Genomic network analysis characterizes genetic architecture and identifies trait-specific biology.

Pervasive genetic overlap across human complex traits necessitates developing multivariate methods that can parse pleiotropic and trait-specific genetic signals. Here, we introduce Genomic Network Analysis (GNA), an analytic framework that applies the principles of network modelling to estimates of genetic overlap derived from genome-wide association study (GWAS) summary statistics. The result is a genomic network that describes the conditionally independent genetic associations between traits that remain when controlling for shared signal with the broader network of traits.

Understanding the Genetic Architecture of Vitamin Status Biomarkers in the Genome-Wide Association Study Era: Biological Insights and Clinical Significance.

Vitamins play an intrinsic role in human health and are targets for clinical intervention through dietary or pharmacological approaches. Biomarkers of vitamin status are complex traits, measurable phenotypes that arise from an interplay between dietary and other environmental factors with a genetic component that is polygenic, meaning many genes are plausibly involved. Studying these genetic influences will improve our knowledge of fundamental vitamin biochemistry, refine estimates of the effects of vitamins on human health, and may in future prove clinically actionable.

Schizophrenia is associated with altered DNA methylation variance.

Varying combinations of genetic and environmental risk factors are thought to underpin phenotypic heterogeneity between individuals in psychiatric conditions such as schizophrenia. While epigenome-wide association studies in schizophrenia have identified extensive alteration of mean DNA methylation levels, less is known about the location and impact of DNA methylation variance, which could contribute to phenotypic and treatment response heterogeneity. To explore this question, we conducted the largest meta-analysis of blood DNA methylation variance in schizophrenia to date, leveraging three cohorts comprising 1036 individuals with schizophrenia and 954 non-psychiatric controls.

Feedbacks Regulating the Salinization of Coastal Landscapes.

The impact of saltwater intrusion on coastal forests and farmland is typically understood as sea-level-driven inundation of a static terrestrial landscape, where ecosystems neither adapt to nor influence saltwater intrusion. Yet recent observations of tree mortality and reduced crop yields have inspired new process-based research into the hydrologic, geomorphic, biotic, and anthropogenic mechanisms involved. We review several negative feedbacks that help stabilize ecosystems in the early stages of salinity stress (e.

Genetic influences on circulating retinol and its relationship to human health.

Retinol is a fat-soluble vitamin that plays an essential role in many biological processes throughout the human lifespan. Here, we perform the largest genome-wide association study (GWAS) of retinol to date in up to 22,274 participants. We identify eight common variant loci associated with retinol, as well as a rare-variant signal.

Using Genetics to Inform Interventions Related to Sodium and Potassium in Hypertension.

Background: Hypertension is a key risk factor for major adverse cardiovascular events but remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure (BP) but are not equally effective across all individuals. BP is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity.

miRNA cargo in circulating vesicles from neurons is altered in individuals with schizophrenia and associated with severe disease.

While RNA expression appears to be altered in several brain disorders, the constraints of postmortem analysis make it impractical for well-powered population studies and biomarker development. Given that the unique molecular composition of neurons are reflected in their extracellular vesicles (EVs), we hypothesized that the fractionation of neuron derived EVs provides an opportunity to specifically profile their encapsulated contents noninvasively from blood. To investigate this hypothesis, we determined miRNA expression in microtubule associated protein 1B (MAP1B)-enriched serum EVs derived from neurons from a large cohort of individuals with schizophrenia and nonpsychiatric comparison participants.

Exploring opportunities for drug repurposing and precision medicine in cannabis use disorder using genetics.

Cannabis use disorder (CUD) remains a significant public health issue globally, affecting up to one in five adults who use cannabis. Despite extensive research into the molecular underpinnings of the condition, there are no effective pharmacological treatment options available. Therefore, we sought to further explore genetic analyses to prioritise opportunities to repurpose existing drugs for CUD.

Alteration of DNA Methylation and Epigenetic Scores Associated With Features of Schizophrenia and Common Variant Genetic Risk.

Background: Unpacking molecular perturbations associated with features of schizophrenia is a critical step toward understanding phenotypic heterogeneity in this disorder. Recent epigenome-wide association studies have uncovered pervasive dysregulation of DNA methylation in schizophrenia; however, clinical features of the disorder that account for a large proportion of phenotypic variability are relatively underexplored.

Methods: We comprehensively analyzed patterns of DNA methylation in a cohort of 381 individuals with schizophrenia from the deeply phenotyped Australian Schizophrenia Research Bank.

Linking Polygenic Risk of Schizophrenia to Variation in Magnetic Resonance Imaging Brain Measures: A Comprehensive Systematic Review.

