ORCID Profile
0000-0003-4026-2964
Current Organisations
University of Western Australia
,
University of Tasmania
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Publisher: Informa UK Limited
Date: 11-01-2021
Publisher: Wiley
Date: 03-02-2011
DOI: 10.1002/AJHB.21153
Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 04-06-2022
DOI: 10.1038/S41598-022-12866-2
Abstract: Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10 –9 ) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic in iduals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI ( PHIL, chr6:79,650,711, p = 2.1 × 10 –6 TRPM3 , rs760461668, p = 5 × 10 –8 SPTY2D1, rs756851199, p = 1.6 × 10 –8 and TSPO, rs566547284, p = 2.4 × 10 –6 ). PHIL encoded protein is involved in pancreatic β-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic β-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting erse and high-risk populations to study variants absent in publicly available repositories.
Publisher: The Endocrine Society
Date: 23-01-2021
Abstract: Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited. To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts. We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed. We identified 2 DMPs with epigenome-wide significant (P & 2.4E−7) associations with TSH and 6 with fT3, including cg00049440 in KLF9 (P = 2.88E−10) and cg04173586 in DOT1L (P = 2.09E−16), both genes known to be induced by fT3. All DMPs had a positive association between DNAm and TSH and a negative association between DNAm and fT3. There were no DMPs significantly associated with fT4. We identified 23 differentially methylated regions associated with fT3, fT4, or TSH. This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.
Publisher: Oxford University Press (OUP)
Date: 12-10-2017
Publisher: Wiley
Date: 24-04-2020
DOI: 10.1111/LIV.14453
Publisher: Oxford University Press (OUP)
Date: 18-02-2013
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.SCHRES.2018.02.034
Abstract: The importance of genomic copy number variants (CNVs) has long been recognized in the etiology of neurodevelopmental diseases. We report here the results from the CNV analysis of whole-genome sequences from 91 multiplex schizophrenia families. Employing four algorithms (CNVnator, Cn.mops, DELLY and LUMPY) to identify CNVs, we find 1231 rare deletions and 287 rare duplications in 300 in iduals (77 with schizophrenia (SZ), 32 with schizoaffective disorder (SAD), 82 with another neuropsychiatric diagnosis and 109 unaffected). The size of the CNVs ranges from a few hundred base-pairs to about 1.3Mb. The total burden of CNVs does not differ significantly between affected (SZ and SAD) and unaffected in iduals. Parent-to-child transmission rate for rare CNVs affecting exonic regions is significantly higher for affected (SZ and SAD) probands as compared to their siblings, but rates for all CNVs is not. We observe heterogeneity between families in terms of genes involved in CNVs, and find several CNVs involving genes previously implicated in either schizophrenia or other neuropsychiatric disorders.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.GENE.2015.03.031
Abstract: Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed in iduals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected in iduals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2020
DOI: 10.1186/S13148-020-00842-4
Abstract: Machine learning is a sub-field of artificial intelligence, which utilises large data sets to make predictions for future events. Although most algorithms used in machine learning were developed as far back as the 1950s, the advent of big data in combination with dramatically increased computing power has spurred renewed interest in this technology over the last two decades. Within the medical field, machine learning is promising in the development of assistive clinical tools for detection of e.g. cancers and prediction of disease. Recent advances in deep learning technologies, a sub-discipline of machine learning that requires less user input but more data and processing power, has provided even greater promise in assisting physicians to achieve accurate diagnoses. Within the fields of genetics and its sub-field epigenetics, both prime ex les of complex data, machine learning methods are on the rise, as the field of personalised medicine is aiming for treatment of the in idual based on their genetic and epigenetic profiles. We now have an ever-growing number of reported epigenetic alterations in disease, and this offers a chance to increase sensitivity and specificity of future diagnostics and therapies. Currently, there are limited studies using machine learning applied to epigenetics. They pertain to a wide variety of disease states and have used mostly supervised machine learning methods.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2023
DOI: 10.1007/S12072-022-10469-7
Abstract: Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value 0.007. EWAS identified dmCpGs related to three genes ( ANK1, MIR10a , PTPRN2 ) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced ( ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p 2.3 × 10 –3 ). We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.
Publisher: Elsevier BV
Date: 05-2017
Publisher: Elsevier BV
Date: 10-2020
Publisher: Frontiers Media SA
Date: 2013
Publisher: Wiley
Date: 15-11-2010
DOI: 10.1002/AJHB.21114
Publisher: Pleiades Publishing Ltd
Date: 12-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-05-2022
DOI: 10.1212/NXG.0000000000200005
Abstract: Advances in genome sequencing technologies have unlocked new possibilities in identifying disease-associated and causative genetic markers, which may in turn enhance disease diagnosis and improve prognostication and management strategies. With the capability of examining genetic variations ranging from single-nucleotide mutations to large structural variants, whole-genome sequencing (WGS) is an increasingly adopted approach to dissect the complex genetic architecture of neurologic diseases. There is emerging evidence for different structural variants and their roles in major neurologic and neurodevelopmental diseases. This review first describes different structural variants and their implicated roles in major neurologic and neurodevelopmental diseases, and then discusses the clinical relevance of WGS applications in neurology. Notably, WGS-based detection of structural variants has shown promising potential in enhancing diagnostic power of genetic tests in clinical settings. Ongoing WGS-based research in structural variations and quantifying mutational constraints can also yield clinical benefits by improving variant interpretation and disease diagnosis, while supporting biomarker discovery and therapeutic development. As a result, wider integration of WGS technologies into health care will likely increase diagnostic yields in difficult-to-diagnose conditions and define potential therapeutic targets or intervention points for genome-editing strategies.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.PREGHY.2014.03.005
Abstract: Four putative single nucleotide polymorphism (SNP) risk variants at the preecl sia susceptibility locus on chromosome 2q22 rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preecl sia risk variants in an independent Australian population-based cohort. The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1246 mothers and 1404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software. Nominal associations (P<0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P=0.005) and decreased blood glucose levels in adolescents (P=0.022). The LRP1B SNP was associated with increased maternal height (P=0.026) and decreased maternal weight (P=0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P=0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preecl tic pregnancy (P=0.003) and having a mother with prior preecl tic pregnancy (P=0.033). Our collective findings support the hypothesis that genetic mechanisms for preecl sia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P<0.001).
