Biology subjects

Gibson, J.

Publications and source records attributed to Gibson, J..

9 recordsLinked to original sources

bioRxiv2018

Genome-wide meta-analysis of depression in 807,553 individuals identifies 102 independent variants with replication in a further 1,507,153 individuals

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 sample sizes due to the polygenic nature of the disorder. To maximise sample size, we meta-analysed data on 807,553 individuals (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 sample of 1,306,354 individuals (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.

genetics↗

bioRxiv2018

Association of whole-genome and NETRIN1 signaling pathway-derived polygenic risk scores for Major Depressive Disorder and thalamic radiation white matter microstructure in UK Biobank

BackgroundMajor Depressive Disorder (MDD) is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome, and growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide an important route for identification of disease mechanisms by focusing on a specific process excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether MDD polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRS) and the whole genome excluding NETRIN1 pathway genes (genomic-PRS) were associated with white matter integrity.\n\nMethodsWe used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: N = 6,401; MD: N = 6,390).\n\nResultsWe found significantly lower FA in the superior longitudinal fasciculus ({beta} = -0.035, pcorrected = 0.029) and significantly higher MD in a global measure of thalamic radiations ({beta} = 0.029, pcorrected = 0.021), as well as higher MD in the superior ({beta} = 0.034, pcorrected = 0.039) and inferior ({beta} = 0.029, pcorrected = 0.043) longitudinal fasciculus and in the anterior ({beta} = 0.025, pcorrected = 0.046) and superior ({beta} = 0.027, pcorrected = 0.043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts.\n\nConclusionsOur findings indicate that variation in the NETRIN1 signaling pathway may confer risk for MDD through effects on thalamic radiation white matter microstructure.

genetics↗

bioRxiv2018

DNA methylation age acceleration and risk factors for Alzheimer’s disease

INTRODUCTIONThe epigenetic clock is a DNA methylation-based estimate of biological age and is correlated with chronological age - the greatest risk factor for Alzheimers disease (AD). Genetic and environmental risk factors exist for AD, several of which are potentially modifiable. Here, we assess the relationship associations between the epigenetic clock and AD risk factors.\n\nMETHODSLinear mixed modelling was used to assess the relationship between age acceleration (the residual of biological age regressed onto chronological age) and AD risk factors relating to cognitive reserve, lifestyle, disease, and genetics in the Generation Scotland study (n=5,100).\n\nRESULTSWe report significant associations between the epigenetic clock and BMI, total:HDL cholesterol ratios, socioeconomic status, and smoking behaviour (Bonferroni-adjusted P<0.05).\n\nDISCUSSIONAssociations are present between environmental risk factors for AD and age acceleration. Measures to modify such risk factors might improve the risk profile for AD and the rate of biological ageing. Future longitudinal analyses are therefore warranted.

genomics↗

bioRxiv2017

Accelerated Epigenetic Ageing in Major Depressive Disorder

BackgroundMajor depressive disorder (MDD) is a severe, heritable psychiatric disorder associated with shortened lifespan and comorbidities of advancing age. It is unknown however whether MDD is associated with accelerated biological ageing relative to chronological age. This hypothesis was tested using the epigenetic clock as a measure of biological age.\n\nMethodsTo address the main hypothesis, using peripheral blood, we derived measures of Epigenetic Age Acceleration (EAA) in 3,833 controls and 1,219 MDD cases based on Hannum and Horvath epigenetic clocks in Generation Scotland (GS:SFHS, mean age 48 years, std dev 14.5). Models controlled for relatedness, sex, cell counts, and processing batch (basic model), as well as additional covariates of smoking and drinking status, and body mass index (BMI) (full models).\n\nResultsAccelerated epigenetic ageing was found in MDD cases versus controls using the Horvath clock ({beta}=0.0804, p=0.012 equivalent to 0.20 years) in both the basic and full models. Significant MDD*age interactions indicated greatest effects at younger age ranges. No significant differences were observed for the Hannum clock. BMI was the only additional covariate found to attenuate the relationship between EAAHorvath and MDD. Further, genetic correlation analysis indicated significant overlap in the genetic aetiology of EAAHorvath with BMI (rG=0.20, p=0.03), between MDD with BMI (rG=0.10, p=9.86x10-6), but not between EAAHorvath and MDD (rG=0.14, p=0.125). Mediation analysis indicated partial mediation of the relationship between EAAHorvath and depression status through BMI ({beta} =0.0028; p=0.0248, ~13%).\n\nConclusionThese data imply that accelerated biological ageing is associated with MDD and partially mediated through BMI.

genomics↗

bioRxiv2017

Dissemination of Cryptococcus neoformans via localised proliferation and blockage of blood vessels