Background And Hypothesis: Schizophrenia is highly heritable, with a polygenic effect of many genes conferring risk. Evidence on whether cumulative risk also predicts alterations in brain morphology and function is inconsistent. This systematic review examined evidence for schizophrenia polygenic risk score (sczPRS) associations with commonly used magnetic resonance imaging (MRI) measures.

Do Degrees Matter? Rethinking Workforce Development for Youth with Intellectual Disabilities and Mental Health Challenges.

The global workforce crisis significantly impacts how evidence-based treatment is provided to youth with developmental disabilities and co-occurring mental health conditions. Addressing the workforce crisis requires re-examining the long-standing methods of selecting individuals for employment based on academic degrees. This project offers an innovative workforce development option that provides specialized training to staff with advanced education degrees and staff with less education.

Multiomic prioritisation of risk genes for anorexia nervosa.

Background: Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of functional genomics data, including transcriptomics and proteomics, would assist to disentangle correlated signals and reveal causally associated genes.

Methods: We used models of genetically imputed expression and splicing from 14 tissues, leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with AN risk.

MicroRNA binding site variation is enriched in psychiatric disorders.

Psychiatric disorders have a polygenic architecture, often associated with dozens or hundreds of independent genomic loci. Most associated loci impact noncoding regions of the genome, suggesting that the majority of disease heritability originates from the disruption of regulatory sequences. While most research has focused on variants that modify regulatory DNA elements, those affecting cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact.

Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals with pharmacological significance.

Almost half of individuals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol (r = 0.

Evidence of genetic overlap and causal relationships between blood-based biochemical traits and human cortical anatomy.

Psychiatric disorders such as schizophrenia are commonly associated with structural brain alterations affecting the cortex. Recent genetic evidence suggests circulating metabolites and other biochemical traits play a causal role in many psychiatric disorders which could be mediated by changes in the cerebral cortex. Here, we leveraged publicly available genome-wide association study data to explore shared genetic architecture and evidence for causal relationships between a panel of 50 biochemical traits and measures of cortical thickness and surface area.

Genetics-informed precision treatment formulation in schizophrenia and bipolar disorder.

Genetically informed drug development and repurposing is an attractive prospect for improving patient outcomes in psychiatry; however, the effectiveness of these endeavors is confounded by heterogeneity. We propose an approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritize individual "directional anchor" genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug.

Constraints on the adjustment of tidal marshes to accelerating sea level rise.

Much uncertainty exists about the vulnerability of valuable tidal marsh ecosystems to relative sea level rise. Previous assessments of resilience to sea level rise, to which marshes can adjust by sediment accretion and elevation gain, revealed contrasting results, depending on contemporary or Holocene geological data. By analyzing globally distributed contemporary data, we found that marsh sediment accretion increases in parity with sea level rise, seemingly confirming previously claimed marsh resilience.

The genetic architecture of pneumonia susceptibility implicates mucin biology and a relationship with psychiatric illness.

Pneumonia remains one of the leading causes of death worldwide. In this study, we use genome-wide meta-analysis of lifetime pneumonia diagnosis (N = 391,044) to identify four association signals outside of the previously implicated major histocompatibility complex region. Integrative analyses and finemapping of these signals support clinically tractable targets, including the mucin MUC5AC and tumour necrosis factor receptor superfamily member TNFRSF1A.

Variation in cardiovascular disease risk factors among older adults in the Hunter Community Study cohort: A comparison of diet quality versus polygenic risk score.

Background: The interplay between cardiovascular disease (CVD) genetic risk indexed by a polygenic risk score (PRS) and diet quality still requires further investigation amongst older adults or those with established or treated CVD. The present study aimed to evaluate the relative contribution of diet quality, measured using the Australian Recommended Food Score (ARFS) and PRS, with respect to explaining variation in plasma lipids CVD outcomes in the Hunter Cohort.

Methods: The study comprised a secondary analysis of cross-sectional data from the Hunter Cohort study.

Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders.

There is a long-standing interest in exploring the relationship between blood-based biomarkers and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable serum biochemical traits to refine our understanding of causal effect in biochemical-psychiatric trait pairings. We observed widespread positive and negative genetic correlation between psychiatric disorders and biochemical traits.

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls).

Advancing the use of genome-wide association studies for drug repurposing.

Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases, which are broadly expected to lead to the identification of new drug targets and opportunities for treatment. Drug development, however, remains hampered by the time taken and costs expended to achieve regulatory approval, leading many clinicians and researchers to consider alternative paths to more immediate clinical outcomes. In this Review, we explore approaches that leverage common variant genetics to identify opportunities for repurposing existing drugs, also known as drug repositioning.

Spatiotemporal distribution of phycotoxins and their co-occurrence within nearshore waters.

Harmful algal blooms (HABs), varying in intensity and causative species, have historically occurred throughout the Chesapeake Bay, U.S.; however, phycotoxin data are sparse.