Per Qvist

• PhD
• Aarhus University

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS2 intracellular domain (ICD) contains...

Janus kinase inhibitors (JAKi) have been associated with an increased risk of venous thromboembolism (VTE) limiting the use of JAKi-based therapy. To improve risk stratification and drug development, it is crucial to understand the implication of dysregulated JAK-Signal Transducers and Activators of Transcription (STAT) signaling in the pathogenesi...

The Vps10p-domain receptors SorCS1-3 have been repeatedly associated with the development of neurological and psychiatric disorders. They have emerged as key regulators of synaptic activity and neurotrophic signaling, but the underlying molecular mechanism remains poorly understood. Here we report that the SorCS1-3 intracellular domains (ICDs) cont...

Background: Mental health encompasses emotional, psychological, and social dimensions, extending beyond the mere absence of illness. Shaped by a complex interplay of hereditary factors and life experiences, mental health can deteriorate into clinical conditions necessitating intervention. However, the ambiguity between pathological and non-patholog...

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia. The disease has a substantial genetic component comprising both highly penetrant familial mutations ( APP , PSEN1, and PSEN2 ) and sporadic cases with complex genetic etiology. Mutations in APP and PSEN1/2 alter the proteolytic processing o...

Current differentiation protocols for generating mesencephalic dopaminergic (mesDA) neurons from human pluripotent stem cells result in grafts containing only a small proportion of mesDA neurons when transplanted in vivo. In this study, we develop lineage-restricted undifferentiated stem cells (LR-USCs) from pluripotent stem cells, which enhances t...

Sorting receptor SORCS2 is a stress-response factor protecting neurons from acute insults, such as during epilepsy. SORCS2 is also expressed in the pancreas, yet its action in this tissue remains unknown. Combining metabolic studies in SORCS2-deficient mice with ex vivo functional analyses and single-cell transcriptomics of pancreatic tissues, we i...

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which a...

Objective SORCS2 is an intracellular sorting receptor genetically associated with body mass index (BMI) in humans, yet its mode of action remains unknown. Elucidating the receptor function that defines its role in metabolic health is the objective of this work. Methods Combining in vivo metabolic studies in SORCS2-deficient mouse models with ex vi...

Motor neuron development requires an orchestrated action of trophic factors and guidance cues for axons to reach their targets. Here, we identify SorCS2 as a novel receptor for progranulin (PGRN) that is required for motor axon outgrowth in zebrafish and mice. In both species motor neurons express SorCS2, and PGRN is produced in cells juxta-positio...

Background: Mental disorders (MDx) comprise a heterogeneous group of conditions collectively characterized by abnormal patterns of feelings, thoughts, and behavior. Differential diagnosis is complicated by their varied and overlapping clinical presentations, which are shaped by a concerted interplay between hereditary risks and environmental exposu...

Major depression (MD) is a common mental disorder and a leading cause of disability worldwide. We conducted a GWAS meta-analysis of more than 1.3 million individuals, including 371,184 with MD, identifying 243 risk loci. Sixty-four loci are novel, including glutamate and GABA receptors that are targets for antidepressant drugs. Several biological p...

Bromodomain containing 1 ( BRD1) encodes an epigenetic regulator that controls the expression of genetic networks linked to mental illness. BRD1 is essential for normal brain development and its role in psychopathology has been demonstrated in genetic and preclinical studies. However, the neurobiology that bridges its molecular and neuropathologica...

Bipolar disorder is a debilitating psychiatric condition that is shaped in a concerted interplay between hereditary and triggering risk factors. Profound depression and mania define the disorder, but high clinical heterogeneity among patients complicates diagnosis as well as pharmacological intervention. Identification of peripheral biomarkers that...

Background Janus kinase inhibitors (JAKi) have been associated with an increased risk of venous thromboembolism (VTE) [1] . VTE comprises deep vein thrombosis and pulmonary embolism and is associated with complications such as recurrent VTE, post thrombotic syndrome, pulmonary hypertension, and death. These concerns limit the use of JAKi-based ther...

Background Depression is a common, complex, and debilitating mental disorder estimated to be under-diagnosed and insufficiently treated in society. Liability to depression is influenced by both genetic and environmental risk factors, which are both capable of impacting DNA methylation (DNAm). Accordingly, numerous studies have researched for DNAm s...

Visceral adipose tissue shows remarkable plasticity, constantly replacing mature adipocytes from an inherent pool of adipocyte precursors. The number of precursors is set in the juvenile organism and remains constant in adult life. Which signals drive precursor pool expansion in juveniles and why they operate in visceral but not in subcutaneous whi...

Isolation of multiple cell populations from limited starting material and with minimal influence on cell homeostasis and viability are common requirements in both basic and clinical research. Fluorescence-activated cell sorting is the most commonly applied sorting methodology with the majority of instruments being based on high pressure and electro...

The differentiation of human pluripotent stem cells (hPSCs) into mesencephalic dopaminergic (mesDA) neurons requires a precise combination of extrinsic factors that recapitulates the in vivo environment and timing. Current methods are capable of generating authentic mesDA neurons after long-term culture in vitro; however, when mesDA progenitors are...

