ORCID Profile
0000-0002-0490-0845
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 20-10-2022
DOI: 10.1101/2022.10.18.22281194
Abstract: Preterm birth is closely associated with a phenotype that includes brain dysmaturation and neurocognitive impairment, commonly termed Encephalopathy of Prematurity (EoP), of which systemic inflammation is considered a key driver. DNA methylation (DNAm) signatures of inflammation from peripheral blood associate with poor brain imaging outcomes in adult cohorts. However, the robustness of DNAm inflammatory scores in infancy, their relation to comorbidities of preterm birth characterised by inflammation, neonatal neuroimaging metrics of EoP, and saliva cross-tissue applicability are unknown. Using salivary DNAm from 258 neonates (n = 155 preterm, gestational age at birth 23.28 – 34.84 weeks, n = 103 term, gestational age at birth 37.00 – 42.14 weeks), we investigated the impact of a DNAm surrogate for C-reactive protein (DNAm CRP) on brain structure and other clinically defined inflammatory exposures. We assessed i) if DNAm CRP estimates varied between preterm infants at term equivalent age and term infants, ii) how DNAm CRP related to different types of inflammatory exposure (maternal, fetal and postnatal) and iii) whether elevated DNAm CRP associated with poorer measures of neonatal brain volume and white matter connectivity. Higher DNAm CRP was linked to preterm status (−0.0107 ± 0.0008, compared with - 0.0118 ± 0.0006 among term infants p 0.001), as well as perinatal inflammatory diseases, including histologic chorioamnionitis, sepsis, bronchopulmonary dysplasia, and necrotising enterocolitis (OR range |2.00 | to |4.71|, p 0.01). Preterm infants with higher DNAm CRP scores had lower brain volume in deep grey matter, white matter, and hippoc i and amygdalae (β range |0.185| to |0.218|). No such associations were observed for term infants. Association magnitudes were largest for measures of white matter microstructure among preterms, where elevated epigenetic inflammation associated with poorer global measures of white matter integrity (β range |0.206| to |0.371|), independent of other confounding exposures. Epigenetic biomarkers of inflammation provide an index of innate immunity in relation to neonatal health. Such DNAm measures complement biological and clinical metrics when investigating the determinants of neurodevelopmental differences.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Springer Science and Business Media LLC
Date: 03-2010
DOI: 10.1038/NMETH.1431
Publisher: Elsevier BV
Date: 07-2014
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: American Association for Cancer Research (AACR)
Date: 14-06-2018
DOI: 10.1158/0008-5472.CAN-17-3034
Abstract: Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN lification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. On the basis of a Bayesian learning network model in which we compared pretumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA–mRNA interaction network. Among the miRNA–mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN- lified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo. Together, these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis. Significance: Network modeling of miRNA–mRNA regulatory interactions in a mouse model of neuroblastoma identifies miR-204 as a tumor suppressor and negative regulator of MYCN. Cancer Res 78(12) 3122–34. ©2018 AACR.
Publisher: Proceedings of the National Academy of Sciences
Date: 15-05-2018
Abstract: Left–right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population and how biological factors such as age, sex, and genetic variation affect these asymmetries. Here, we describe by far the largest-ever study of cerebral cortical asymmetry, based on data from 17,141 participants. We found a global anterior–posterior “torque” pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an online resource that will serve future studies of human brain anatomy in health and disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2018
DOI: 10.1161/STROKEAHA.118.020689
Abstract: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. In the discovery s le we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P ×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221 P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524 P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication s les yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
Publisher: Elsevier BV
Date: 05-2015
Publisher: Springer Science and Business Media LLC
Date: 18-01-2017
DOI: 10.1038/NCOMMS13624
Abstract: The hippoc al formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippoc al volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippoc al structure here we perform a genome-wide association study (GWAS) of 33,536 in iduals and discover six independent loci significantly associated with hippoc al volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2 , DPP4 and MAST4 ) and one is found 200 kb upstream of SHH . A hippoc al subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippoc al volume are also associated with increased risk for Alzheimer’s disease ( r g =−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippoc al volume and risk for neuropsychiatric illness.