Publisher: Springer Science and Business Media LLC
Date: 06-2014
Publisher: Wiley
Date: 05-2007
DOI: 10.1002/AJPA.20581
Abstract: We examined mitochondrial DNA (mtDNA) haplogroup and haplotype ersity in 188 in iduals from three Chibchan (Kogi, Arsario, and Ijka) populations and one Arawak (Wayuú) group from northeast Colombia to determine the biological relationship between lower Central American and northern South American Chibchan speakers. mtDNA haplogroups were obtained for all in iduals and mtDNA HVS-I sequence data were obtained for 110 s les. Resulting sequence data were compared to 16 other Caribbean, South, and Central American populations using ersity measures, neutrality test statistics, sudden and spatial mismatch models, intermatch distributions, phylogenetic networks, and a multidimensional scaling plot. Our results demonstrate the existence of a shared maternal genetic structure between Central American Chibchan, Mayan populations and northern South American Chibchan-speakers. Additionally, these results suggest an expansion of Chibchan-speakers into South America associated with a shift in subsistence strategies because of changing ecological conditions that occurred in the region between 10,000-14,000 years before present.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2019
DOI: 10.1038/S41467-019-09671-3
Abstract: Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (P Bonferroni 1.06 x 10 −7 ). In additional analyses in 7,278 participants, .3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10 −74 ) and BMI in pregnancy (3/914, p = 1.13x10 −3 ), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
Publisher: Elsevier BV
Date: 05-2019
DOI: 10.1016/J.BURNS.2018.10.027
Abstract: After similar extent of injury there is considerable variability in scarring between in iduals, in part due to genetic factors. This study aimed to identify genetic variants associated with scar height and pliability after burn injury. An exome-wide array association study and gene pathway analysis were performed on a prospective cohort of 665 patients treated for burn injury. Outcomes were scar height (SH) and scar pliability (SP) sub-scores of the modified Vancouver Scar Scale (mVSS). DNA was genotyped using the Infinium
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: Elsevier BV
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 10-2016
Publisher: Elsevier BV
Date: 2021
Publisher: Springer Science and Business Media LLC
Date: 03-02-2016
Publisher: Elsevier BV
Date: 06-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
DOI: 10.1161/CIRCGENETICS.113.000079
Abstract: Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these 2 arteries yet, they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components. IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS using 931219 single-nucleotide polymorphisms was undertaken with 6 internal and common carotid artery IMT phenotypes using an additive measured genotype model. The most robust association detected was for 2 single-nucleotide polymorphisms (rs16983261, rs6113474 P =1.60e −7 ) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1 . We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at P .0e −6 . The genetic correlation between the 2 carotid IMT arterial segments was 0.51. This study represents the first large-scale GWAS of carotid IMT in a non–European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments, but the moderate genetic correlation implies both common and unique genetic components.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
Publisher: Public Library of Science (PLoS)
Date: 26-05-2015
Publisher: Springer Science and Business Media LLC
Date: 03-05-2019
Publisher: Springer Science and Business Media LLC
Date: 27-11-2017
DOI: 10.1007/S00439-017-1856-X
Abstract: Over two billion adults are overweight or obese and therefore at an increased risk of cardiometabolic syndrome (CMS). Obesity-related anthropometric traits genetically correlated with CMS may provide insight into CMS aetiology. The aim of this study was to utilise an empirically derived genetic relatedness matrix to calculate heritabilities and genetic correlations between CMS and anthropometric traits to determine whether they share genetic risk factors (pleiotropy). We used genome-wide single nucleotide polymorphism (SNP) data on 4671 Busselton Health Study participants. Exploiting both known and unknown relatedness, empirical kinship probabilities were estimated using these SNP data. General linear mixed models implemented in SOLAR were used to estimate narrow-sense heritabilities (h
Publisher: Springer Science and Business Media LLC
Date: 06-06-2022
DOI: 10.1038/S41467-022-30875-7
Abstract: We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 in iduals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 in iduals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association ( P 1 × 10 −3 ), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
Publisher: The Endocrine Society
Date: 20-02-2019
Abstract: “Accelerated aging,” assessed by adult DNA methylation, predicts cardiovascular disease (CVD). Adolescent accelerated aging might predict CVD earlier. We investigated whether epigenetic age acceleration (assessed age, 17 years) was associated with adiposity/CVD risk measured (ages 17, 20, and 22 years) and projected CVD by middle age. DNA methylation measured in peripheral blood provided two estimates of epigenetic age acceleration: intrinsic (IEAA preserved across cell types) and extrinsic (EEAA dependent on cell admixture and methylation levels within each cell type). Adiposity was assessed by anthropometry, ultrasound, and dual-energy x-ray absorptiometry (ages 17, 20, and 22 years). CVD risk factors [lipids, homeostatic model assessment of insulin resistance (HOMA-IR), blood pressure, inflammatory markers] were assessed at age 17 years. CVD development by age 47 years was calculated by Framingham algorithms. Results are presented as regression coefficients per 5-year epigenetic age acceleration (IEAA/EEAA) for adiposity, CVD risk factors, and CVD development. In 995 participants (49.6% female age, 17.3 ± 0.6 years), EEAA (per 5 years) was associated with increased body mass index (BMI) of 2.4% (95% CI, 1.2% to 3.6%) and 2.4% (0.8% to 3.9%) at 17 and 22 years, respectively. EEAA was associated with increases of 23% (3% to 33%) in high-sensitivity C-reactive protein, 10% (4% to 17%) in interferon-γ–inducible protein of 10 kDa, and 4% (2% to 6%) in soluble TNF receptor 2, adjusted for BMI and HOMA-IR. EEAA (per 5 years) results in a 4% increase in hard endpoints of CVD by 47 years of age and a 3% increase, after adjustment for conventional risk factors. Accelerated epigenetic age in adolescence was associated with inflammation, BMI measured 5 years later, and probability of middle age CVD. Irrespective of whether this is cause or effect, assessing epigenetic age might refine disease prediction.
