Search

Charlene Bron, Heidi G Sutherland, Lyn R Griffiths Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland, 4059, AustraliaCorrespondence: Lyn R Griffiths Tel +617 3138 6102Fax +617 3138 6039Email lyn.griffiths@qut.edu.auAbstract: Migraine is a common neurological disorder which affects 15– 20% of the population; it has a high socioeconomic impact through treatment and loss of productivity. Current forms of diagnosis are primarily clinical and can be difficult owing to comorbidity and symptom overlap with other neurological disorders. As such, there is a need for better diagnostic tools in the form of genetic testing. Migraine is a complex disorder, encompassing various subtypes, and has a large genetic component. Genetic studies conducted on rare monogenic subtypes, including familial hemiplegic migraine, have led to insights into its pathogenesis via identification of causal mutations in three genes (CACNA1A, ATP1A2 and SCN1A) that are involved in transport of ions at synapses and glutamatergic transmission. Study of familial migraine with aura pedigrees has also revealed other causal genes for monogenic forms of migraine. With respect to the more common polygenic form of migraine, large genome-wide association studies have increased our understanding of the genes, pathways and mechanisms involved in susceptibility, which are largely involved in neuronal and vascular functions. Given the preponderance of female migraineurs (3:1), there is evidence to suggest that hormonal or X-linked components can also contribute to migraine, and the role of genetic variants in mitochondrial DNA in migraine has been another avenue of exploration. Epigenetic studies of migraine have shown links between hormonal variation and alterations in DNA methylation and gene expression. While there is an abundance of preliminary studies identifying many potentially causative migraine genes and pathways, more comprehensive genomic and functional analysis to better understand mechanisms may aid in better diagnostic and treatment outcomes.Keywords: migraine, migraine without aura, migraine with aura, familial hemiplegic migraine, X-linked, mitochondrial variants, epigenetics

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) shares common symptoms with migraine. Most CADASIL causative mutations occur in exons 3 and 4 of the Notch 3 gene. This study investigated the role of C381T (rs 3815188) and G684A (rs 1043994) single nucleotide polymorphisms (SNP) in exons 3 and 4, respectively, of the Notch 3 gene in migraine.Results: The first part of the study, in a population of 275 migraineurs and 275 control individuals, found a significant association between the C381T variant and migraine, specifically in migraine without aura (MO) sufferers. The G684A variant was also found to be significantly associated with migraine, specifically in migraine with aura (MA) sufferers. A follow-up study in 300 migraineurs and 300 control individuals did not show replicated association of the C381T variant with migraineurs. However, the G684A variant was again shown to be significantly associated with migraine, specifically with MA.Conclusion: Further investigation of the G684A variant and the Notch 3 gene is warranted to understand their role in migraine. [ABSTRACT FROM PUBLISHER]

The exponential growth of next-generation sequencing (NGS) data requires innovative bioinformatics approaches to unravel the genetic underpinnings of diseases. Hemiplegic migraine (HM), a debilitating neurological disorder with a genetic basis, is one such condition that warrants further investigation. Notably, the genetic heterogeneity of HM is underscored by the fact that approximately two-thirds of patients lack pathogenic variants in the known causal ion channel genes. In this context, we have developed PathVar, a novel bioinformatics algorithm that harnesses publicly available tools and software for pathogenic variant discovery in NGS data. PathVar integrates a suite of tools, including HaplotypeCaller from the Genome Analysis Toolkit (GATK) for variant calling, Variant Effect Predictor (VEP) and ANNOVAR for variant annotation, and TAPES for assigning the American College of Medical Genetics and Genomics (ACMG) pathogenicity labels. Applying PathVar to whole exome sequencing data from 184 HM patients, we detected 648 variants that are probably pathogenic in multiple patients. Moreover, we have identified several candidate genes for HM, many of which cluster around the Rho GTPases pathway. Future research can leverage PathVar to generate high quality, candidate pathogenic variants, which may enhance our understanding of HM and other complex diseases., (© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)

Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised., Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants., Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches., Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD., Funding: The Wellcome Trust, the MRC., Competing Interests: Declaration of interests Wendy Chung is on the board of directors of Prime Medicine. Stephan Zuchner has received consultancy honoraria from Neurogene, AegleaBioTherapeutics, Applied Therapeutics, and is an unpaid officer of the TGP foundation, all unrelated to the present manuscript. Elisa Fazzi has received honoraria from GW Pharma. Nicola De Stefano has received honoraria from Biogen-Idec, Genzyme, Immunic, Merck, Novartis, Roche, Celgene, and Teva for consulting services, speaking, and travel support. He serves on advisory boards for Merck, Novartis, Biogen-Idec, Immunic, Roche, and Genzyme, and he has received research grant support from the Italian MS Society. Lyn R Griffiths has received grants from the Australian National Health and Medical Research Council, Variant Bio, US Department of Defense and US Migraine Research Foundation as well as honoraria from Teva, Springer Nature, and Association of Migraine Disorders and she is Board of Censors, Diagnostic Genomics Human Genetics Assoc Australia and member of the Human Genetics Australasia Advisory Board. Hugh S Markus has received peer reviewed grants from the Medical Research Council, British Heart Foundation, National Institute of Health Research, and the Alzheimer Society, and is editor in chief of the International Journal of Stroke., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Stem cell therapies hold promise in addressing the burden of neurodegenerative diseases with human embryonic neural stem cells (hNSC-H9s) and bone marrow-derived human mesenchymal stem cells (hMSCs) as viable candidates. The induction of hMSC neurospheres (hMSC-IN) generate a more lineage-restricted common neural progenitor-like cell population, potentially tunable by heparan sulfate proteoglycans (HSPGs). We examined CpG (5 mC) site methylation patterns using Illumina Infinium 850 K EPIC arrays in hNSC-H9, hMSCs and hMSC-IN cultures with HSPG agonist heparin at early and late phases of growth. We identified key regulatory CpG sites in syndecans (SDC2; SDC4) that potentially regulate gene expression in monolayers. Unique hMSC-IN hypomethylation in glypicans (GPC3; GPC4) underscore their significance in neural lineages with Sulfatase 1 and 2 (SULF1 &2) CpG methylation changes potentially driving the neurogenic shift. hMSC-INs methylation levels at SULF1 CpG sites and SULF2:cg25401628 were more closely aligned with hNSC-H9 cells than with hMSCs. We further suggest SOX2 regulation governed by lncSOX2-Overall Transcript (lncSOX2-OT) methylation changes with preferential activation of ENO2 over other neuronal markers within hMSC-INs. Our findings illuminate epigenetic dynamics governing neural lineage commitment of hMSC-INs offering insights for targeted mechanisms for regenerative medicine and therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare no relevant financial or non-financial interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dysfunction in ion channels or processes involved in maintaining ionic homeostasis is thought to lower the threshold for cortical spreading depression (CSD), and plays a role in susceptibility to associated neurological disorders, including pathogenesis of a migraine. Rare pathogenic variants in specific ion channels have been implicated in monogenic migraine subtypes. In this study, we further examined the channelopathic nature of a migraine through the analysis of common genetic variants in three selected ion channel or transporter genes: SLC4A4 , SLC1A3 , and CHRNA4 . Using the Agena MassARRAY platform, 28 single-nucleotide polymorphisms (SNPs) across the three candidate genes were genotyped in a case-control cohort comprised of 182 migraine cases and 179 matched controls. Initial results identified significant associations between migraine and rs3776578 ( p = 0.04) and rs16903247 ( p = 0.05) genotypes within the SLC1A3 gene, which encodes the EAAT1 glutamate transporter. These SNPs were subsequently genotyped in an independent cohort of 258 migraine cases and 290 controls using a high-resolution melt assay, and association testing supported the replication of initial findings-rs3776578 ( p = 0.0041) and rs16903247 ( p = 0.0127). The polymorphisms are in linkage disequilibrium and localise within a putative intronic enhancer region of SLC1A3 . The minor alleles of both SNPs show a protective effect on migraine risk, which may be conferred via influencing the expression of SLC1A3 .

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression., Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials., Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile., Competing Interests: LRG has received unrelated migraine research funding from the Australian NHMRC, US Migraine Research Foundation, US Dept of Defence and Teva. LN-S is supported by an Emerging Leadership 1 Fellowship from the Australian NHMRC. PSS is supported by a Leadership 3 Fellowship from the Australian NHMRC, and previously served on advisory committees for Biogen Australia and Roche Australia. RAS has received unrelated migraine research funding from the Australian NHMRC, US Migraine Research Foundation, and US Dept of Defence. No other authors have conflicts of interest to declare., (© 2024 The Author(s). Published by Elsevier B.V.)