Cryptococcus neoformans is an opportunistic fungal pathogen that can cause life-threatening cryptoccocal meningitis, predominantly within immunocompromised individuals. Cortical infarcts are observed in as many as 30% of cryptococcal meningitis cases, being particularly common in severe infection. Limited clinical case studies suggest infarcts are secondary to vasculitis and blood vessel damage caused by cryptococcal infection. However, the cause of infarcts in cryptococcal infection has not been determined. To examine potential causes of vascular damage and cryptococcal dissemination in cryptococcal infection, the zebrafish C. neoformans infection model was used. We demonstrate that spread of cryptococci from the vasculature occurs at sites where cryptococci grow within the blood vessels, originating from a single or small number of cryptococci. We find that cryptococcal cells become trapped within the vasculature and can proliferate there resulting in vasodilation. Localised cryptococcal growth in the vasculature is also associated with sites of dissemination - in some cases simultaneously with a loss of blood vessel integrity. Using a cell-cell junction protein reporter (VE-cadherin) we identified sites dissemination associated with both intact blood vessels and where vessel rupture occurred. Thus, we have identified a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of the vascular damage and cortical infarction observed in cryptococcal meningitis.\n\nAuthor summaryHuman infection by the fungal pathogen, Cryptococcus neoformans, can lead to life-threatening cryptococcal meningitis. In severe cases of cryptococcal meningitis, a lack of blood supply can cause tissue death and a resulting area of dead tissue (infarct) in the brain. Although vasculature inflammation in known to occur in cryptococcal meningitis, the cause of infarcts in unknown. Using a zebrafish model of cryptococcal infection, the growth and dissemination of fungal cells was observed over time. We show that cryptococcal cells become trapped and proliferate in the vasculature, resulting in cryptococcoma that damage the blood vessels. We propose that vessel damage results from increased blood pressure caused by cryptococci blocking blood vessels suggesting that the vascular damage that ensues on cryptococcoma formation may in turn be a cause of infarct formation seen in cryptococcal meningitis.

microbiology↗

bioRxiv2017

Identification of 55,000 Replicated DNA Methylation QTL

DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n=614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5 UTR regions. No association was observed between either the SNPs or DNA methylation sites of trans mQTL and telomere length. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1x10-10), ulcerative colitis (p = 2x10-5), Crohns disease (p = 6x10-8) and coronary artery disease (p = 5.5x10-6) when compared to a random sample of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs.

genomics↗

bioRxiv2017

The Stratification Of Major Depressive Disorder Into Genetic Subgroups

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations was used to test for evidence of subgroups by examining whether there was clustering of independent genetic variants associated with eleven other complex traits and disorders in people with depression. We found evidence of a subgroup within depression using age of natural menopause variants (P = 1.69 x 10-3) and this effect remained significant in females (P = 1.18 x 10-3), but not males (P = 0.186). However, no evidence for this subgroup (P > 0.05) was found in Generation Scotland, iPSYCH, a UK Biobank replication cohort or the GERA cohort. In the UK Biobank, having depression was also associated with a later age of menopause (beta = 0.34, standard error = 0.06, P = 9.92 x 10-8). A potential age of natural menopause subgroup within depression and the association between depression and a later age of menopause suggests that they partially share a developmental pathway.

genetics↗

bioRxiv2017

Genome-Wide Meta-Analyses Of Stratified Depression In Generation Scotland And UK Biobank

Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. However recent studies of depression have identified common risk variants by using either a broader phenotype definition in very large samples, or by reducing the phenotypic and ancestral heterogeneity of MDD cases. Here, a range of genetic analyses were applied to data from two large British cohorts, Generation Scotland and UK Biobank, to ascertain whether it is more informative to maximize the sample size by using data from all available cases and controls, or to use a refined subset of the data - stratifying by MDD recurrence or sex. Meta-analysis of GWAS data in males from these two studies yielded one genome-wide significant locus on 3p22.3. Three associated genes within this region (CRTAP, GLB1, and TMPPE) were significantly associated in subsequent gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD were each genetically correlated with 6 of 200 health-correlated traits, namely neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder. Meta-analyzed male MDD showed no statistically significant correlations with these traits after correction for multiple testing. Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, the equivalent SNP-based heritability estimates and the consistent pattern of genetic correlation with other health-related traits suggests that phenotypic stratification in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.

genetics↗

bioRxiv2016

Environmental DNA Barcode Sequence Capture: Targeted, PCR-free Sequence Capture for Biodiversity Analysis from Bulk Environmental Samples

Environmental DNA analysis using PCR amplified marker genes has been a key application of high-throughput sequencing (HTS). However, PCR bias is a major drawback to gain accurate qualitative and quantitative biodiversity data. We developed a PCR-free approach using enrichment baits for species-specific mitochondrial cytochrome c oxidase 1(COI) DNA barcodes. The sequence capture was tested on species-rich bulk terrestrial and aquatic benthic samples. Hybridization capture recovered an average of 6 and 4.7 more arthropod orders than amplicon sequencing for terrestrial and benthic samples, respectively. For the terrestrial sample, the four most abundant arthropod orders comprised 94.0% of the sample biomass. These same four orders comprised 95.5% and 97.5% of the COI sequences recovered by amplification and capture, respectively. Hybridization capture recovered three arthropod orders that were detected by biomass analysis, but not by amplicon sequencing and two other insect orders that were not detected by either biomass or amplicon methods. These results indicate the advantage of using sequence capture for a more accurate analysis of biodiversity in bulk environmental samples. The protocol can be easily customized to other DNA barcode markers or gene regions of interest for a wide range of taxa or for a specific target group.

genomics↗