Publisher: Oxford University Press (OUP)
Date: 23-04-2021
Abstract: Do the epigenome-wide DNA methylation profiles of adolescents born from ART differ from the epigenome of naturally conceived counterparts? No significant differences in the DNA methylation profiles of adolescents born from ART [IVF or ICSI] were observed when compared to their naturally conceived, similar aged counterparts. Short-term and longer-term studies have investigated the general health outcomes of children born from IVF treatment, albeit without common agreement as to the cause and underlying mechanisms of these adverse health findings. Growing evidence suggests that the reported adverse health outcomes in IVF-born offspring might have underlying epigenetic mechanisms. The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 adolescents and young adults, conceived through ART, to compare various long-term health outcomes and DNA methylation profiles with similar aged counterparts from Generation 2 from the Raine Study. GUHS assessments were conducted between 2013 and 2017. The effect of ART on DNA methylation levels of 231 adolescents mean age 15.96 ± 1.59 years (52.8% male) was compared to 1188 naturally conceived counterparts, 17.25 ± 0.58 years (50.9% male) from the Raine Study. DNA methylation profiles from a subset of 231 adolescents (13–19.9 years) from the GUHS, generated using the Infinium Methylation Epic Bead Chip (EPIC) array were compared to 1188 profiles from the Raine Study previously measured using the Illumina 450K array. We conducted epigenome-wide association approach (EWAS) and tested for an association between the cohorts applying Firth’s bias reduced logistic regression against the outcome of ART versus naturally conceived offspring. Additionally, within the GUHS cohort, we investigated differences in methylation status in fresh versus frozen embryo transfers, cause of infertility as well as IVF versus ICSI conceived offspring. Following the EWAS analysis we investigated nominally significant probes using Gene Set Enrichment Analysis (GSEA) to identify enriched biological pathways. Finally, within GUHS we compared four estimates (Horvath, Hanuum, PhenoAge [Levine], and skin Horvath) of epigenetic age and their correlation with chronological age. Between the two cohorts, we did not identify any DNA methylation probes that reached a Bonferroni corrected P-value & 1.24E−0.7. When comparing IVF versus ICSI conceived adolescents within the GUHS cohort, after adjustment for participant age, sex, maternal smoking, multiple births, and batch effect, three methylation probes (cg15016734, cg26744878 and cg20233073) reached a Bonferroni correction of 6.31E−08. After correcting for cell count heterogeneity, two of the aforementioned probes remained significant and an additional two probes (cg 0331628 and cg 20235051) were identified. A general trend towards hypomethylation in the ICSI offspring was observed. All four measures of epigenetic age were highly correlated with chronological age and showed no evidence of accelerated epigenetic aging within their whole blood. The small s le size coupled with the use of whole blood, where epigenetic differences may occur in other tissue. This was corrected by the utilized statistical method that accounts for imbalanced s le size between groups and adjusting for cell count heterogeneity. Only a small portion of the methylome was analysed and rare in idual differences may be missed. Our findings provide further reassurance that the effects of the ART manipulations occurring during early embryogenesis, existing in the neonatal period are indeed of a transient nature and do not persist into adolescence. However, we have not excluded that alternative epigenetic mechanisms may be at play. This project was supported by NHMRC project Grant no. 1042269 and R.J.H. received funding support from Ferring Pharmaceuticals Pty Ltd. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from Merck Sharp & Dohme Corp.- Australia, Merck-Serono Australia Pty Ltd and Ferring Pharmaceuticals Pty Ltd. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. The remaining authors have no conflicts of interest.
Publisher: Wiley
Date: 22-03-2018
DOI: 10.1111/DOM.13262
Abstract: There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP‐activated protein kinase (AMPK). Activated AMPK can phosphorylate numerous substrates, including epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), usually resulting in their inhibition however, HAT1 activity may be increased. Metformin has also been reported to decrease expression of multiple histone methyltransferases, to increase the activity of the class III HDAC SIRT1 and to decrease the influence of DNMT inhibitors. There is evidence that these alterations influence the epigenome and gene expression, and may contribute to the antidiabetic properties of metformin and, potentially, may protect against cancer, cardiovascular disease, cognitive decline and aging. The expression levels of numerous microRNAs are also reportedly influenced by metformin treatment and may confer antidiabetic and anticancer activities. However, as the reported effects of metformin on epigenetic enzymes act to both increase and decrease histone acetylation, histone and DNA methylation, and gene expression, a significant degree of uncertainty exists concerning the overall effect of metformin on the epigenome, on gene expression, and on the subsequent effect on the health of metformin users.
Publisher: Wiley
Date: 2006
DOI: 10.1002/AJHB.20514
Abstract: This study investigated mortality in 568 in iduals from the Goessel Mennonite community in rural central Kansas. There were three main objectives to this research: 1) characterize mortality trends within a biologically well-defined Mennonite community 2) determine what biochemical, morphological, and physiological risk factors could be related to all-cause mortality, stratified by age and sex and 3) compare these results to previously described variables that were associated with both biological age and mortality in this population. Mortality data were obtained from three sources: Kansas Vital Records, the Social Security death index, and church records. In total, 221 (39%) in iduals were found to have died in this population between January 1980-June 2002. Analogous to the larger US population, the three leading causes of death in this community were heart disease, cancer, and stroke, accounting for 60% of all deaths. Besides advancing age, the greatest biological risk factor in this population was decreased amounts of albumin in men (relative risk, 2.47), potentially indicating underreported cases of either chronic kidney disease or frailty syndrome for males. Cox proportional hazard models demonstrated that increased amounts of total cholesterol may provide a protective effect for elderly in iduals. We conclude, based on the previously described heritability of both albumin (h(2) = 0.40) and total cholesterol (h(2) = 0.50) in this population, that underlying genetic factors associated with both chronic degenerative diseases and biological aging may have important implications for understanding mortality patterns in this community.