Migraine is a common neurological disorder with large burden in terms of disability for individuals and costs for society. Accurate diagnosis and effective treatments remain priorities. Understanding the genetic factors that contribute to migraine risk and symptom manifestation could improve individual management. Migraine has a strong genetic basis that includes both monogenic and polygenic forms. Some distinct, rare, familial migraine subtypes are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitatory-inhibitory balance in the brain, which might be exacerbated by disruption of homoeostasis and lead to migraine. For more prevalent migraine subtypes, genetic studies have identified many susceptibility loci, implicating genes involved in both neuronal and vascular pathways. Genetic factors can also reveal the nature of relationships between migraine and its associated biomarkers and comorbidities and could potentially be used to identify new therapeutic targets and predict treatment response., Competing Interests: Declaration of interests HGS receives partial salary funding from the Australian National Health and Medical Research Council (APP1122387) and previous research support from the US Migraine Research Foundation and the Centre for Genomics and Personalised Health of Queensland University of Technology. BJ has received advisory board fees from Allergan–Abbvie, Eli Lilly, Lundbeck, Novartis, Pfizer, and Teva; speaker fees from Allergan–Abbvie, Eli Lilly, GPCE, HealthEd, Lundbeck, Novartis, Pfizer, The Limbic, and Teva; and travel support from Care Pharmacy and Pfizer. BJ was the Australian principal investigator for an Allergan–Abbvie trial and is the President of the Australian and New Zealand Headache Society. LRG received consultancy fees from Teva; participated on the Australian Novartis migraine advisory board; has received research support from the Australian National Health and Medical Research Council, the US Migraine Research Foundation, the US Department of Defence, VariantBio, and an Australian International Science Linkages grant; was on the board of the Heart Foundation of Australia, QLD division; and is chair for the board of censors of the Human Genetics Society Australasia for diagnostic genomics., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Migraine is a severe, debilitating neurovascular disorder. Hemiplegic migraine (HM) is a rare and debilitating neurological condition with a strong genetic basis. Sequencing technologies have improved the diagnosis and our understanding of the molecular pathophysiology of HM. Linkage analysis and sequencing studies in HM families have identified pathogenic variants in ion channels and related genes, including CACNA1A , ATP1A2 , and SCN1A , that cause HM. However, approximately 75% of HM patients are negative for these mutations, indicating there are other genes involved in disease causation. In this review, we explored our current understanding of the genetics of HM. The evidence presented herein summarises the current knowledge of the genetics of HM, which can be expanded further to explain the remaining heritability of this debilitating condition. Innovative bioinformatics and computational strategies to cover the entire genetic spectrum of HM are also discussed in this review.

Cancer pain is the most feared symptom at end of life. Methadone has advantages over other opioids but is associated with significant variability in clinical response, making dosing challenging in practice. OPRM1 is the most studied pharmacogene associated with the pharmacodynamics of opioids, however reports on the association of the A118G polymorphism on opioid dose requirements are conflicting, with no reports including methadone as the primary intervention. This association study on OPRM1 A118G and response to methadone for pain management, includes a review of this genetic factor's role in inter-patient variability. Fifty-four adult patients with advanced cancer were recruited in a prospective, multi-centre, open label dose individualization study. Patient characteristics were not shown to influence methadone response, and no significant associations were observed for methadone dose or pain score. The findings of our review of association studies for OPRM1 A118G in advanced cancer pain demonstrate the importance of taking ancestry into account. While our sample size was small, our results were consistent with European populations, but in contrast to studies in Chinese patients, where carriers of the A118G polymorphism were associated with higher opioid dose requirements. Pharmacogenetic studies in palliative care are challenging, continued contribution will support future genotype-based drug dosing guidelines., (© 2024. The Author(s).)

