Cis-effects on gene expression in the human prenatal brain associated with genetic risk for neuropsychiatric disorders

The majority of common risk alleles identified for neuropsychiatric disorders reside in non-coding regions of the genome and are therefore likely to impact gene regulation. However, the genes that are primarily affected and the nature and developmental timing of these effects remain unclear. Given the hypothesised role for early neurodevelopmental processes in these conditions, we here define genetic predictors of gene expression in the human fetal brain with which we perform transcriptome-wide association studies (TWASs) of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, bipolar disorder, major depressive disorder and schizophrenia. We identify prenatal cis-regulatory effects on 63 genes and 166 individual transcripts associated with genetic risk for these conditions. We observe pleiotropic effects of expression predictors for a number of genes and transcripts, including those of decreased DDHD2 expression in association with risk for schizophrenia and bipolar disorder, increased expression of a ST3GAL3 transcript with risk for schizophrenia and ADHD, and increased expression of an XPNPEP3 transcript with risk for schizophrenia, bipolar disorder and major depression. For the protocadherin alpha cluster genes PCDHA7 and PCDHA8, we find that predictors of low expression are associated with risk for major depressive disorder while those of higher expression are associated with risk for schizophrenia. Our findings support a role for altered gene regulation in the prenatal brain in susceptibility to various neuropsychiatric disorders and prioritize potential risk genes for further neurobiological investigation

Amino acid residues in five separate HLA genes can explain most of the known associations between the MHC and primary biliary cholangitis.

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterised by progressive destruction of intrahepatic bile ducts. The strongest genetic association is with HLA-DQA1*04:01, but at least three additional independent HLA haplotypes contribute to susceptibility. We used dense single nucleotide polymorphism (SNP) data in 2861 PBC cases and 8514 controls to impute classical HLA alleles and amino acid polymorphisms using state-of-the-art methodologies. We then demonstrated through stepwise regression that association in the HLA region can be largely explained by variation at five separate amino acid positions. Three-dimensional modelling of protein structures and calculation of electrostatic potentials for the implicated HLA alleles/amino acid substitutions demonstrated a correlation between the electrostatic potential of pocket P6 in HLA-DP molecules and the HLA-DPB1 alleles/amino acid substitutions conferring PBC susceptibility/protection, highlighting potential new avenues for future functional investigation

A transcriptome-wide association study implicates specific pre- and post-synaptic abnormalities in schizophrenia

chizophrenia is a complex highly heritable disorder. Genome-wide association studies (GWAS) have identified multiple loci that influence the risk of developing schizophrenia, although the causal variants driving these associations and their impacts on specific genes are largely unknown. We identify a significant correlation between schizophrenia risk and expression at 89 genes in dorsolateral prefrontal cortex (P ≤ 9.43x10−6), including 20 novel genes. Genes whose expression correlate with schizophrenia were enriched for those involved in abnormal CNS synaptic transmission (PFDR = 0.02) and antigen processing and presentation of peptide antigen via MHC class I (PFDR = 0.02). Within the CNS synaptic transmission set, we identify individual significant candidate genes to which we assign direction of expression changes in schizophrenia. The findings provide strong candidates for experimentally probing the molecular basis of synaptic pathology in schizophrenia

Novel insight into the etiology of autism spectrum disorder gained by integrating expression data with genome-wide association statistics

Background A recent genome-wide association study (GWAS) of autism spectrum disorders (ASD) (Ncases=18,381, Ncontrols=27,969) has provided novel opportunities for investigating the aetiology of ASD. Here, we integrate the ASD GWAS summary statistics with summary-level gene expression data to infer differential gene expression in ASD, an approach called transcriptome-wide association study (TWAS). Methods Using FUSION software, ASD GWAS summary statistics were integrated with predictors of gene expression from 16 human datasets, including adult and fetal brain. A novel adaptation of established statistical methods was then used to test for enrichment within candidate pathways, specific tissues, and at different stages of brain development. The proportion of ASD heritability explained by predicted expression of genes in the TWAS was estimated using stratified linkage disequilibrium-score regression. Results This study identified 14 genes as significantly differentially expressed in ASD, 13 of which were outside of known genome-wide significant loci (±500kb). XRN2, a gene proximal to an ASD GWAS locus, was inferred to be significantly upregulated in ASD, providing insight into functional consequence of this associated locus. One novel transcriptome-wide significant association from this study is the downregulation of PDIA6, which showed minimal evidence of association in the GWAS, and in gene-based analysis using MAGMA. Predicted gene expression in this study accounted for 13.0% of the total ASD SNP-heritability. Conclusion This study has implicated several genes as significantly up-/down-regulated in ASD providing novel and useful information for subsequent functional studies. This study also explores the utility of TWAS-based enrichment analysis and compares TWAS results with a functionally agnostic approach

Pond ecology and conservation: research priorities and knowledge gaps

Ponds are among the most biodiverse and ecologically important freshwater habitats globally and may provide a significant opportunity to mitigate anthropogenic pressures and reverse the decline of aquatic biodiversity. Ponds also provide important contributions to society through the provision of ecosystem services. Despite the ecological and societal importance of ponds, freshwater research, policy, and conservation have historically focused on larger water bodies, with significant gaps remaining in our understanding and conservation of pond ecosystems. In May 2019, pond researchers and practitioners participated in a workshop to tackle several pond ecology, conservation, and management issues. Nine research themes and 30 research questions were identified during and following the workshop to address knowledge gaps around: (1) pond habitat definition; (2) global and long-term data availability; (3) anthropogenic stressors; (4) aquatic–terrestrial interactions; (5) succession and disturbance; (6) freshwater connectivity; (7) pond monitoring and technological advances; (8) socio-economic factors; and (9) conservation, management, and policy. Key areas for the future inclusion of ponds in environmental and conservation policy were also discussed. Addressing gaps in our fundamental understanding of pond ecosystems will facilitate more effective research-led conservation and management of pondscapes, their inclusion in environmental policy, support the sustainability of ecosystem services, and help address many of the global threats driving the decline in freshwater biodiversity

