The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.Peer reviewe

Astrocytic cell adhesion genes linked to schizophrenia correlate with synaptic programs in neurons

The maturation of neurons and the development of synapses, although emblematic of neurons, also relies on interactions with astrocytes and other glia. Here, to study the role of glia-neuron interactions, we analyze the transcriptomes of human pluripotent stem cell (hPSC)-derived neurons, from 80 human donors, that were cultured with or without contact with glial cells. We find that the presence of astrocytes enhances synaptic gene-expression programs in neurons when in physical contact with astrocytes. These changes in neurons correlate with increased expression, in the cocultured glia, of genes that encode synaptic cell adhesion molecules. Both the neuronal and astrocyte gene-expression programs are enriched for genes associated with schizophrenia risk. Our results suggest that astrocyte-expressed genes with synaptic functions are associated with stronger expression of synaptic genetic programs in neurons, and they suggest a potential role for astrocyte-neuron interactions in schizophrenia.Peer reviewe

A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression

Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases

“I’d like more options!” : Interviews to explore young people and family decision-making needs for pain management in juvenile idiopathic arthritis

Background: Juvenile idiopathic arthritis (JIA) is a common pediatric rheumatic condition and is associated with symptoms such as joint pain that can negatively impact health-related quality of life. To effectively manage pain in JIA, young people, their families, and health care providers (HCPs) should be supported to discuss pain management options and make a shared decision. However, pain is often under-recognized, and pain management discussions are not optimal. No studies have explored decision-making needs for pain management in JIA using a shared decision making (SDM) model. We sought to explore families’ decision-making needs with respect to pain management among young people with JIA, parents/caregivers, and HCPs. Methods We conducted semi-structured virtual or face-to-face individual interviews with young people with JIA 8–18 years of age, parents/caregivers and HCPs using a qualitative descriptive study design. We recruited participants online across Canada and the United States, from a hospital and from a quality improvement network. We used interview guides based on the Ottawa Decision Support Framework to assess decision-making needs. We audiotaped, transcribed verbatim and analyzed interviews using thematic analysis. Results A total of 12 young people (n = 6 children and n = 6 adolescents), 13 parents/caregivers and 11 HCPs participated in interviews. Pediatric HCPs were comprised of rheumatologists (n = 4), physical therapists (n = 3), rheumatology nurses (n = 2) and occupational therapists (n = 2). The following themes were identified: (1) need to assess pain in an accurate manner; (2) need to address pain in pediatric rheumatology consultations; (3) need for information on pain management options, especially nonpharmacological approaches; (4) importance of effectiveness, safety and ease of use of treatments; (5) need to discuss young people/families’ values and preferences for pain management options; and the (6) need for decision support. Themes were similar for young people, parents/caregivers and HCPs, although their respective importance varied. Conclusions Findings suggest a need for evidence-based information and communication about pain management options, which would be addressed by decision support interventions and HCP training in pain and SDM. Work is underway to develop such interventions and implement them into practice to improve pain management in JIA and in turn lead to better health outcomes.Medicine, Faculty ofNon UBCPhysical Therapy, Department ofReviewedFacultyResearcherGraduateOthe