Genetic studies have repeatedly shown that the Bromodomain containing 1 gene, BRD1, is involved in determining mental health, and the importance of the BRD1 protein for normal brain function has been studied in both cell models and constitutive haploinsufficient Brd1+/− mice. Homozygosity for inactivated Brd1 alleles is lethal during embryonic deve...

Aims Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). Here, we investigate associations between plasma ACE2 and outcome of COVID-19. Methods and results This analysis used da...

Aim: Mental illness comprises a group of heterogeneous conditions attributable to a complex interplay between hereditary and environmental components. Acting at the interface between environmental stimuli and their genomic actions, nuclear receptors (NRs) appear uniquely suited to facilitate gene-environment interactions in the context of mental he...

Neurons produced by reprogramming of other cell types are used to study cellular mechanisms of age-related neurodegenerative diseases. To model Alzheimer’s disease and other tauopathies, it is essential that alternative splicing of the MAPT transcript in these neurons produces the relevant tau isoforms. Human neurons derived from induced pluripoten...

Neuropsin is a brain-expressed extracellular matrix serine protease that governs synaptic plasticity through activity-induced proteolytic cleavage of synaptic proteins. Its substrates comprise several molecules central to structural synaptic plasticity, and studies in rodents have documented its role in cognition and the behavioral and neurobiologi...

The 22q11.2 deletion has been identified as a risk factor for multiple neurodevelopmental disorders. Behavioral and cognitive impairments are common among carriers of the 22q11.2 deletion. Parvalbumin expressing (PV+) interneurons provide perisomatic inhibition of excitatory neuronal circuits through GABAA receptors, and a deficit of PV+ inhibitory...

Direct neuronal conversion describes the process of generating induced neurons from somatic cells such as fibroblasts by overexpressing cell type-specific transcription factors, microRNAs or by culturing in the presence of small molecules. This was first achieved by expressing Brn2, Ascl1 and Myt1L in mouse fibroblasts, and was later achieved in hu...

The schizophrenia-associated gene, BRD1, encodes an epigenetic regulator in which chromatin interactome is enriched with genes implicated in mental health. Alterations in histone modifications and epigenetic regulation contribute to brain transcriptomic changes in affective disorders and preclinical data supports a role for BRD1 in psychopathology....

Aggregation of α-synuclein (αSN) is an important histological feature of Parkinson disease. Recent studies showed that the release of misfolded αSN from human and rodent neurons is relevant to the progression and spread of αSN pathology. Little is known, however, about the mechanisms responsible for clearance of extracellular αSN. This study found...

Porcine embryonic and induced pluripotent stem cells (ESCs; iPSCs) have proven difficult to derive and maintain in vitro. This may be due to inappropriate culturing conditions and incomplete activation of proper pluripotency networks. To this end, we characterized the transcriptome of porcine inner cell mass, epiblast, and transgene-dependent iPSCs...

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, follow...

Neuropsin is an extracellular matrix serine protease that governs the proteolytic cleavage of synaptic proteins and consequently synaptic structural plasticity. In the brain, its substrates include the cell adhesion molecules Neuregulin-1 and L1CAM, that have been linked to neurodevelopmental processes and disorders, such as schizophrenia and bipol...

BACKGROUND AND PURPOSE In vivo detection of β‐amyloid (Aβ) plaques in Alzheimer's disease (AD) is now possible with ¹¹C‐PiB positron emission tomography (PET). Conventionally, a cortical:cerebellar PiB uptake ratio threshold of 1.4‐1.5 has been used to categorize at‐risk subjects as “amyloid‐positive” and “amyloid‐negative.” It has been suggested t...

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danis...

Genetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1+/− mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that a...

Schizophrenia is a common and severe mental disorder arising from complex gene-environment interactions affecting brain development and functioning. While a consensus on the neuroanatomical correlates of schizophrenia is emerging, much of its fundamental pathobiology remains unknown. In this study, we explore brain morphometry in mice with genetic...

The blood-brain barrier consists of a tightly sealed monolayer of endothelial cells being vital in maintaining a stable intracerebral microenvironment. The barrier is receptive to leakage upon exposure to environmental factors, like hypoxia, and its disruption has been suggested as a constituent in the pathophysiology of both neurological and psych...

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features...

The schizophrenia and bipolar disorder associated gene, BRD1 , encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1 +/− mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the p...

Introductory paragraph Cannabis is the most frequently used illicit psychoactive substance worldwide ¹ . Life time use has been reported among 35-40% of adults in Denmark ² and the United States ³ . Cannabis use is increasing in the population 4–6 and among users around 9% become dependent ⁷ . The genetic risk component is high with heritability es...

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danis...

Major depressive disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. ¹ It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. ²⁻⁷ MDD is a major cause of disability worldwide. ⁸ We conducted a genome-wide association (GWA) me...