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.PLACENTA.2021.04.008
Abstract: The placenta is a short-lived organ, yet it shows signs of progressive ageing in the third trimester. Studies of ageing chorionic placental tissue have recently flourished, providing evidence of advanced ageing of tissues in the late ost-term (L/PT) period of gestation. However, ageing of the maternal aspect of the maternal-fetal interface, specifically the decidua basalis, is poorly understood. Here, we investigated whether the L/PT period was associated with advanced ageing and exhaustion of important decidua basalis mesenchymal stem/stromal cells (DMSCs) functions. In this study, DMSCs were isolated and characterised from early term (ET) and L/PT placental tissue and they were then investigated by employing various MSC potency and ageing assays. RNA sequencing was also performed to screen for specific microRNAs that are associated with stem cell exhaustion and ageing between ET- and L/PT-DMSCs. L/PT-DMSCs, when compared to ET-DMSCs, showed significantly lower cell proliferation and a significant higher level of cell apoptosis. L/PT-DMSCs showed significantly lower resistance to oxidative stress and a significant decrease in antioxidant capacity compared with ET-DMSCs. Western blot analysis revealed increased expression of the stress-mediated P-p38MAPK protein in L/PT-DMSCs. RNA Sequencing showed microRNA (miR) miR-516b-5p, was present at significantly lower levels in L/PT-DMSCs. Inhibition of miR-516b-5p in ET-DMSCs revealed a decline in the ability of the inhibited cells to survive in extended cell culture. These data provide the first evidence of advanced ageing and exhaustion of important stem cell functions in L/PT-DMSCs, and the involvement of specific miRs in the DMSC ageing process.
Publisher: Human Biology (The International Journal of Population Biology and Genetics)
Date: 06-2010
DOI: 10.3378/027.082.0302
Abstract: We examined mitochondrial DNA (mtDNA) variation in six Mennonite communities from Kansas (Goessel, Lone Tree, Garden View, Meridian, and Garden City) and Nebraska (Henderson) to determine their genetic structure and its relationship to population history. Mitochondrial DNA haplogroup and haplotype information were obtained from blood s les from 118 in iduals. Molecular genetic variation was analyzed using ersity measures, neutrality test statistics, spatial analysis of molecular variance (SAMOVA), and multidimensional scaling plots. The Mennonite s les exhibited eight western European mtDNA haplogroups: H, HV0, I, J, K, T, U, and X. Comparable to other populations of European descent, haplogroup H was the most frequent in all six communities and ranged from 35% in Lone Tree to 75% in Old Order Mennonites from Garden City. Fifty-eight different mtDNA haplotypes were found in these groups with only one shared among all six populations. Haplotype ersities varied from 0.81 in Goessel to 0.96 in Henderson and Garden View. Multivariate statistical analysis of these populations indicates that these Anabaptist communities formed new congregations by fissioning along familial lines. Population sub ision of these communities into congregations supports previously documented patterns of fission-fusion. These haploid molecular data provide a more accurate reflection of biological relationships between midwestern Mennonite communities than evidence based on classical genetic markers.
Publisher: Frontiers Media SA
Date: 19-03-2019
Publisher: Environmental Health Perspectives
Date: 09-2020
DOI: 10.1289/EHP6076
Publisher: Future Medicine Ltd
Date: 09-2020
Abstract: Aim: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African–American adults in the Atherosclerosis Risk in Communities study. Materials & methods: We validated significantly associated cytosine–phosphate–guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). Results & conclusion: We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1 and RAP1GAP2 that had not previously been associated with obesity-related traits.
Publisher: Oxford University Press (OUP)
Date: 21-07-2017
DOI: 10.1093/HMG/DDX290
Publisher: Wiley
Date: 04-04-2013
DOI: 10.1002/AJHB.22382
Abstract: This research examines the coevolution of languages and uniparental genetic marker (mitochondrial DNA [mtDNA] and nonrecombining Y-chromosome [NRY]) variation within five Lower Central American (Rama, Chorotega, Maléku, Zapatón-Huetar, and Abrojo-Guaymí) Amerindian groups. This pattern occurred since European contact. We examined mtDNA sequence variation from the hypervariable region 1 (HVS-1) and NRY genetic variation using short tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, and DYS439) and NRY haplogroups (Q1a3a, Q1a3*, C3b, R1b1b2, E1b1, G2a2, and I) identified through single-nucleotide polymorphisms. Phylogenetic analysis included multidimensional scaling (MDS), heterozygosity versus rii , and analysis of molecular variance (AMOVA). Eighteen mtDNA haplotypes were characterized in 131 participants with 94.6% of these assigned to the Amerindian mtDNA subclades, A2 and B2. The Amerindian NRY haplogroup, Q1a3a, was present in all five groups and ranged from 85% (Zapatón-Huetar) to 35% (Chorotega). Four populations (Rama, Chorotega, Zapatón-Huetar, and Abrojo-Guaymí) were also characterized by the presence of NRY haplogroup R1b1b2 indicative of western European admixture. Seventy NRY STR haplotypes were identified of which 69 (97%) were population specific. MDS plots demonstrated genetic similarities between Mesoamericans and northern Chibchan Amerindian populations, absent in mtDNA analyses, which is further supported by heterozygosity versus rii results. We conclude that although these linguistically related populations in geographic proximity demonstrate a high degree of paternal genetic differentiation, recent demographic events have dramatically altered the paternal genetic structure of the regions Amerindian populations.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.LUNGCAN.2013.04.018
Abstract: Malignant mesothelioma (MM) is a uniformly fatal tumour of mesothelial cells. MM is caused by exposure to asbestos however most in iduals with documented asbestos exposure do not develop MM. Although MM appears to aggregate within families, the genetics of MM susceptibility is a relatively unexplored area. The aim of the current study was to identify genetic factors that contribute to MM risk. A genome-wide association analysis of 2,508,203 single nucleotide polymorphisms (SNPs) from 428 MM cases and 1269 controls from Western Australia was performed. Additional genotyping was performed on a s le of 778 asbestos-exposed Western Australian controls. Replication of the most strongly associated SNPs was undertaken in an independent case-control study of 392 asbestos-exposed cases and 367 asbestos-exposed controls from Italy. No SNPs achieved formal genome-wide statistical significance in the Western Australian study. However, suggestive results for MM risk were identified in the SDK1, CRTAM and RASGRF2 genes, and in the 2p12 chromosomal region. These findings were not replicated in the Italian study, although there was some evidence of replication in the region of SDK1. These suggestive associations will be further investigated in sequencing and functional studies.