Publisher: Springer Science and Business Media LLC
Date: 18-06-2009
DOI: 10.1007/S00415-009-5202-7
Abstract: MR diffusion erfusion mismatch may help identify patients for acute stroke treatment, but mixed results from clinical trials suggest that further evaluation of the mismatch concept is required. To work effectively, mismatch should predict prognosis on arrival at hospital. We assessed mismatch duration and associations with functional outcome in acute stroke. We recruited consecutive patients with acute stroke, recorded baseline clinical variables, performed MR diffusion and perfusion imaging and assessed 3-month functional outcome. We assessed practicalities, agreement between mismatch on mean transit time (MTT) or cerebral blood flow (CBF) maps, visually and with lesion volume, and the relationship of each to functional outcome. Of 82 patients starting imaging, 14 (17%) failed perfusion imaging. Overall, 42% had mismatch (56% at <6 h 41% at 12-24 h 23% at 24-48 h). Agreement for mismatch by visual versus volume assessment was fair using MTT (kappa 0.59, 95% CI 0.34-0.84) but poor using CBF (kappa 0.24, 95% CI 0.01-0.48). Mismatch by either definition was not associated with functional outcome, even when the analysis was restricted to just those with mismatch. Visual estimation is a reasonable proxy for mismatch volume on MTT but not CBF. Perfusion is more difficult for acute stroke patients than diffusion imaging. Mismatch is present in many patients beyond 12 h after stroke. Mismatch alone does not distinguish patients with good and poor prognosis both can do well or poorly. Other factors, e.g. reperfusion, may influence outcome more strongly, even in patients without mismatch.
Publisher: Springer Science and Business Media LLC
Date: 26-09-2018
DOI: 10.1038/S41467-018-06234-W
Abstract: The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly in iduals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes ( ρ genetic = −0.59, p -value = 3.14 × 10 −6 ), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
Publisher: Cold Spring Harbor Laboratory
Date: 10-04-2021
DOI: 10.1101/2021.04.08.21255064
Abstract: Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation (DNAm) is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes (DMPs) or regions (DMRs). We tested the hypothesis that variation in DNAm could underpin the association between preterm birth and atypical brain development by linking DMPs with measures of white matter connectivity derived from diffusion MRI metrics: peak width of skeletonised mean diffusivity (PSMD), fractional anisotropy (PSFA) and neurite density index (PSNDI). Gestational age at birth was associated with widespread differential methylation, with genome-wide significant associations observed for 8,870 CpG probes ( p .6×10 −8 ) and 1,767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component (PC1) that explained 23.5% of variance in DNAm, and this was negatively associated with gestational age at birth. PC1 was associated with PSMD (β=0.349, p =8.37×10 −10 ) and PSNDI (β=0.364, p =4.15×10 −5 ), but not with PSFA (β=−0.035, p =0.510) these relationships mirrored the imaging metrics’ associations with gestational age at birth. Gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNAm and image markers of white matter tract microstructure suggest that variation in DNAm may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterises atypical brain development in preterm infants.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
Publisher: Cold Spring Harbor Laboratory
Date: 05-11-2018
DOI: 10.1101/460444
Abstract: DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small s le sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3,337 in iduals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippoc us, thalamus and nucleus accumbens (NAcc) –three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of in idual CpGs revealed genome-wide significant associations with hippoc al volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. CpG sites associated with hippoc us volume were significantly enriched within cancer-related genes and within regulatory elements containing the transcriptionally repressive histone H3K27 tri-methylation mark that is vital for stem cell fate specification. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippoc al volume. DNA methylation at these loci affected expression of proximal genes involved in in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
Publisher: Cold Spring Harbor Laboratory
Date: 13-10-2020
DOI: 10.1101/2020.10.08.20205245
Abstract: Low-level chronic inflammation increases with age and is associated with cognitive decline. DNA methylation (DNAm) levels may provide more stable reflections of cumulative inflammatory burden than traditional serum approaches. Using structural and diffusion MRI data from 521 in iduals aged 73, we demonstrate that a DNAm proxy of C-Reactive Protein (CRP) shows significantly (on average 6.4-fold) stronger associations with brain structural outcomes than serum CRP. We additionally find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial and memory) cognitive functioning, and that brain structure partially mediates this CRP-cognitive association (up to 29.4%), dependent on lifestyle and health factors. These data support the hypothesis that chronic systemic inflammation may contribute to neurodegenerative brain changes which underlie differences in cognitive ability in later life. DNA methylation-based predictors could be used as proxies for chronic inflammatory status.