Genome-wide association study of antidepressant treatment resistance in a population-based cohort using health service prescription data and meta-analysis with GENDEP

Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power

Severe COVID-19 outcomes after full vaccination of primary schedule and initial boosters : pooled analysis of national prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales

National Core Studies–Immunity, UK Research and Innovation (Medical Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.Peer reviewedPublisher PD

Pond ecology and conservation: research priorities and knowledge gaps

Ponds are among the most biodiverse and ecologically important freshwater habitats globally and may provide a significant opportunity to mitigate anthropogenic pressures and reverse the decline of aquatic biodiversity. Ponds also provide important contributions to society through the provision of ecosystem services. Despite the ecological and societal importance of ponds, freshwater research, policy, and conservation have historically focused on larger water bodies, with significant gaps remaining in our understanding and conservation of pond ecosystems. In May 2019, pond researchers and practitioners participated in a workshop to tackle several pond ecology, conservation, and management issues. Nine research themes and 30 research questions were identified during and following the workshop to address knowledge gaps around: (1) pond habitat definition; (2) global and long-term data availability; (3) anthropogenic stressors; (4) aquatic–terrestrial interactions; (5) succession and disturbance; (6) freshwater connectivity; (7) pond monitoring and technological advances; (8) socio-economic factors; and (9) conservation, management, and policy. Key areas for the future inclusion of ponds in environmental and conservation policy were also discussed. Addressing gaps in our fundamental understanding of pond ecosystems will facilitate more effective research-led conservation and management of pondscapes, their inclusion in environmental policy, support the sustainability of ecosystem services, and help address many of the global threats driving the decline in freshwater biodiversity.Additional co-authors: James C. White, Robert A. Briers, Kate L. Mathers, Michael J. Jeffries, and Paul J. Woo

A Combined Pathway and Regional Heritability Analysis Indicates NETRIN1 Pathway is Associated with Major Depressive Disorder

AbstractBackgroundGenome-wide association studies (GWASs) of major depressive disorder (MDD) have identified few significant associations. Testing the aggregation of genetic variants, in particular biological pathways, may be more powerful. Regional heritability analysis can be used to detect genomic regions that contribute to disease risk.MethodsWe integrated pathway analysis and multilevel regional heritability analyses in a pipeline designed to identify MDD-associated pathways. The pipeline was applied to two independent GWAS samples [Generation Scotland: The Scottish Family Health Study (GS:SFHS, N = 6455) and Psychiatric Genomics Consortium (PGC:MDD) (N = 18,759)]. A polygenic risk score (PRS) composed of single nucleotide polymorphisms from the pathway most consistently associated with MDD was created, and its accuracy to predict MDD, using area under the curve, logistic regression, and linear mixed model analyses, was tested.ResultsIn GS:SFHS, four pathways were significantly associated with MDD, and two of these explained a significant amount of pathway-level regional heritability. In PGC:MDD, one pathway was significantly associated with MDD. Pathway-level regional heritability was significant in this pathway in one subset of PGC:MDD. For both samples the regional heritabilities were further localized to the gene and subregion levels. The NETRIN1 signaling pathway showed the most consistent association with MDD across the two samples. PRSs from this pathway showed competitive predictive accuracy compared with the whole-genome PRSs when using area under the curve statistics, logistic regression, and linear mixed model.ConclusionsThese post-GWAS analyses highlight the value of combining multiple methods on multiple GWAS data for the identification of risk pathways for MDD. The NETRIN1 signaling pathway is identified as a candidate pathway for MDD and should be explored in further large population studies

The effects of juvenile stress on anxiety, cognitive bias and decision making in adulthood:a rat model

Stress experienced in childhood is associated with an increased risk of developing psychiatric disorders in adulthood. These disorders are particularly characterized by disturbances to emotional and cognitive processes, which are not currently fully modeled in animals. Assays of cognitive bias have recently been used with animals to give an indication of their emotional/cognitive state. We used a cognitive bias test, alongside a traditional measure of anxiety (elevated plus maze), to investigate the effects of juvenile stress (JS) on adulthood behaviour using a rodent model. During the cognitive bias test, animals were trained to discriminate between two reward bowls based on a stimulus (rough/smooth sandpaper) encountered before they reached the bowls. One stimulus (e.g. rough) was associated with a lower value reward than the other (e.g. smooth). Once rats were trained, their cognitive bias was explored through the presentation of an ambiguous stimulus (intermediate grade sandpaper): a rat was classed as optimistic if it chose the bowl ordinarily associated with the high value reward. JS animals were lighter than controls, exhibited increased anxiety-like behaviour in the elevated plus maze and were more optimistic in the cognitive bias test. This increased optimism may represent an optimal foraging strategy for these underweight animals. JS animals were also faster than controls to make a decision when presented with an ambiguous stimulus, suggesting altered decision making. These results demonstrate that stress in the juvenile phase can increase anxiety-like behaviour and alter cognitive bias and decision making in adulthood in a rat model