Publisher: Springer Science and Business Media LLC
Date: 07-2020
DOI: 10.1007/S10654-020-00662-Z
Abstract: Early life is an important window of opportunity to improve health across the full lifecycle. An accumulating body of evidence suggests that exposure to adverse stressors during early life leads to developmental adaptations, which subsequently affect disease risk in later life. Also, geographical, socio-economic, and ethnic differences are related to health inequalities from early life onwards. To address these important public health challenges, many European pregnancy and childhood cohorts have been established over the last 30 years. The enormous wealth of data of these cohorts has led to important new biological insights and important impact for health from early life onwards. The impact of these cohorts and their data could be further increased by combining data from different cohorts. Combining data will lead to the possibility of identifying smaller effect estimates, and the opportunity to better identify risk groups and risk factors leading to disease across the lifecycle across countries. Also, it enables research on better causal understanding and modelling of life course health trajectories. The EU Child Cohort Network, established by the Horizon2020-funded LifeCycle Project, brings together nineteen pregnancy and childhood cohorts, together including more than 250,000 children and their parents. A large set of variables has been harmonised and standardized across these cohorts. The harmonized data are kept within each institution and can be accessed by external researchers through a shared federated data analysis platform using the R-based platform DataSHIELD, which takes relevant national and international data regulations into account. The EU Child Cohort Network has an open character. All protocols for data harmonization and setting up the data analysis platform are available online. The EU Child Cohort Network creates great opportunities for researchers to use data from different cohorts, during and beyond the LifeCycle Project duration. It also provides a novel model for collaborative research in large research infrastructures with in idual-level data. The LifeCycle Project will translate results from research using the EU Child Cohort Network into recommendations for targeted prevention strategies to improve health trajectories for current and future generations by optimizing their earliest phases of life.
Publisher: Public Library of Science (PLoS)
Date: 09-02-2018
Publisher: MDPI AG
Date: 03-07-2202
DOI: 10.3390/BIOMEDICINES8070181
Abstract: As a part of an abnormal healing process of dermal injuries and irritation, keloid scars arise on the skin as benign fibroproliferative tumors. Although the etiology of keloid scarring remains unsettled, considerable recent evidence suggested that keloidogenesis may be driven by epigenetic changes, particularly, DNA methylation. Therefore, genome-wide scanning of methylated cytosine-phosphoguanine (CpG) sites in extracted DNA from 12 keloid scar fibroblasts (KF) and 12 control skin fibroblasts (CF) (six normal skin fibroblasts and six normotrophic fibroblasts) was conducted using the Illumina Human Methylation 450K BeadChip in two replicates for each s le. Comparing KF and CF used a Linear Models for Microarray Data (Limma) model revealed 100,000 differentially methylated (DM) CpG sites, 20,695 of which were found to be hypomethylated and 79,305 were hypermethylated. The top DM CpG sites were associated with TNKS2, FAM45B, LOC723972, GAS7, RHBDD2 and CAMKK1. Subsequently, the most functionally enriched genes with the top 100 DM CpG sites were significantly (p ≤ 0.05) associated with SH2 domain binding, regulation of transcription, DNA-templated, nucleus, positive regulation of protein targeting to mitochondrion, nucleoplasm, Swr1 complex, histone exchange, and cellular response to organic substance. In addition, NLK, CAMKK1, LPAR2, CASP1, and NHS showed to be the most common regulators in the signaling network analysis. Taken together, these findings shed light on the methylation status of keloids that could be implicated in the underlying mechanism of keloid scars formation and remission.
