ORCID Profile
0000-0001-8967-683X
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 28-10-2023
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-0044
DOI: 10.1101/2021.03.10.21253201
Abstract: The environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes in adulthood are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data was assayed at 713,522 CpG sites from 9,537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive data on genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes were conducted using DNA methylation data collected from adult whole blood s les. Two genes involved with different developmental pathways (PRICKLE2 and ABI1) were annotated to CpG sites associated with preterm birth (P 1.27 × 10 −9 ). A further two genes important to the development of sensory pathways (SOBP and RPGRIP1) were annotated to sites associated with low birth weight (P 4.35 × 10 −8 ). Genes and gene-sets annotated from associated CpGs sites and methylation profile scores were then used to quantify any overlap between the early life environment and mental health traits. However, there was no evidence of any overlap after applying a correction for multiple testing. Time of year of birth was found to be associated with a significant difference in estimated lymphocyte and neutrophil counts. Early life environments influence the risk of developing mental health disorders later in life however, this study provides no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.
Publisher: Cold Spring Harbor Laboratory
Date: 05-07-2021
DOI: 10.1101/2021.06.30.21259731
Abstract: Depression is a disabling and highly prevalent condition where genetic and epigenetic differences, such as DNA methylation (DNAm), contribute to prediction of disease liability. We investigated the association between polygenic risk scores (PRS) for depression and DNAm by conducting a methylome-wide association study (MWAS) in Generation Scotland (N=8,898, mean age=49.8 years) with replication in the Lothian Birth Cohorts of 1921 and 1936 and adults in Avon Longitudinal Study of Parents and Children (ALSPAC) (N combined =2,049, mean age=79.1, 69.6 and 47.2 years, respectively). We also conducted a replication MWAS in the ALSPAC children (N=423, mean age=17.1 years). Wide-spread associations were found between PRS constructed using genetic risk variants for depression and DNAm in cytosine-guanine dinucleotide (CpG) probes that localised to genes involved in immune responses and neural development (N CpG =599, p Bonferroni .05, p .5×10 −8 ). The effect sizes for the significant associations were highly correlated between the discovery and replication s les in adults (r=0.83) and in adolescents (r=0.76). Additional analysis on the methylome-wide associations was conducted for each lead genetic risk variant. Over 40% of the independent genetic risk variants showed associations with CpG probe DNAm located in both the same ( cis ) and distal probes ( trans ) to the genetic loci (p Bonferroni .045). Subsequent Mendelian randomisation analysis showed that DNAm and depression are mutually causal (p FDR .039), and there is a greater number of causal effects found from DNAm to depression (DNAm to depression: p FDR ranged from 0.045 to 2.06×10 −120 depression to DNAm: p FDR ranged from 0.046 to 2.1×10 −23 ). Polygenic risk scores for depression, especially those constructed from genome-wide significant genetic risk variants, showed epigenome-wide methylation association differences in the methylome associated with immune responses and brain development. We also found evidence from Mendelian randomisation evidence that DNAm may be causal to depression, as well as a causal consequence of depression.
Publisher: Cold Spring Harbor Laboratory
Date: 09-10-2018
DOI: 10.1101/433367
Abstract: Major depression is a debilitating psychiatric illness that is typically associated with low mood, anhedonia and a range of comorbidities. Depression has a heritable component that has remained difficult to elucidate with current s le sizes due to the polygenic nature of the disorder. To maximise s le size, we meta-analysed data on 807,553 in iduals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 gene-sets associated with depression, including both genes and gene-pathways associated with synaptic structure and neurotransmission. Further evidence of the importance of prefrontal brain regions in depression was provided by an enrichment analysis. In an independent replication s le of 1,306,354 in iduals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant following multiple testing correction. Based on the putative genes associated with depression this work also highlights several potential drug repositioning opportunities. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding aetiology and developing new treatment approaches.
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: Springer Science and Business Media LLC
Date: 16-04-2018
DOI: 10.1038/S41467-018-03819-3
Abstract: Depression is a polygenic trait that causes extensive periods of disability. Previous genetic studies have identified common risk variants which have progressively increased in number with increasing s le sizes of the respective studies. Here, we conduct a genome-wide association study in 322,580 UK Biobank participants for three depression-related phenotypes: broad depression, probable major depressive disorder (MDD), and International Classification of Diseases (ICD, version 9 or 10)-coded MDD. We identify 17 independent loci that are significantly associated ( P 5 × 10 −8 ) across the three phenotypes. The direction of effect of these loci is consistently replicated in an independent s le, with 14 loci likely representing novel findings. Gene sets are enriched in excitatory neurotransmission, mechanosensory behaviour, post synapse, neuron spine and dendrite functions. Our findings suggest that broad depression is the most tractable UK Biobank phenotype for discovering genes and gene sets that further our understanding of the biological pathways underlying depression.
Publisher: Cold Spring Harbor Laboratory
Date: 28-06-2019
DOI: 10.1101/19001123
Abstract: DNA methylation (DNAm) is associated with environmental risk factors for major depressive disorder (MDD) but has not yet been tested for its ability to discriminate in iduals with MDD from unaffected in iduals. Using penalized regression based on genome-wide CpG methylation, we trained a DNAm risk score of MDD (DNAm-RS) in 1,223 cases and 1,824 controls and tested in a second independent s le of 363 prevalent cases and 1,417 controls. Using DNA from 1,607 unaffected in iduals, we tested whether DNAm-RS could discriminate the 190 incident cases of lifetime MDD from the 1,417 in iduals who remained unaffected at follow-up. A weighted linear combination of 196 CpG sites were derived from the training s le to form a DNAm-RS. The DNAm-RS explained 1.75% of the variance in MDD risk in an independent case-control s le and significantly predicted future incident episodes of MDD at follow up (R 2 =0.52%). DNAm-RS and MDD polygenic risk scores together additively explained 3.99% of the variance in prevalent MDD. The DNAm-RS was also significantly associated with lifestyle factors associated with MDD, including smoking status (β=0.440, p= ×10 −16 ) and alcohol use (β=0.092, p=9.85×10 −5 ). The DNAm-RS remained significantly associated with MDD after adjustment for these environmental factors (independent association: β=0.338, p=1.17×10 −7 association post-adjustment: β=0.081, p=0.0006). A novel risk score of MDD based on DNAm data significantly discriminated MDD cases from controls in an independent dataset, and controls who would subsequently develop MDD from those who remained unaffected. DNAm-RS captured the effects of exposure to key lifestyle risk factors for MDD, revealing a potential role in risk stratification.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2019
Publisher: Cold Spring Harbor Laboratory
Date: 06-09-2021
DOI: 10.1101/2021.09.03.21263066
Abstract: Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4,058 plasma proteins are performed (N=774), identifying 2,928 CpG-protein associations after adjustment for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N=1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.
Publisher: Elsevier BV
Date: 10-2023
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Miruna Carmen Barbu.