The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

The role of non-coding RNAs (ncRNAs) in disease is best understood for microRNAs in cancer. However, there is increasing interest in the disease-related roles of other ncRNAs — including piRNAs, snoRNAs, T-UCRs and lncRNAs — and in using this knowledge for therapy.

Non-coding RNAs in human disease

In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

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Biological properties of extracellular vesicles and their physiological functions

Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.

10 Years of GWAS Discovery: Biology, Function, and Translation

An Expanded View of Complex Traits: From Polygenic to Omnigenic

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 (rg = 0.3685, SE = 0.0768, P = 1.61 x 10-06), cannabis use disorder (rg = 0.309, SE = 0.0332, P = 1.19 x 10-20) and nicotine dependence (rg = 0.1177, SE = 0.0436, P = 7.0 x 10-03), as well as lifetime cannabis use (rg = 0.234, SE = 0.0298, P = 3.73 x 10-15) and drinks per week (rg = 0.0688, SE = 0.0217, P = 1.5 x 10-03). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22, P = 1.6 x 10-03). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders, we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four individual substance dependence phenotypes in up to 790,806 individuals. These bivariate meta-analyses identified 44 associations not observed in the individual GWAS, including five shared genes that play a key role in early central nervous system development. These genes may play an important role in substance dependence in schizophrenia, and, as a result, could represent important targets for future treatment or early intervention, as comorbid substance dependence is associated with poor treatment adherence, greater chronicity and increased mortality.

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Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals

Grey matter volume (GMV) may be associated with polygenic risk for schizophrenia (PRS-SZ) and severe cognitive deficits in people with schizophrenia, schizoaffective disorder (collectively SSD), and bipolar disorder (BD). This study examined the interactive effects of PRS-SZ and cognitive subtypes of SSD and BD in relation to GMV. Two-step cluster analysis was performed on 146 clinical cases (69 SSD and 77 BD) assessed on eight cognitive domains (verbal and visual memory, executive function, processing speed, visual processing, language ability, working memory, and planning). Among them, 55 BD, 51 SSD, and 58 healthy controls (HC), contributed to focal analyses of the relationships between cognitive subtypes, PRS-SZ and their interaction on GMV. Two distinct cognitive subtypes were evident among the combined sample of cases: a 'cognitive deficit' group (CD; N = 31, 20SSD/11BD) showed severe impairment across all cognitive indices, and a 'cognitively spared' (CS; N = 75; 31SSD/44BD) group showed intermediate cognitive performance that was significantly worse than the HC group but better than the CD subgroup. A cognitive subgroup-by-PRS-SZ interaction was significantly associated with GMV in the left precentral gyrus. Moderation analyses revealed a significant negative relationship between PRS-SZ and GMV in the CD group only. At low and average (but not high) PRS-SZ, larger precentral GMV was evident in the CD group compared to both CS and HC groups, and in the CS group compared to HCs. This study provides evidence for a relationship between regional GMV changes and PRS-SZ in psychosis spectrum cases with cognitive deficits, but not in cases cognitively spared. 

https://link.springer.com/content/pdf/10.1007/s00406-022-01450-4.pdf

Interactive effects of polygenic risk and cognitive subtype on brain morphology in schizophrenia spectrum and bipolar disorders