Publisher: Cold Spring Harbor Laboratory
Date: 03-05-2023
DOI: 10.1101/2023.05.02.23289430
Abstract: Women with a history of preecl sia (PE) have been shown to have up to five times the risk of developing later-life cardiovascular disease (CVD). While PE and CVD are known to share clinical and molecular characteristics, there are limited studies investigating their shared genomics (genetics, epigenetics or transcriptomics) variation over time. Therefore, we sought to systematically review the literature to identify longitudinal studies focused on the genomic progression to CVD following PE. A literature search of primary sources through PubMed, Scopus, Web of Science and Embase via OVID was performed. Studies published from January 1 st , 1980, to February 02 nd , 2023, that investigated genomics in PE and CVD were eligible for inclusion. Studies that did not include CVD or related risk factors as outcome, were in non-human species or focused on pregnancy complications other than PE were excluded. Included studies were screened based on Cochrane systematic review guidelines in conjunction with the PRISMA 2020 checklist. Eligible articles were further assessed for quality using the Newcastle-Ottawa scale. A total of 8929 articles were screened with 14 studies subjected to quality assessment. Following further evaluation, six studies were included for final review. All six of these studies were heterogenous in regard to CVD/risk factor as outcome, gene mapping approach, and in different targeted genes. The only common variable across all six studies was use of a case-control study design. Our results provide critical insight into the heterogeneous nature of genomic studies investigating CVD following PE and highlight the urgent need for longitudinal studies to further investigate the genetic variation underlying the progression to CVD following PE.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2011
Publisher: Research Square Platform LLC
Date: 06-10-2022
DOI: 10.21203/RS.3.RS-2114814/V1
Abstract: BACKGROUND AND AIMS : Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. APPROACH & RESULTS: We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially-methylated CpG sites (dmCpGs) for which ≥2 probes per gene remained significant across four statistical models with a nominal p-value .007. EWAS identified dmCpGs related to three genes ( ANK1, MIR10a , PTPRN2 ) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced ( ANK1 n =6, MIR10a n =7, PTPRN2 n =3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p .3 x 10 -3 ). CONCLUSIONS: We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.
Publisher: Frontiers Media SA
Date: 10-09-2019
Publisher: Cambridge University Press
Date: 08-11-2012
Publisher: Wiley
Date: 11-08-2014
DOI: 10.1002/GEPI.21829
Abstract: The analysis of whole-genome sequence (WGS) data using longitudinal phenotypes offers a potentially rich resource for the examination of the genetic variants and their covariates that affect complex phenotypes over time. We summarize eight contributions to the Genetic Analysis Workshop 18, which applied a erse array of statistical genetic methods to analyze WGS data in combination with data from genome-wide association studies (GWAS) from up to four different time points on blood pressure phenotypes. The common goal of these analyses was to develop and apply appropriate methods that utilize longitudinal repeated measures to potentially increase the analytic efficiency of WGS and GWAS data. These erse methods can be grouped into two categories, based on the way they model dependence structures: (1) linear mixed-effects (LME) models, where the random effect terms in the linear models are used to capture the dependence structures and (2) variance-components models, where the dependence structures are constructed directly based on multiple components of variance-covariance matrices for the multivariate Gaussian responses. Despite the heterogeneous nature of these analytical methods, the group came to the following conclusions: (1) the use of repeat measurements can gain power to identify variants associated with the phenotype (2) the inclusion of family data may correct genotyping errors and allow for more accurate detection of rare variants than using unrelated in iduals only and (3) fitting mixed-effects and variance-components models for longitudinal data presents computational challenges. The challenges and computational burden demanded by WGS data were addressed in the eight contributions.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
DOI: 10.1038/S41598-022-05744-4
Abstract: Advanced biological aging, as assessed through DNA methylation markers, is associated with several complex diseases. The associations between maternal DNA methylation age and preecl sia (PE) have not been fully assessed. The aim of this study was to examine if increased maternal DNA methylation age ( DNAm Age) was shown to be accelerated in women with PE when compared to women who had normotensive pregnancies. The case/control cohort available for study consisted of 166 women (89 with normotensive pregnancy, 77 with PE) recruited previously at the Royal Women’s Hospital in Melbourne, Australia. DNA methylation profiles were obtained using the Illumina EPIC Infinium array for analysis of genomic DNA isolated from whole blood. These profiles were used to calculate seven estimates of DNAm Age and included (1) Horvath, (2) Hannum, (3) Horvath Skin and Blood, (4) Wu, (5) PhenoAge, (6) telomere length and (7) GrimAge and its surrogate measures. Three measures of DNA methylation age acceleration were calculated for all seven measures using linear regression. Pearson's correlation was performed to investigate associations between chronological age and DNAm Age. Differences between chronological age and DNAm Age and epigenetic age acceleration were investigated using t-tests. No significant difference was observed for chronological age between women with PE (age = 30.53 ± 5.68) and women who had normotensive pregnancies (age = 31.76 ± 4.76). All seven DNAm Age measures were significantly correlated ( p 0.001) with chronological age. After accounting for multiple testing and investigating differences in DNAm Age between normotensive women and women with PE, only Wu DNAm Age was significant ( p = 0.001). When examining differences for epigenetic age acceleration between PE and normotensive women Hannum, Wu, and PhenoAge DNAm Age estimates ( p 0.001) were significant for both epigenetic age acceleration and intrinsic acceleration models. We found that accelerated maternal DNAm Age is increased in women with PE in some models of epigenetic aging. This research underlines the importance for further investigation into the potential changes of differential DNA methylation in PE.