There is evidence to suggest that hormonal migraine is associated with altered cerebrovascular function. We aimed to investigate whether the expression of genes related to endothelial function in venous blood (1) might influence cerebrovascular function, (2) differs between hormonal migraineur and non-migraineur women, and (3) changes following resveratrol supplementation. This study utilised data obtained from 87 women (59 hormonal migraineurs and 28 controls) where RNA from venous blood was used to quantify gene expression and transcranial Doppler ultrasound was used to evaluate cerebrovascular function. Spearman's correlation analyses were performed between gene expression, cerebrovascular function, and migraine-related disability. We compared the expression of genes associated with endothelial function between migraineurs and non-migraineurs, and between resveratrol and placebo. The expression of several genes related to endothelial function was associated with alterations in cerebrovascular function. Notably, the expression of CALCA was associated with increased neurovascular coupling capacity ( p = 0.013), and both CALCA ( p = 0.035) and VEGF ( p = 0.014) expression were associated with increased cerebral blood flow velocity in the overall study population. Additionally, VCAM1 expression correlated with decreased pulsatility index (a measure of cerebral arterial stiffness) ( p = 0.009) and headache impact test-6 scores ( p = 0.007) in the migraineurs. No significant differences in gene expression were observed between migraineurs and controls, or between placebo and resveratrol treatments in migraineurs. Thus, altering the expression of genes related to endothelial function may improve cerebrovascular function and decrease migraine-related disability.

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The identification of historical military remains by Unrecovered War Casualties-Army (UWC-A) currently relies on Y-chromosome Short Tandem Repeat (Y-STR) testing when maternal relatives are not available, or when a mitochondrial DNA match does not provide sufficient certainty of identification. However, common Y-STR profiles (using Yfiler™) between sets of remains or families often prevent identification. To resolve these cases, an investigation of additional Y-DNA markers is needed for their potential inclusion into the DNA identification strategy. The number of genetic transmissions between missing soldiers and their living relatives needs to be considered to avoid false exclusions between paternal relatives. Analysis of 236 World War I/II (WWI/II) era pairs of relatives identified up to seven genetic transmissions between WWII soldiers and their living relatives, and nine for WWI. Previous Y-STR meta-analyses were published approximately 10 years ago when rapidly mutating markers were relatively new. This paper reports a contemporary literature review and meta-analysis of 35 studies (which includes 23 studies not previously used in meta-analysis) and 23 commonly used Y-STR's mutation rates to inform the inclusion of additional loci to UWC-A's DNA identification strategy. Meta-analysis found mutation data for a given Y-STR locus could be pooled between studies and that the mutation rates were significantly different between some loci (at P  < 0.05). Based on this meta-analysis, we have identified two additional markers from PowerPlex® Y23 for potential inclusion in UWC-A's identification strategy. Further avenues for potential experimental exploration are discussed., Key Points: From 236 UWC-A pairs of relatives, we observed up to nine genetic transmissions between WWI soldiers and their living relatives, and seven for WWII.MedCalc® software for meta-analysis utilizing the Freeman-Tukey transformation was run, which analysed 35 published studies and 23 commonly used loci. Previous Y-STR mutation rate meta-analyses are now 10 years old; this paper includes 23 studies that were not included in previous meta-analyses.Through meta-analysis, we identify two markers from PowerPlex® Y23 for potential inclusion in UWC-A's historical remains identification strategy (alongside Yfiler™). We discuss potential next steps for experimental exploration of additional Y-DNA markers., (© The Author(s) 2024. Published by OUP on behalf of the Academy of Forensic Science.)

Neuropeptides are mostly expressed in regions of the brain responsible for learning and memory and are centrally involved in cognitive pathways. The majority of neuropeptide research has been performed in animal models; with acknowledged differences between species, more research into the role of neuropeptides in humans is necessary to understand their contribution to higher cognitive function. In this study, we investigated the influence of genetic polymorphisms in neuropeptide genes on verbal learning and memory. Variants in genes encoding neuropeptides and neuropeptide receptors were tested for association with learning and memory measures using the Hopkins Verbal Learning Test-Revised (HVLT-R) in a healthy cohort of individuals (n = 597). The HVLT-R is a widely used task for verbal learning and memory assessment and provides five sub-scores: recall, delay, learning, retention, and discrimination. To determine the effect of candidate variants on learning and memory performance, genetic association analyses were performed for each HVLT-R sub-score with over 1300 genetic variants from 124 neuropeptide and neuropeptide receptor genes, genotyped on Illumina OmniExpress BeadChip arrays. This targeted analysis revealed numerous suggestive associations between HVLT-R test scores and neuropeptide and neuropeptide receptor gene variants; candidates include the SCG5 , IGFR1 , GALR1 , OXTR , CCK, and VIPR1 genes. Further characterization of these genes and their variants will improve our understanding of the genetic contribution to learning and memory and provide insight into the importance of the neuropeptide network in humans.

