Altered H19/miR‐675 expression in skeletal muscle is associated with low muscle mass in community‐dwelling older adults

Background: Despite increasing knowledge of the pathogenesis of muscle ageing, the molecular mechanisms are poorly understood. Based on an expression analysis of muscle biopsies from older Caucasian men, we undertook an in-depth analysis of the expression of the long non-coding RNA, H19, to identify molecular mechanisms that may contribute to the loss of muscle mass with age. Methods: We carried out transcriptome analysis of vastus lateralis muscle biopsies from 40 healthy Caucasian men aged 68–76 years from the Hertfordshire Sarcopenia Study (HSS) with respect to appendicular lean mass adjusted for height (ALMi). Validation and replication was carried out using qRT-PCR in 130 independent male and female participants aged 73–83 years recruited into an extension of the HSS (HSSe). DNA methylation was assessed using pyrosequencing. Results: Lower ALMi was associated with higher muscle H19 expression (r2 = 0.177, P < 0.001). The microRNAs, miR-675-5p/3p encoded by exon 1 of H19, were positively correlated with H19 expression (Pearson r = 0.192 and 0.182, respectively, P < 0.03), and miR-675-5p expression negatively associated with ALMi (r2 = 0.629, P = 0.005). The methylation of CpGs within the H19 imprinting control region (ICR) were negatively correlated with H19 expression (Pearson r = −0.211 to −0.245, P ≤ 0.05). Moreover, RNA and protein levels of SMAD1 and 5, targets of miR-675-3p, were negatively associated with miR-675-3p (r2 = 0.792 and 0.760, respectively) and miR-675-5p (r2 = 0.584 and 0.723, respectively) expression, and SMAD1 and 5 RNA levels positively associated with greater type II fibre size (r2 = 0.184 and 0.246, respectively, P < 0.05). Conclusions: Increased expression profiles of H19/miR-675-5p/3p and lower expression of the anabolic SMAD1/5 effectors of bone morphogenetic protein (BMP) signalling are associated with low muscle mass in older individuals

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients

Studying neuroanatomy using MRI

The study of neuroanatomy using imaging enables key insights into how our brains function, are shaped by genes and environment, and change with development, aging, and disease. Developments in MRI acquisition, image processing, and data modelling have been key to these advances. However, MRI provides an indirect measurement of the biological signals we aim to investigate. Thus, artifacts and key questions of correct interpretation can confound the readouts provided by anatomical MRI. In this review we provide an overview of the methods for measuring macro- and mesoscopic structure and inferring microstructural properties; we also describe key artefacts and confounds that can lead to incorrect conclusions. Ultimately, we believe that, though methods need to improve and caution is required in its interpretation, structural MRI continues to have great promise in furthering our understanding of how the brain works

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Genomic and clinical predictors of lacosamide response in refractory epilepsies

Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (<25% seizure reduction). No variants reached the genome-wide significance threshold in our case-control analysis. Significance: No genetic predictor of lacosamide response was identified. Patients with refractory GGE might benefit from treatment with lacosamide

Adiposity is associated with widespread transcriptional changes and downregulation of longevity pathways in aged skeletal muscle

Background: amongst healthy older people, a number of correlates of impaired skeletal muscle mass and function have been defined. Although the prevalence of obesity is increasing markedly in this age group, information is sparse about the particular impacts of obesity on ageing skeletal muscle or the molecular mechanisms that underlie this and associated disease risk. Methods: here, we examined genome-wide transcriptional changes using RNA sequencing in muscle biopsies from 40 older community-dwelling men from the Hertfordshire Sarcopenia Study with regard to obesity (body mass index [BMI] &gt;30 kg/m 2, n = 7), overweight (BMI 25–30, n = 19), normal weight (BMI &lt; 25, n = 14), and per cent and total fat mass. In addition, we used EPIC DNA methylation array data to investigate correlations between DNA methylation and gene expression in aged skeletal muscle tissue and investigated the relationship between genes within altered regulatory pathways and muscle histological parameters. Results: individuals with obesity demonstrated a prominent modified transcriptional signature in muscle tissue, with a total of 542 differentially expressed genes associated with obesity (false discovery rate ≤0.05), of which 425 genes were upregulated when compared with normal weight. Upregulated genes were enriched in immune response (P = 3.18 × 10 −41) and inflammation (leucocyte activation, P = 1.47 × 10 −41; tumour necrosis factor, P = 2.75 × 10 −15) signalling pathways and downregulated genes enriched in longevity (P = 1.5 × 10 −3) and AMP-activated protein kinase (AMPK) (P = 4.5 × 10 −3) signalling pathways. Furthermore, differentially expressed genes in both longevity and AMPK signalling pathways were associated with a change in DNA methylation, with a total of 256 and 360 significant cytosine–phosphate–guanine–gene correlations identified, respectively. Similar changes in the muscle transcriptome were observed with respect to per cent fat mass and total fat mass. Obesity was further associated with a significant increase in type II fast-fibre area (P = 0.026), of which key regulatory genes within both longevity and AMPK pathways were significantly associated. Conclusions: we provide for the first time a global transcriptomic profile of skeletal muscle in older people with and without obesity, demonstrating modulation of key genes and pathways implicated in the regulation of muscle function, changes in DNA methylation associated with such pathways and associations between genes within the modified pathways implicated in muscle regulation and changes in muscle fibre type. </p

DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human Methylation EPIC array, we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women’s Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p ≤ 6.45×10−8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195 g (95%CI: −241, −149 g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin-releasing hormone-binding protein (CRHBP). Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p = 1.37×10−255), maternal smoking (7.71%, p = 1.50 x 10−57) and maternal plasma folate levels during pregnancy (0.33%, p = 0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs

De-novo mutations in patients with chronic ultra-refractory epilepsy with onset after age five years

We set out to investigate whether a de-novo paradigm could explain genetic causes of chronic ultra-refractory epilepsy, with onset later than the typical age for the epileptic encephalopathies. We performed exome sequencing on nine adult patients with MRI-negative epilepsy and no preceding intellectual disability. All had an onset of seizures after five years old and had chronic ultra-refractory epilepsy defined here as having failed more than six anti-epileptic drugs and currently experiencing ≥4 disabling seizures per month. Parents were sequenced to identify de-novo mutations and these were assessed for likelihood of pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) criteria. We confirmed the presence of functional and predicted-damaging de-novo mutations in 3/9 patients. One of these pathogenic de-novo mutations, in DNM1L, was previously reported in a patient with severe epilepsy and chronic pharmacoresistance adding to the evidence for DNM1L as an epilepsy gene. Exome sequencing is a successful strategy for identifying de-novo mutations in paediatric epileptic encephalopathies and rare neurological disorders. Our study demonstrates the potential benefit of considering ultra-refractory epilepsy patients with later onset for genetic testing. Identifying genetic mutations underpinning severe epilepsy of unknown aetiology may provide new insight into the underlying biology and offers the potential for therapeutic intervention in the form of precision medicine in older patients

Development and validation of a predictive model of drug-resistant genetic generalized epilepsy.

To develop and validate a clinical prediction model for antiepileptic drug (AED)-resistant genetic generalized epilepsy (GGE).info:eu-repo/semantics/publishe