Publisher: Elsevier BV
Date: 07-2015
Publisher: MDPI AG
Date: 10-04-2019
Abstract: The potential anticancer effects of statins—a widely used class of cholesterol lowering drugs—has generated significant interest, as has the use of epigenetic modifying drugs such as HDAC and DNMT inhibitors. We set out to investigate the effect of statin drugs on epigenetic modifications in multiple cell lines, including hepatocellular carcinoma, breast carcinoma, leukemic macrophages, cervical adenocarcinoma, and insulin-secreting cells, as well as liver extracts from statin-treated C57B1/6J mice. Cells or cell extracts were treated with statins and with established epigenetic modulators, and HDAC, HAT, and DNMT activities were quantified. We also examined histone acetylation by immunoblotting. Statins altered neither HDAC nor HAT activity. Accordingly, acetylation of histones H3 and H4 was unchanged with statin treatment. However, statins tended to increase DNMT activity. These results indicate that direct inhibition of the major classes of epigenetic modifying enzymes, as previously reported elsewhere, is unlikely to contribute to any anticancer effects of statins. This study concerned global effects on epigenetic enzyme activities and histone acetylation whether statins influence epigenetic modifications in certain genomic regions, cannot be ruled out and remains to be investigated.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2019
Publisher: Research Square Platform LLC
Date: 27-04-2022
DOI: 10.21203/RS.3.RS-1547958/V1
Abstract: The contribution of multiple sclerosis relapses to worsening of disability, and vice-versa, remains unclear. Vitamin D supplementation (VitD) and disease modifying therapies (DMTs) are potential modulators of this association. Understanding how these endo-phenotypes interact may provide insights to disease pathogenesis and treatment practice. Here, we examined independent associations between relapses and treatment and the risk of worsening of disability, and vice-versa. We find suggestive evidence that early relapses predict early worsening of disability but do not contribute to long-term worsening. Conversely, the effects of worsening of disability on relapse risk was pronounced and persisted. VitD and DMTs interacted significantly to markedly reduce the risk of future relapses and worsening of disability, particularly when commenced early. Personalised real-time survival probabilities revealed in iduals having higher risk of future worsening. Worsening of disability in ROMS occurs in ways not clearly tied to relapses and is strongly linked to an increased risk of future relapses.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2016
DOI: 10.1038/SREP26846
Abstract: Age is well-known to be a significant factor in both disease pathology and response to treatment, yet the molecular changes that occur with age in humans remain ill-defined. Here, using transcriptome profiling of healthy human male skin, we demonstrate that there is a period of significantly elevated, transcriptome-wide expression changes occurring predominantly in middle age. Both pre and post this period, the transcriptome appears to undergo much smaller, linear changes with increasing age. Functional analysis of the transient changes in middle age suggest a period of heightened metabolic activity and cellular damage associated with NF-kappa-B and TNF signaling pathways. Through meta-analysis we also show the presence of global, tissue independent linear transcriptome changes with age which appear to be regulated by NF-kappa-B. These results suggest that aging in human skin is associated with a critical mid-life period with widespread transcriptome changes, both preceded and proceeded by a relatively steady rate of linear change in the transcriptome. The data provides insight into molecular changes associated with normal aging and will help to better understand the increasingly important pathological changes associated with aging.
Publisher: Wiley
Date: 2011
DOI: 10.1002/GEPI.20653
Abstract: The joint analysis of multiple disease phenotypes aims to increase statistical power and potentially identify pleiotropic genes involved in the biological development of common chronic diseases. As next-generation sequencing data become more common, it will be important to consider ways to maximize the ability to detect rare variants within the human genome. The two exome sequence data sets provided for analysis at Genetic Analysis Workshop 17 (GAW17) offered three quantitative phenotypes related to disease status in 200 simulated replicates for both families and unrelated in iduals. Participants in Group 10 addressed the challenges and potential uses of next-generation sequencing data to identify causal variants through a broad range of statistical methods. These methods included investigating multiple phenotypes either through data reduction or joint methods, using family or unrelated in iduals, and reducing the dimensionality inherent in these data. Most of the research teams regarded the use of multiple phenotypes as a means of increasing analytical power and as a way to clarify the biology of complex disease. Three major observations were gleaned from these Group 10 contributions. First, family and unrelated case-control s les are suited to finding different types of variants. In addition, collapsing either phenotypes or genotypes can reduce the dimensionality of the data and alleviate some of the problems of multiple testing. Finally, we were able to demonstrate in certain cases that performing a joint analysis of disease status and a quantitative trait can improve statistical power.
Publisher: Springer Science and Business Media LLC
Date: 10-2016
Publisher: Informa UK Limited
Date: 26-05-2023
Publisher: Springer Science and Business Media LLC
Date: 06-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-10-2022
DOI: 10.1097/J.PAIN.0000000000002411
Abstract: There is a need to better understand biological factors that increase the risk of persistent musculoskeletal (MSK) pain and heightened pain sensitivity. Knowing the heritability (how genes account for differences in people's traits) can enhance the understanding of genetic vs environmental influences of pain and pain sensitivity. However, there are gaps in current knowledge, including the need for intergenerational studies to broaden our understanding of the genetic basis of pain. Data from Gen1 and Gen2 of the Raine Study were used to investigate the heritability of MSK pain and pressure and cold pain sensitivity. Participants included parents (Gen1, n = 1092) and their offspring (Gen2, n = 688) who underwent a battery of testing and questionnaires including pressure and cold pain threshold testing and assessments of physical activity, sleep, MSK pain, mental health, and adiposity. Heritability estimates were derived using the Sequential Oligogenic Linkage Analysis Routines software. Heritability estimates for MSK pain and pressure pain sensitivity were significant, accounting for between 0.190 and 0.289 of the variation in the phenotype. By contrast, heritability of cold pain sensitivity was not significant. This is the largest intergenerational study to date to comprehensively investigate the heritability of both MSK pain and pain sensitivity, using robust statistical analysis. This study provides support for the heritability of MSK pain and pain sensitivity to pressure, suggesting the need for further convergence of genetic and environmental factors in models for the development or maintenance of these pain disorders.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2020
DOI: 10.1186/S13073-020-00810-W
Abstract: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P 1.06 × 10 −7 , with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P enrichment = 1 childhood P enrichment = 2.00 × 10 −4 adolescence P enrichment = 2.10 × 10 −7 ). There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
Publisher: Wiley
Date: 03-03-2023
DOI: 10.1111/APA.16719
Abstract: Investigate if childhood measures of sleep health are associated with epigenetic age acceleration in late adolescence. Parent‐reported sleep trajectories from age 5 to 17, self‐reported sleep problems at age 17, and six measures of epigenetic age acceleration at age 17 were studied in 1192 young Australians from the Raine Study Gen2. There was no evidence for a relationship between the parent‐reported sleep trajectories and epigenetic age acceleration ( p ≥ 0.17). There was a positive cross‐sectional relationship between self‐reported sleep problem score and intrinsic epigenetic age acceleration at age 17 ( b = 0.14, p = 0.04), which was attenuated after controlling for depressive symptom score at the same age ( b = 0.08, p = 0.34). Follow‐up analyses suggested this finding may represent greater overtiredness and intrinsic epigenetic age acceleration in adolescents with higher depressive symptoms. There was no evidence for a relationship between self‐ or parent‐reported sleep health and epigenetic age acceleration in late adolescence after adjusting for depressive symptoms. Mental health should be considered as a potential confounding variable in future research on sleep and epigenetic age acceleration, particularly if subjective measures of sleep are used.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JID.2021.08.445
Abstract: Scars are maintained for life and increase in size during periods of growth such as puberty. Epigenetic changes in fibroblasts after injury may underpin the maintenance and growth of scars. In this study, we combined methylome and transcriptome data from normotrophic mature scar and contralateral uninjured normal skin fibroblasts to identify potential regulators of scar maintenance. In total, 219 significantly differentially expressed and 1,199 significantly differentially methylated promoters were identified, of which there were 12 genes both significantly differentially methylated and expressed. Of these, the two transcription factors, FOXF2 and MKX, were selected for further analysis. Immunocytochemistry and qPCR suggested that FOXF2 but not MKX had elevated expression in scar fibroblasts. Using RNA sequencing, FOXF2 knockdown was shown to significantly reduce the expression of extracellular matrix‒related genes, whereas MKX did not appear to affect similar pathways. Finally, FOXF2 knockdown was also shown to significantly decrease collagen I production in scar and keloid fibroblasts. This study provides insights into the maintenance of normotrophic scar, suggesting that FOXF2 is an important regulator of this process. Targeting genes responsible for maintenance of scar phenotype may ameliorate scar appearance and improve patient outcomes in the future.