Multiomic prioritisation of risk genes for anorexia nervosa

So-called D-neuron (trace amine (TA) neuron) is the ligand neuron of trace amine-associated receptor, type 1 (TAAR1). Reduced stimulation of TAAR1 on dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) has been revealed to increase firing frequency of VTA DA neurons. A Patent Cooperation Treaty (PCT)-required histochemical methods (K. Ikemoto) were used to specify subgroups of D-neurons in the human brain (Ikemoto et al. 1997, 2016 (in press)), and to show D-neuron decrease in the nucleus accumbens (Acc) (D16, subgroup of D-neurons) of postmortem brains with schizophrenia (Ikemoto et  al. 2003). The human D-neuron system is found to be far developed in the forebrain in comparison with that of other species, including non-human primates (Kitahama et  al.2009). TA decrease caused by D-neuron reduction, and consequent TAAR1 stimulation decrease on terminals of midbrain VTA DA neurons leads to mesolimbic DA hyperactivity. Neural stem cell (NSC) dysfunction in the subventricular zone of lateral ventricle, which overlaps with the Acc, is supposed to be the cause of D-neuron reduction of schizophrenia. The rational is that the “D-cell hypothesis (TA hypothesis)” (Ikemoto 2012)  is essential hypothesis to link DA hypothesis (Hokfelt et  al, 1974)  with NSC dysfunction hypothesis (Reif et  al. 2006). From a therapeutic direction, (1) TAAR1 agonists or TAAR1 partial agonists (Revel et al. 2013), (2) DA D2 antagonists, and (3) neurotropic substances (e.g., brainderived neurotrophic factor (BDNF), lithium, anticonvulsants, and antidepressants) have potential to normalize mesolimbic DA hyperactivity. Intranasal administration of these neuroactive substances and/or their precursors to reach the neuroleptic acting site, such as the subventricular-accumbal region, by using nanotechnology, is a possible prospective therapeutic strategy, which is devoid of gastrointestinal side effects. PM495 Neuropathology and functional analysis of schizophrenia associated variant in the MIR137 locus Murray Cairns, Heath Cairns, Adam Carroll, Simonne Sherwin University of Newcastle, Australia Abstract Small non-coding microRNA (miRNA) coordinate mRNA translation in the brain, and their dysregulation has significant consequences in neurodevelopmental disorders. This hypothesis is supported by strong genetic evidence at the genome-wide associated variant in MIR137 (rs1625579) in recent PGC mega analysis of schizophrenia. We used a TaqMan genotyping and expression strategy to investigate the allelic expression (rs2660304) in postmortem DLPFC from subjects with schizophrenia and controls with no history of psychiatric disorder (n=74). While no significant difference was observed in the expression of miR-137 in postmortem DLPFC between the controls and schizophrenia, we found that mature miR-137 expression was significantly reduced in the samples homozygous for the risk allele compared to those homozygous for the alternative. Expression in the heterozygotes was not significantly different to either of the homozygotes, however, when we examined the allelic imbalance by differentiating pri-miR-137 expression at each allele (rs2660304), the risk allele was significantly lower compared to the alternative. Functional consequences of dysregulated miR137 in neurons was then examined human SH-SY5Y neuroblastsSmall non-coding microRNA (miRNA) coordinate mRNA translation in the brain, and their dysregulation has significant consequences in neurodevelopmental disorders. This hypothesis is supported by strong genetic evidence at the genome-wide associated variant in MIR137 (rs1625579) in recent PGC mega analysis of schizophrenia. We used a TaqMan genotyping and expression strategy to investigate the allelic expression (rs2660304) in postmortem DLPFC from subjects with schizophrenia and controls with no history of psychiatric disorder (n=74). While no significant difference was observed in the expression of miR-137 in postmortem DLPFC between the controls and schizophrenia, we found that mature miR-137 expression was significantly reduced in the samples homozygous for the risk allele compared to those homozygous for the alternative. Expression in the heterozygotes was not significantly different to either of the homozygotes, however, when we examined the allelic imbalance by differentiating pri-miR-137 expression at each allele (rs2660304), the risk allele was significantly lower compared to the alternative. Functional consequences of dysregulated miR137 in neurons was then examined human SH-SY5Y neuroblasts electroporated synthetic miR-137 and its antisense antagonist using gene expression profiling. While over expression of miR137 produced relatively few changes in target gene expression the repression of miR-137 in these cells produced changes in a large number of target genes, many of which have also been associated with schizophrenia. These genes were also enriched in several pathways believed to be involved in the neuropathology of the disorder including, axon guidance, glucocorticoid receptor signalling, ErbB signalling, dopamine-DARPP32 feedback in cAMP signalling, and mTOR signalling. This suggests that the risk variant in MIR137 is an eQTL and results in haploinsuficiency in carriers causing dysfunction in several pathways relevant to schizophrenia. PM496 How delusion is formed? Hee Jun Kim, M.Da, Jong Suk Park a,d, Ung Gu Kang a,b,c,* a Department of Psychiatry, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110–744, Republic of Korea b Department of Psychiatry and Behavioral Science, Seoul National

Murray J. Cairns

Papers

Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals

Interactive effects of polygenic risk and cognitive subtype on brain morphology in schizophrenia spectrum and bipolar disorders

Multiomic prioritisation of risk genes for anorexia nervosa

PM495. Neuropathology and functional analysis of schizophrenia associated variant in the MIR137 locus

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