Background: Chronic migraine, a highly disabling migraine subtype, affects nearly 2% of the general population. Understanding migraine chronification is vital for developing better treatment and prevention strategies. An important factor in the chronification of migraine is the overuse of acute headache medication. However, the mechanisms behind the transformation of episodic migraine to chronic migraine and vice versa have not yet been elucidated. We performed a longitudinal epigenome-wide association study to identify DNA methylation (DNAm) changes associated with treatment response in patients with chronic migraine and medication overuse as part of the Chronification and Reversibility of Migraine clinical trial. Blood was taken from patients with chronic migraine (n = 98) at baseline and after a 12-week medication withdrawal period. Treatment responders, patients with ≥ 50% reduction in monthly headache days (MHD), were compared with non-responders to identify DNAm changes associated with treatment response. Similarly, patients with ≥ 50% versus < 50% reduction in monthly migraine days (MMD) were compared., Results: At the epigenome-wide significant level (p < 9.42 × 10 -8 ), a longitudinal reduction in DNAm at an intronic CpG site (cg14377273) within the HDAC4 gene was associated with MHD response following the withdrawal of acute medication. HDAC4 is highly expressed in the brain, plays a major role in synaptic plasticity, and modulates the expression and release of several neuroinflammation markers which have been implicated in migraine pathophysiology. Investigating whether baseline DNAm associated with treatment response, we identified lower baseline DNAm at a CpG site (cg15205829) within MARK3 that was significantly associated with MMD response at 12 weeks., Conclusions: Our findings of a longitudinal reduction in HDAC4 DNAm status associated with treatment response and baseline MARK3 DNAm status as an early biomarker for treatment response, provide support for a role of pathways related to chromatin structure and synaptic plasticity in headache chronification and introduce HDAC4 and MARK3 as novel therapeutic targets., (© 2023. The Author(s).)

DNA methylation is an epigenetic factor that is modifiable and can change over a lifespan. While many studies have identified methylation sites (CpGs) related to aging, the relationship of these to gene function and age-related disease phenotypes remains unclear. This research explores this question by testing for the conjoint association of age-related CpGs with gene expression and the relation of these to body fat phenotypes. The study included blood-based gene transcripts and intragenic CpG methylation data from Illumina 450 K arrays in 74 healthy adults from the Norfolk Island population. First, a series of regression analyses were performed to detect associations between gene transcript level and intragenic CpGs and their conjoint relationship with age. Second, we explored how these age-related expression CpGs (eCpGs) correlated with obesity-related phenotypes, including body fat percentage, body mass index, and waist-to-hip ratio. We identified 35 age-related eCpGs associated with age. Of these, ten eCpGs were associated with at least one body fat phenotype. Collagen Type XI Alpha 2 Chain ( COL11A2 ), Complement C1s ( C1s ), and four and a half LIM domains 2 ( FHL2 ) genes were among the most significant genes with multiple eCpGs associated with both age and multiple body fat phenotypes. The COL11A2 gene contributes to the correct assembly of the extracellular matrix in maintaining the healthy structural arrangement of various components, with the C1s gene part of complement systems functioning in inflammation. Moreover, FHL2 expression was upregulated under hypermethylation in both blood and adipose tissue with aging. These results suggest new targets for future studies and require further validation to confirm the specific function of these genes on body fat regulation.

