ORCID Profile
0000-0002-2444-5675
Current Organisations
The University of Edinburgh
,
NHS Lothian
,
University of Münster
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 02-2016
DOI: 10.1038/NN.4228
Publisher: Cold Spring Harbor Laboratory
Date: 12-07-2022
DOI: 10.1101/2022.07.12.22277553
Abstract: Schizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies (GWAS) have reported an increasing number of risk-associated variants and polygenic risk scores (PRS) now explain 17% of the variance in the disorder. There exists substantial heterogeneity in the effect of these variants and aggregating them based on biologically relevant functions may provide mechanistic insight into the disorder. Using the largest schizophrenia GWAS to date, we calculated PRS based on 5 gene-sets previously found to contribute to the pathophysiology of schizophrenia: the postsynaptic density of excitatory synapses, postsynaptic membrane, dendritic spine, axon, and histone H3-K4 methylation gene-sets. We associated each PRS, along with respective whole-genome PRS (excluding single nucleotide polymorphisms in each gene-set), with neuroimaging (N ,000 cortical, subcortical, and white matter microstructure) and clinical (N ,000 psychotic-like experiences including conspiracies, communications, voices, visions, and distress) variables in healthy subjects in UK Biobank. A number of clinical and neuroimaging variables were significantly associated with the axon gene-set (psychotic-like communications: β=0.0916, p FDR =0.04, parahippoc al gyrus volume: β=0.0156, p FDR =0.03, FA thalamic radiations: β=-0.014, p FDR =0.036, FA posterior thalamic radiations: β=-0.016, p FDR =0.048), postsynaptic density gene-set (distress due to psychotic-like experiences: β=0.0588, p FDR =0.02, global surface area: β=-0.012, p FDR =0.034, and cingulate lobe surface area: β=-0.014, p FDR =0.04), and histone gene-set (entorhinal surface area: β=-0.016, p FDR =0.035). In the associations above, whole-genome PRS were significantly associated with psychotic-like communications (β=0.2218, p FDR =1.34×10 −7 ), distress (β=0.1943, p FDR =7.28×10 −16 ), and FA thalamic radiations (β=-0.0143, p FDR =0.036). Permutation analysis carried out for these associations revealed that they were not due to chance. Our results indicate that genetic variation in 3 gene-sets relevant to schizophrenia (axon, postsynaptic density, histone) may confer risk for the disorder through effects on a number of neuroimaging variables that have previously been implicated in schizophrenia. As neuroimaging associations were stronger for gene-set PRS than whole-genome PRS, findings here highlight that selection of biologically relevant variants may address the heterogeneity of the disorder by providing further mechanistic insight into schizophrenia.
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.BIOPSYCH.2022.02.959
Abstract: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre erinatal periods may be reflected in in idual variations in cortical surface area later in life. Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 in iduals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre erinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
Publisher: Proceedings of the National Academy of Sciences
Date: 28-03-2023
Abstract: Left–right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small s les and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case–control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected in iduals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected in iduals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case–control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case–control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case–control status. Subtle case–control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: Elsevier BV
Date: 11-2018
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: 19-03-2018
DOI: 10.1038/S41537-018-0047-7
Abstract: Recent work has highlighted a possible role for altered epigenetic modifications, including differential DNA methylation, in susceptibility to psychiatric illness. Here, we investigate blood-based DNA methylation in a large family where a balanced translocation between chromosomes 1 and 11 shows genome-wide significant linkage to psychiatric illness. Genome-wide DNA methylation was profiled in whole-blood-derived DNA from 41 in iduals using the Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, CA). We found significant differences in DNA methylation when translocation carriers ( n = 17) were compared to related non-carriers ( n = 24) at 13 loci. All but one of the 13 significant differentially methylated positions (DMPs) mapped to the regions surrounding the translocation breakpoints. Methylation levels of five DMPs were associated with genotype at SNPs in linkage disequilibrium with the translocation. Two of the five genes harbouring significant DMPs, DISC1 and DUSP10 , have been previously shown to be differentially methylated in schizophrenia. Gene Ontology analysis revealed enrichment for terms relating to neuronal function and neurodevelopment among the genes harbouring the most significant DMPs. Differentially methylated region (DMR) analysis highlighted a number of genes from the MHC region, which has been implicated in psychiatric illness previously through genetic studies. We show that inheritance of a translocation linked to major mental illness is associated with differential DNA methylation at loci implicated in neuronal development/function and in psychiatric illness. As genomic rearrangements are over-represented in in iduals with psychiatric illness, such analyses may be valuable more widely in the study of these conditions.