ORCID Profile
0000-0002-4208-5271
Current Organisation
The University of Edinburgh
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Publisher: Springer Science and Business Media LLC
Date: 24-04-2007
Abstract: Several independent linkage studies have identified chromosome 4p15-p16 as a putative region of susceptibility for bipolar disorder (BP), schizophrenia (SCZ) and related phenotypes. Previously, we identified two subregions (B and D) of the 4p15-p16 region that are shared by three of four 4p-linked families examined. Here, we describe a large-scale association analysis of regions B and D (3.8 and 4.5 Mb, respectively). We selected 408 haplotype-tagging single nucleotide polymorphisms (SNPs) on a block-by-block basis from the International HapMap project and tested them in 368 BP, 386 SCZ and 458 control in iduals. Nominal significance thresholds were determined using principal component analysis as implemented in the program SNPSpD. In region B, overlapping SNPs and haplotypes met the region-wide threshold (P<or=0.0005) at the global and in idual haplotype test level and clustered in two regions. In region D, no in idual SNPs were nominally significant, but multiple global and in idual haplotypes were associated with BP and/or SCZ (region-wide threshold, P<or=0.0003). These overlapping haplotypes fell into two regions. Within each of these four clusters, at least one globally significant haplotype withstood permutation testing (P(gp)<or=0.05). Five predicted genes were found within these associated regions, while Known/RefSeq genes, including KIAA0746 and PPARGC1A, mapped nearby. There were also nine other clusters within regions B and D with nominally significant haplotypes, but only at the in idual haplotype level. KIAA0746, PPARGC1A, GPR125, CCKAR and DKFZp761B107 overlapped with these regions. This study has identified significant associations between BP and SCZ within the chromosome 4p linkage region, resulting in candidate regions worthy of further investigation.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2005
Publisher: Elsevier BV
Date: 07-2020
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: S. Karger AG
Date: 2000
DOI: 10.1159/000056772
Publisher: F1000 Research Ltd
Date: 14-02-2018
DOI: 10.12688/WELLCOMEOPENRES.13893.1
Abstract: Background: Stressful life events (SLEs) and neuroticism are risk factors for major depressive disorder (MDD). However, SLEs and neuroticism are heritable and genetic risk for SLEs is correlated with risk for MDD. We sought to investigate the genetic and environmental contributions to SLEs in a family-based s le, and quantify genetic overlap with MDD and neuroticism. Methods: A subset of Generation Scotland: the Scottish Family Health Study (GS), consisting of 9618 in iduals with information on MDD, past 6 month SLEs, neuroticism and genome-wide genotype data was used in the present study. We estimated the heritability of SLEs using GCTA software. The environmental contribution to SLEs was assessed by modelling familial, couple and sibling components. Using polygenic risk scores (PRS) and LD score regression (LDSC) we analysed the genetic overlap between MDD, neuroticism and SLEs. Results: Past 6-month life events were positively correlated with lifetime MDD status (β=0.21, r 2 =1.1%, p=2.5 x 10 -25 ) and neuroticism (β =0.13, r 2 =1.9%, p=1.04 x 10 -37 ) at the phenotypic level. Common SNPs explained 8% of the phenotypic variance in personal life events (those directly affecting the in idual) (S.E.=0.03, p= 9 x 10 -4 ). A significant effect of couple environment was detected accounting for 13% (S.E.=0.03, p=0.016) of the phenotypic variation in SLEs. PRS analyses found that reporting more SLEs was associated with a higher polygenic risk for MDD (β =0.05, r 2 =0.3%, p=3 x 10 -5 ), but not a higher polygenic risk for neuroticism. LDSC showed a significant genetic correlation between SLEs and both MDD (r G =0.33, S.E.=0.08 ) and neuroticism (r G =0.15, S.E.=0.07). Conclusions: These findings suggest that SLEs should not be regarded solely as environmental risk factors for MDD as they are partially heritable and this heritability is shared with risk for MDD and neuroticism. Further work is needed to determine the causal direction and source of these associations.
Publisher: American Medical Association (AMA)
Date: 04-2019
DOI: 10.1001/JAMAPSYCHIATRY.2018.4175
Abstract: Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear physical activity may protect against depression, and/or depression may result in decreased physical activity. To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference. This 2-s le mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes—self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)—and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in erse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR–Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018. MDD and physical activity. GWAS summary data were available for a combined s le size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration 95% CI, 0.59-0.92 P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = −0.08 in mean acceleration per MDD vs control status 95% CI, −0.47 to 0.32 P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity 95% CI, 0.57-3.37 P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status 95% CI, −0.008 to 0.05 P = .15). Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed—but not self-reported—physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.
Publisher: Cold Spring Harbor Laboratory
Date: 03-06-2019
DOI: 10.1101/657163
Abstract: Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1 ) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging (DTI) and cellular studies to evaluate the consequences of the t(1 ) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption in white matter integrity compared to familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) case derived oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro . Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1 ) oligodendrocyte progenitors were significantly reduced compared to controls. Thus we provide evidence that the t(1 ) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.