Background: Exercise training elicits changes in muscle physiology, epigenomics, transcriptomics, and proteomics, with males and females exhibiting differing physiological responses to exercise training. However, the molecular mechanisms contributing to the differing adaptations between the sexes are poorly understood., Methods: We performed a meta-analysis for sex differences in skeletal muscle DNA methylation following an endurance training intervention (Gene SMART cohort and E-MTAB-11282 cohort). We investigated for sex differences in the skeletal muscle proteome following an endurance training intervention (Gene SMART cohort). Lastly, we investigated whether the methylome and proteome are associated with baseline cardiorespiratory fitness (maximal oxygen consumption; VO 2 max) in a sex-specific manner., Results: Here, we investigated for the first time, DNA methylome and proteome sex differences in response to exercise training in human skeletal muscle (n = 78; 50 males, 28 females). We identified 92 DNA methylation sites (CpGs) associated with exercise training; however, no CpGs changed in a sex-dependent manner. In contrast, we identified 189 proteins that are differentially expressed between the sexes following training, with 82 proteins differentially expressed between the sexes at baseline. Proteins showing the most robust sex-specific response to exercise include SIRT3, MRPL41, and MBP. Irrespective of sex, cardiorespiratory fitness was associated with robust methylome changes (19,257 CpGs) and no proteomic changes. We did not observe sex differences in the association between cardiorespiratory fitness and the DNA methylome. Integrative multi-omic analysis identified sex-specific mitochondrial metabolism pathways associated with exercise responses. Lastly, exercise training and cardiorespiratory fitness shifted the DNA methylomes to be more similar between the sexes., Conclusions: We identified sex differences in protein expression changes, but not DNA methylation changes, following an endurance exercise training intervention; whereas we identified no sex differences in the DNA methylome or proteome response to lifelong training. Given the delicate interaction between sex and training as well as the limitations of the current study, more studies are required to elucidate whether there is a sex-specific training effect on the DNA methylome. We found that genes involved in mitochondrial metabolism pathways are differentially modulated between the sexes following endurance exercise training. These results shed light on sex differences in molecular adaptations to exercise training in skeletal muscle., (© 2023. Society for Women's Health Research and BioMed Central Ltd.)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15-23% of individuals clinically suspected of CADASIL have mutations in NOTCH3. Based on this, whole exome sequencing was used to identify novel genetic variants for CADASIL-like cerebral small-vessel disease (CSVD). Analysis of functionally important variants in 50 individuals was investigated using overrepresentation tests in Gene ontology software to identify biological processes that are potentially affected in this group of patients. Further investigation of the genes in these processes was completed using the TRAPD software to identify if there is an increased number (burden) of mutations that are associated with CADASIL-like pathology. Results from this study identified that cell-cell adhesion genes were positively overrepresented in the PANTHER GO-slim database. TRAPD burden testing identified n = 15 genes that had a higher number of rare (MAF < 0.001) and predicted functionally relevant (SIFT < 0.05, PolyPhen > 0.8) mutations compared to the gnomAD v2.1.1 exome control dataset. Furthermore, these results identified ARVCF, GPR17, PTPRS, and CELSR1 as novel candidate genes in CADASIL-related pathology. This study identified a novel process that may be playing a role in the vascular damage related to CADASIL-related CSVD and implicated n = 15 genes in playing a role in the disease., (© 2023. The Author(s).)

Alzheimer's disease (AD) is the most common form of dementia that affects millions of individuals worldwide. Although the research over the last decades has provided new insight into AD pathophysiology, there is currently no cure for the disease. AD is often only diagnosed once the symptoms have become prominent, particularly in the late-onset (sporadic) form of AD. Consequently, it is essential to further new avenues for early diagnosis. With recent advances in genomic analysis and a lower cost of use, the exploration of genetic markers alongside RNA molecules can offer a key avenue for early diagnosis. We have here provided a brief overview of potential genetic markers differentially expressed in peripheral tissues in AD cases compared to controls, as well as considering the changes to the dynamics of RNA molecules. By integrating both genotype and RNA changes reported in AD, biomarker profiling can be key for developing reliable AD diagnostic tools., Competing Interests: The authors declare no conflict of interest.

Purpose: We aimed to identify a gene signature that discriminates between sepsis and aseptic inflammation in patients administered antibiotics in the intensive care unit and compare it to commonly utilised sepsis biomarkers., Methods: 91 patients commenced on antibiotics were retrospectively diagnosed as having: (i) blood culture positive sepsis; (ii) blood culture negative sepsis; or (iii) aseptic inflammation. Bloods were collected after <24 h of antibiotic commencement for both gene expression sequencing analysis and measurement of previously identified biomarkers., Results: 53 differentially expressed genes were identified that accurately discriminated between blood culture positive sepsis and aseptic inflammation in a cohort of patients given antibiotics [aROC 0.97 (95% CI, 0.95-0.99)]. This gene signature was validated in a publicly available database. The gene signature outperformed previously identified sepsis biomarkers including C-reactive protein [aROC 0.72 (95% CI, 0.57-0.87)], NT-Pro B-type Natriuretic Peptide [aROC 0.84 (95% CI, 0.73-0.96)], and Septicyte™ LAB [aROC 0.8 (95% CI, 0.68-0.93)], but was comparable to Procalcitonin [aROC 0.96 (95% CI, 0.9-1)]., Conclusions: A gene expression signature was identified that accurately discriminates between sepsis and aseptic inflammation in patients given antibiotics in the intensive care unit., Competing Interests: Declaration of Competing Interest None to declare., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)