Publisher: Frontiers Media SA
Date: 05-09-2019
Publisher: Springer Science and Business Media LLC
Date: 09-2021
Publisher: American Academy of Sleep Medicine (AASM)
Date: 06-2022
DOI: 10.5664/JCSM.9886
Publisher: Informa UK Limited
Date: 08-02-2021
Publisher: Oxford University Press (OUP)
Date: 03-07-2010
DOI: 10.1093/HMG/DDQ274
Publisher: Springer Science and Business Media LLC
Date: 09-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-04-2022
DOI: 10.1002/HEP4.1955
Abstract: Genome‐wide association studies in adults have identified variants in hydroxysteroid 17‐beta dehydrogenase 13 ( HSD17B13 ) and mitochondrial amidoxime reducing component 1 ( MTARC1 ) as protective against nonalcoholic fatty liver disease (NAFLD). We aimed to test their association with pediatric NAFLD liver histology and investigate their function using metabolomics. A total of 1450 children (729 with NAFLD, 399 with liver histology) were genotyped for rs72613567T TA in HSD17B13 , rs2642438G A in MTARC1 , and rs738409C G in patatin‐like phospholipase domain‐containing protein 3 ( PNPLA3 ). Genotype–histology associations were tested using ordinal regression. Untargeted hepatic proteomics and plasma lipidomics were performed in a subset of children. We found rs72613567T TA in HSD17B13 to be associated with lower odds of NAFLD diagnosis (odds ratio, 0.7 95% confidence interval, 0.6–0.9) and a lower grade of portal inflammation ( p 0.001). rs2642438G A in MTARC1 was associated with a lower grade of hepatic steatosis ( p = 0.02). Proteomics found reduced expression of HSD17B13 in carriers of the protective ‐TA allele. MTARC1 levels were unaffected by genotype. Both variants were associated with down‐regulation of fibrogenic pathways. HSD17B13 perturbs plasma phosphatidylcholines and triglycerides. In silico modeling suggested p.Ala165Thr disrupts the stability and metal binding of MTARC1 . Conclusion: Both HSD17B13 and MTARC1 variants are associated with less severe pediatric NAFLD. These results provide further evidence for shared genetic mechanisms between pediatric and adult NAFLD.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Oxford University Press (OUP)
Date: 11-2021
DOI: 10.1530/EJE-21-0614
Abstract: Genetic factors underpin the narrow intrain idual variability of thyroid function, although precise contributions of environmental vs genetic factors remain uncertain. We sought to clarify the heritability of thyroid function traits and thyroid peroxidase antibody (TPOAb) positivity and identify single nucleotide polymorphisms (SNPs) contributing to the trait variance. Heritability of thyroid-stimulating hormone (TSH), free T4 (fT4), free T3 (fT3) and TPOAb in a cohort of 2854 euthyroid, dizygous and monozygous twins (age range 11.9–16.9 years) from the Brisbane Longitudinal Twin Study (BLTS) was assessed using structural equation modelling. A genome-wide analysis was conducted on 2832 of these in iduals across 7 522 526 SNPs as well as gene-based association analyses. Replication analysis of the association results was performed in the Raine Study ( n = 1115) followed by meta-analysis to maximise power for discovery. Heritability of thyroid function parameters in the BLTS was 70.8% (95% CI: 66.7–74.9%) for TSH, 67.5% (59.8–75.3%) for fT4, 59.7% (54.4–65.0%) for fT3 and 48.8% (40.6–56.9%) for TPOAb. The genome-wide association study (GWAS) in the discovery cohort identified a novel association between rs2026401 upstream of NCOA3 and TPOAb. GWAS meta-analysis found associations between TPOAb and rs445219, also near NCOA3 , and fT3 and rs12687280 near SERPINA7 . Gene-based association analysis highlighted SERPINA7 for fT3 and NPAS3 for fT4. Our findings resolve former contention regarding heritability estimates of thyroid function traits and TPOAb positivity. GWAS and gene-based association analysis identified variants accounting for a component of this heritability.
Publisher: Public Library of Science (PLoS)
Date: 10-01-2013
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 02-03-2020
DOI: 10.1186/S13073-020-0716-9
Abstract: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P 1.06 × 10 − 7 , of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
Location: United States of America
Start Date: 2021
End Date: 2023
Funder: National Health and Medical Research Council
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