CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org

Genomics yields biological and phenotypic insights into bipolar disorder

Bipolar disorder is a leading contributor to the global burden of disease(1). Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown(2). We analysed data from participants of European, East Asian, African American and Latino ancestries (n=158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings(3), and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder(4), highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder

Intersexuality and Trans-Identities within the Diversity Management Discourse

Within both the scientific discourse on workforce diversity, and diversity management practice, intersexuality and transgender issues have hitherto remained marginalized topics. This chapter gives an overview of the discourses on both phenomena, and proposes starting points for more inclusive organizational diversity management initiatives. It is shown that both topics represent different aspects of the category of "gender". The common practice of conceptually lumping together intersexuality, transgenderism, and sexual orientation can be seen as one important reason that intersexuality and transgenderism are rarely considered in organizational diversity management programs in terms of concrete action. Against this background, a modified, and more integrated approach to structuring the workforce alongside the different dimensions of diversity is proposed. It is shown that the categories of "biological sex and gender", "gender identity", and "sexual orientation" cannot be regarded as being separate from each other. They represent, rather, an interrelated organizational field of action that should be considered as being one interrelated topic for organizational diversity practices. This chapter derives this claim theoretically and discusses the consequences for organizational diversity management practices. For most organizations, this would mean a fundamental rethinking of their goals, in terms of workforce diversity, and the shaping of their diversity management programs

Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most com- mon chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA 21 that directly contribute to cognitive de fi cits remain incompletely understood. Here, we found that the HSA21- encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued de fi cits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes

Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia

RNA editing critically regulates neurodevelopment and normal neuronal function. The global landscape of RNA editing was surveyed across 364 schizophrenia cases and 383 control postmortem brain samples from the CommonMind Consortium, comprising two regions: dorsolateral prefrontal cortex and anterior cingulate cortex. In schizophrenia, RNA editing sites in genes encoding AMPA-type glutamate receptors and postsynaptic density proteins were less edited, whereas those encoding translation initiation machinery were edited more. These sites replicate between brain regions, map to 3′-untranslated regions and intronic regions, share common sequence motifs and overlap with binding sites for RNA-binding proteins crucial for neurodevelopment. These findings cross-validate in hundreds of non-overlapping dorsolateral prefrontal cortex samples. Furthermore, ~30% of RNA editing sites associate with cis-regulatory variants (editing quantitative trait loci or edQTLs). Fine-mapping edQTLs with schizophrenia risk loci revealed co-localization of eleven edQTLs with six loci. The findings demonstrate widespread altered RNA editing in schizophrenia and its genetic regulation, and suggest a causal and mechanistic role of RNA editing in schizophrenia neuropathology

Functional annotation of rare structural variation in the human brain

Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs

Duality and fallibility in practices of the self: The 'inclusive subject’ in diversity training

The concept of ‘inclusion’ has been gaining ground in a field known as equality and diversity work. Scholars have begun to both theorise what this concept means as a normative goal and to critically examine how it is mobilised in organisational practice. This paper contributes to the latter conversation by asking what comes to count as ‘doing inclusion’ at the level of the individual. I examine the practices of diversity training in United Kingdom organisations, in which diversity practitioners seek to transform their trainees into people who will act inclusively toward others, asking: Who is the ‘inclusive subject’ that is being constructed – imagined, sought and legitimised – through diversity training? What are the conditions of possibility that shape the emergence of this subject? And what are the possibilities that this subject affords to marginalised groups struggling for recognition within organisations? The analysis mobilises Foucault’s notions of power/knowledge, discipline, and practices of the self to describe and discuss the performance of inclusive subjectivity in the context of diversity training in the UK. The practices described are found to be facilitated by two key forms of knowledge about how the subject is characterised: duality and fallibility. The discussion of these two forms of knowledge leads us to consider the relations of both discipline and freedom that take place in diversity training.</p