Publisher: Cambridge University Press (CUP)
Date: 02-10-2015
DOI: 10.1017/THG.2015.71
Abstract: Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippoc al, and total brain volumes to estimate polygenic scores for these traits in three Scottish s les: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115–8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction s les that closely match the demographics of the GWA s les from which prediction is based. Ideally, these analyses should be repeated in larger s les with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-03-2006
DOI: 10.1212/01.WNL.0000202524.43850.81
Abstract: MR diffusion-weighted imaging (DWI) shows acute ischemic lesions early after stroke so it might improve outcome prediction and reduce s le sizes in stroke treatment trials. Previous studies of DWI and outcome produced conflicting results. To determine whether DWI lesion characteristics independently predict outcome in a broad range of patients with acute stroke. The authors recruited hospital-admitted patients with all severities of suspected stroke, assessed stroke severity on the NIH Stroke Scale (NIHSS), performed early brain DWI, and assessed outcome at 3 months (modified Rankin Scale). Clinical data and DWI lesion parameters were evaluated in a logistic regression model to identify independent predictors of outcome at 3 months and a previously described "Three-Item Scale" (including DWI) was tested for outcome prediction. Among 82 patients (mean NIHSS 7.1 [+/-6.3 SD]), the only independent outcome predictors were age and stroke severity. Neither DWI lesion volume nor apparent diffusion coefficient nor the previously described Three-Item Scale predicted outcome independently. Comparison with previous studies suggested that DWI may predict outcome only in patients with more severe cortical ischemic strokes. Across a broad range of stroke severities, diffusion-weighted imaging (DWI) did not predict outcome beyond that of key clinical variables. Thus, DWI is unlikely to reduce s le sizes in acute stroke trials assessing functional outcome, especially where estimated treatment effects are modest.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-12-2015
Publisher: Springer Science and Business Media LLC
Date: 13-10-2016
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 11-2013
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: Springer Science and Business Media LLC
Date: 25-04-2017
DOI: 10.1038/MP.2017.62
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-12-2021
DOI: 10.1212/WNL.0000000000012997
Abstract: To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes. At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption, body mass index), and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation—serum C-reactive protein (CRP)—and an epigenetic measure (DNA methylation [DNAm] signature of CRP). Linear models were used to examine the inflammation–brain health associations mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure, and cognitive functioning. We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = −0.197, 95% confidence interval [CI] −0.28 to −0.12, p FDR = 8.42 × 10 −6 ), gray matter volume (β = −0.200, 95% CI −0.28 to −0.12, p FDR = 1.66 × 10 −5 ), and white matter volume (β = −0.150, 95% CI −0.23 to −0.07, p FDR = 0.001) and regional brain atrophy. We also find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial, and memory) cognitive functioning and that brain structure partially mediates this CRP–cognitive association (up to 29.7%), dependent on lifestyle and health factors. These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes that underlie differences in cognitive ability in later life and highlight the potential of DNAm proxies for indexing chronic inflammatory status. This study provides Class II evidence that a DNAm signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.
Publisher: Cold Spring Harbor Laboratory
Date: 10-2017
DOI: 10.1101/196634
Abstract: Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across in iduals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy in iduals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippoc al gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets ( N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders. Left-right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population, and how biological factors such as age, sex and genetic variation affect these asymmetries. Here we describe by far the largest ever study of cerebral cortical brain asymmetry, based on data from 17,141 participants. We found a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an on-line resource that will serve future studies of human brain anatomy in health and disease.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2237
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Mark Bastin.