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2019
Publisher: Springer Science and Business Media LLC
Date: 26-07-2022
DOI: 10.1038/S41398-022-02057-Y
Abstract: In iduals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P in iduals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P in iduals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or ergence of neuroanatomical profiles between in iduals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in in iduals at CHR-P. CHR-P in iduals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical ergence in global SA, CT and SV profiles in CHR-P in iduals compared with HC. Normative PBSI analysis identified 11 CHR-P in iduals (0.70%) with marked deviation ( .5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater ergence in neuroanatomical profiles at an in idual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.
Publisher: American Psychiatric Association Publishing
Date: 03-2017
Publisher: F1000 Research Ltd
Date: 16-07-2021
DOI: 10.12688/WELLCOMEOPENRES.15538.2
Abstract: STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables physical measures questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder laboratory s les cognitive tests and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures relevant to the study of depression, psychological resilience, and cognition. In addition, routinely collected historic NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 21-08-2019
Publisher: Elsevier BV
Date: 07-2011
DOI: 10.1016/J.BIOPSYCH.2011.01.032
Abstract: It is well established that schizophrenia is associated with structural brain abnormalities, but whether these are static or progress over time remains controversial. A systematic review of longitudinal volumetric studies using region-of-interest structural magnetic resonance imaging in patients with schizophrenia and healthy control subjects. The percentage change in volume between scans for each brain region of interest was obtained, and data were combined using random effects meta-analysis. Twenty-seven studies were included in the meta-analysis, with 928 patients and 867 control subjects, and 32 different brain regions of interest. Subjects with schizophrenia showed significantly greater decreases over time in whole brain volume, whole brain gray matter, frontal gray and white matter, parietal white matter, and temporal white matter volume, as well as larger increases in lateral ventricular volume, than healthy control subjects. The time between baseline and follow-up magnetic resonance imaging scans ranged from 1 to 10 years. The differences between patients and control subjects in annualized percentage volume change were -.07% for whole brain volume, -.59% for whole brain gray matter, -.32% for frontal white matter, -.32% for parietal white matter, -.39% for temporal white matter, and +.36% for bilateral lateral ventricles. These findings suggest that schizophrenia is associated with progressive structural brain abnormalities, affecting both gray and white matter. We found no evidence to suggest progressive medial temporal lobe involvement but did find evidence that this may be partly explained by heterogeneity between studies in patient age and illness duration. The causes and clinical correlates of these progressive brain changes should now be the focus of investigation.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2015
DOI: 10.1038/NATURE14101
Publisher: Springer Science and Business Media LLC
Date: 25-08-2013
DOI: 10.1038/NG.2742
Publisher: Oxford University Press (OUP)
Date: 17-07-2018
DOI: 10.1093/BRAIN/AWY175
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
Publisher: Springer Science and Business Media LLC
Date: 17-10-2017
DOI: 10.1038/MP.2017.170
Publisher: Elsevier BV
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 29-08-2023
DOI: 10.1038/S41380-023-02221-W
Abstract: Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 in iduals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subs led data from 944 in iduals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of in iduals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2019
DOI: 10.1038/S41386-019-0521-6
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: MDPI AG
Date: 06-10-2023
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 Stephen Lawrie.