences between the lines developed and further response to selection seemed to have arrested, reverse selection was initiated by breeding the slowest FAST mice with each other and the fastest SLOW mice with each other. The reverse-selected lines, named r-FAST and r-SLOW, were virtually equally sensitive to the stimulant effects of the selection dose of ethanol after 16 generations of reverse selection. METHODS: These experiments used this unique genetic model to examine two responses, putatively genetically correlated with sensitivity to ethanol stimulation: handling-induced convulsions during chronic ethanol withdrawal, and ethanol-induced hypothermia. Ethanol clearance, for which a small difference was previously found between the FAST and SLOW lines, was also examined. RESULTS: Handling-induced convulsions during chronic ethanol withdrawal were significantly greater in both FAST lines compared with both SLOW lines. Reverse selection eliminated the difference between the replicate 1 lines but did not alter the difference between the replicate 2 lines. Ethanol-induced hypothermia was greater in both SLOW lines compared with the FAST lines. This difference was significantly reduced by reverse selection in r-SLOW mice only. Ethanol clearance rates were similar among all lines and replicates. CONCLUSIONS: These data demonstrate the usefulness of reverse-selected lines for examining putatively genetically correlated traits. Changes in the correlated traits demonstrated the existence of persistent trait-relevant genetic heterogeneity and some genetic overlap between the correlated traits and the selection trait. Absence of a change after reverse selection suggests that trait-relevant genetic heterogeneity was eliminated by forward selection or, alternatively, that the trait was not influenced by genes associated with successful reverse selection.

Animals↗

PubMed2026

Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID (LC19), post-traumatic stress disorder (PTSD), rheumatoid arthritis (RA), and multiple sclerosis (MS) are clinically distinct disorders that share substantial symptom overlap, including persistent fatigue, cognitive impairment, autonomic dysfunction, and immune dysregulation. Although these conditions differ in diagnosis and clinical presentation, their underlying biological mechanisms remain poorly understood and may involve convergent regulatory pathways. METHODS: The EpiSwitch® 3D genomics platform and Orion knowledgebase were used to integrate chromosome conformation signatures with genome-wide association study (GWAS)-derived datasets across ME/CFS, LC19, PTSD, RA, and MS. Three-dimensional genomic anchors were mapped to coding genes and analysed using STRING protein-protein interaction networks and Cytoscape-based systems biology approaches. Disease-specific anchor datasets were generated and compared at both gene and network levels to identify shared biological processes and regulatory mechanisms. RESULTS: Analysis of the ME/CFS dataset identified 552 unique 3D genomic anchors mapped to 567 genes, with analogous disease-specific anchor sets generated for LC19, PTSD, RA, and MS. Direct overlap between disease-associated genes was limited; however, higher-order network analyses revealed substantial interconnectivity and convergence across conditions. Shared biological pathways included immune and cytokine signalling, interferon responses, mitochondrial function, metabolic regulation, and neuroendocrine processes. Highly connected hub genes included immune regulatory nodes such as LAG3 and components of the mTOR signalling pathway, implicating T-cell exhaustion, chronic immune activation, and immunometabolic dysregulation as common mechanisms underlying these disorders. CONCLUSIONS: These findings support a systems-level model in which clinically overlapping fatigue-associated syndromes arise from perturbations of interconnected regulatory networks rather than discrete disease-specific pathways. Despite limited genetic overlap, substantial convergence at the network level suggests shared biological architecture across ME/CFS, LC19, PTSD, RA, and MS. The identification of common regulatory pathways provides a mechanistic framework for the development of cross-disease diagnostic and therapeutic strategies. By capturing dynamic regulatory states, 3D genomic biomarkers offer significant potential for objective blood-based diagnostics, patient stratification, and the identification of shared therapeutic targets across complex chronic disorders. These findings support the application of precision medicine approaches and may accelerate the development of novel interventions for fatigue-associated multisystem diseases.

Humans↗