Publisher: Elsevier BV
Date: 11-2021
Publisher: Cold Spring Harbor Laboratory
Date: 2003
Publisher: Springer Science and Business Media LLC
Date: 18-01-2019
DOI: 10.1038/S41398-018-0356-7
Abstract: Depression has well-established influences from genetic and environmental risk factors. This has led to the diathesis-stress theory, which assumes a multiplicative gene-by-environment interaction (GxE) effect on risk. Recently, Colodro-Conde et al . empirically tested this theory, using the polygenic risk score for major depressive disorder (PRS, genes) and stressful life events (SLE, environment) effects on depressive symptoms, identifying significant GxE effects with an additive contribution to liability. We have tested the diathesis-stress theory on an independent s le of 4919 in iduals. We identified nominally significant positive GxE effects in the full cohort ( R 2 = 0.08%, p = 0.049) and in women ( R 2 = 0.19%, p = 0.017), but not in men ( R 2 = 0.15%, p = 0.07). GxE effects were nominally significant, but only in women, when SLE were split into those in which the respondent plays an active or passive role ( R 2 = 0.15%, p = 0.038 R 2 = 0.16%, p = 0.033, respectively). High PRS increased the risk of depression in participants reporting high numbers of SLE ( p = 2.86 × 10 −4 ). However, in those participants who reported no recent SLE, a higher PRS appeared to increase the risk of depressive symptoms in men ( β = 0.082, p = 0.016) but had a protective effect in women ( β = −0.061, p = 0.037). This difference was nominally significant ( p = 0.017). Our study reinforces the evidence of additional risk in the aetiology of depression due to GxE effects. However, larger s le sizes are required to robustly validate these findings.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2019
DOI: 10.1038/S41467-019-10461-0
Abstract: Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2019
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier BV
Date: 09-2017
Publisher: Springer Science and Business Media LLC
Date: 10-03-2015
DOI: 10.1038/MP.2015.12
Publisher: Public Library of Science (PLoS)
Date: 20-12-2018
Publisher: Springer Science and Business Media LLC
Date: 23-10-2019
Publisher: Springer Science and Business Media LLC
Date: 19-04-2005
Abstract: The Translin-associated factor X/Disrupted in Schizophrenia 1 (TRAX/DISC) region was first implicated as a susceptibility locus for schizophrenia by analysis of a large Scottish family in which a t(1 ) translocation cosegregates with schizophrenia, bipolar disorder and recurrent major depression. We now report evidence for association between bipolar disorder and schizophrenia and this locus in the general Scottish population. A systematic study of linkage disequilibrium in a representative s le of the Scottish population was undertaken across the 510 kb of TRAX and DISC1. SNPs representing each haplotype block were selected for case-control association studies of both schizophrenia and bipolar disorder. Significant association with bipolar disorder in women P=0.00026 (P=0.0016 in men and women combined) was detected in a region of DISC1. This same region also showed nominally significant association with schizophrenia in both men and women combined, P=0.0056. Two further regions, one in TRAX and the second in DISC1, showed weaker evidence for sex-specific associations of in idual haplotypes with bipolar disorder in men and women respectively, P<0.01. Only the association between bipolar women and DISC1 remained significant after correction for multiple testing. This result provides further supporting evidence for DISC1 as a susceptibility factor for both bipolar disorder and schizophrenia, consistent with the diagnoses in the original Scottish translocation family.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2018
Publisher: Springer Science and Business Media LLC
Date: 13-07-2004
Publisher: Springer Science and Business Media LLC
Date: 03-01-2006
Abstract: The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a s le of 377 BPAD, 392 schizophrenia (SCZ) and 470 control in iduals. Using standard chi(2) statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (chi(2) P=0.044 LRT P=0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR)=1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR=5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR=5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P=0.017). No single-marker association was detected in the SCZ males, in the BPAD in iduals or with any other SNP. Haplotype analysis of the case-control s les revealed several global and in idual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD in iduals (P=0.038 and 0.032) and in the full s le of affected female in iduals (P=0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.
Publisher: Cold Spring Harbor Laboratory
Date: 11-09-2020
DOI: 10.1101/2020.09.10.20192310
Abstract: Polygenic scores (PGSs), which assess the genetic risk of in iduals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies (GWASs). PGS methods differ in which DNA variants are included and the weights assigned to them some require an independent tuning s le to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors. The Psychiatric Genomics Consortium working groups for schizophrenia (SCZ) and major depressive disorder (MDD) bring together many independently collected case- control cohorts. We used these resources (31K SCZ cases, 41K controls 248K MDD cases, 563K controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and nine methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) are compared. Compared to PC+T, the other nine methods give higher prediction statistics, MegaPRS, LDPred2 and SBayesR significantly so, up to 9.2% variance in liability for SCZ across 30 target cohorts, an increase of 44%. For MDD across 26 target cohorts these statistics were 3.5% and 59%, respectively. Although the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparison and are recommended in applications to psychiatric disorders.
Publisher: Cambridge University Press (CUP)
Date: 06-03-2015
DOI: 10.1017/THG.2015.10
Abstract: Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to in idual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish in iduals were selected for high scores on a general component of intelligence ( g ). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g . Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g . The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g . Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger s les would be worthwhile.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.BIOPSYCH.2006.06.029
Abstract: Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2017
DOI: 10.1101/167577
Abstract: Major depressive disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. 1 It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. 2-7 MDD is a major cause of disability worldwide. 8 We conducted a genome-wide association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls, and identified 44 independent loci that met criteria for statistical significance. We present extensive analyses of these results which provide new insights into the nature of MDD. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences between MDD cases and controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5×10 −10 ), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
Publisher: Springer Science and Business Media LLC
Date: 08-10-2018
DOI: 10.1038/S42003-018-0155-Y
Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree ( n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected in iduals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
Publisher: Elsevier BV
Date: 09-2021
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Pippa Thomson.