Schizophrenia is a debilitating brain disorder characterized by disturbances of emotion, perception and cognition. Cognitive impairments predict functional outcome in schizophrenia and are detectable even in the prodromal stage of the disorder. However, our understanding of the underlying neurobiology is limited and procognitive treatments remain e...

The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promote...

Primer sequences, expected amplicon sizes, and PCR annealing temperatures for bisulfite sequencing and pyrosequencing. (DOCX)

Primer sequences, expected amplicon sizes, and PCR extension times for transcript variant analysis. (DOCX)

Summary statistics for 6 selected DNA methylation differences between fetal and postnatal human cortex and their correlation to BRD1 expression. (DOCX)

PCR amplification of transcript regions. (a) PCR amplification of transcript regions starting at exon 1A. Left gel: HeLa cells, right gel: SH-SY5Y cells. Lane 1: 1 kb DNA ladder (Thermo Scientific), lane 2: exon 1A F + exon 2 R, lane 3: exon 1A F + exon 4 R, lane 4: exon 1A F + exon 6 R, lane 4: exon 1A F + exon 7 R, lane 5: exon 1A F + exon 8 R. (...

Primer sequences and expected amplicon sizes for real-time qPCR. (DOCX)

Expression of BRD1 transcript variants in SH-SY5Y cells following Zebularine treatment. The total BRD1 expression and expression of transcript variants containing exon 1C, 1B, and 1A were measured in RNA extracted from SH-SY5Y cells following exposure to 0, 0.05, 0.1, or 0.25 mM Zebularine for 72 hours. POLR2A and TBP were found to be the most stab...

Region 2 pyrosequencing assay example. A representative pyrogram from a region 2 assay run on a homozygous (A/A) individual. CpG methylation proportions were measured at two sites, CpG sites 3 and 4 marked with blue columns at dispensation 9–10 and 20–21, respectively. In this example methylation proportions are 93% at site 3 and 88% at site 4. At...

Supplementary materials and methods. Detailed description of the materials and methods used for transcript variant analysis. (DOCX)

Background: The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative. Methods: This study assessed the transcriptional drive of a schizophrenia-associated BRD1...

Background: Massively parallel cDNA sequencing (RNA-seq) experiments are gradually superseding microarrays in quantitative gene expression profiling. However, many biologists are uncertain about the choice of differentially expressed gene (DEG) analysis methods and the validity of cost-saving sample pooling strategies for their RNA-seq experiments...

Significance DNA double-strand breaks (DSBs) are one of the most deleterious types of DNA lesions and may pose a severe threat to genome integrity. Breast cancer type 1 susceptibility protein (BRCA1) is a multifunctional DNA damage response factor that is known to protect the chromosome/genome stability by participating in one of the major DSB repa...

Objectives Breakpoints of chromosomal abnormalities facilitate identification of novel candidate genes for psychiatric disorders. Genome-wide significant evidence supports the linkage between chromosome 17q25.3 and bipolar disorder (BD). Co-segregation of translocation t(9;17)(q33.2;q25.3) with psychiatric disorders has been reported. We aimed to n...

Anterior cingulate cortex (ACC) is a brain region that is critical for higher cognitive functions as attention, control of behavior and remote memory expression. Synchronization of pyramidal neurons of ACC is essential for the performance of neuronal circuits and dependent on activity of local GABAergic interneurons (Goldman-Rakic 1995). Alteration...

Pedigrees of consanguineous families investigated. A Jawad Family. B SCKL2 Family. (PDF)

Cell cycle distributions for lymphoblastoid populations. Cells were obtained from the SCKL2 family (s/s and +/s, representing homozygous and heterozygous cells for the CtIPs mutation, respectively) and a healthy unrelated control individual (bottom). The percentages of cells in each phase of the cell cycle are represented in graphs. See methods for...

Schematics showing splice-site prediction of the altered 15th exon/intron transition. Upper panels indicate coding potential; middle panels represent donor-site predictions; lower panels represent acceptor-site predictions. Coloured lines: variable 90% threshold. Encircled numbers 1/2 indicate exon 15 wild-type (wt) acceptor-/donor-site; 3 indicate...

Sequence alignment of the C-termini of full-length CtIP, CtIPSCKL2 and CtIPJawad. Alternative splicing of the CtIPSeckle transcript leads to a 20 amino acid sequence change (aa 763 to 782) and a C-terminal truncation. The 2 base-pair deletion in CtIPJawad changes the reading frame and leads to a 5 amino acid sequence change (aa 603-607) and a large...

List of primers used for mutational analysis. Pair of primers (F:Forward and R: Reverse) that anneal at introns were used to amplify genomic DNA. PCR products were directly sequenced. See Methods for details. (DOC)

Accumulation of truncated CtIP at sites of laser microirradiation. Cells expressing GFP-tagged C-terminal truncated CtIP were laser microirradiated and filmed at maximum acquisition speed. (MOV)

Accumulation of wild type CtIP at sites of laser microirradiation. Cells expressing GFP-tagged full length CtIP were laser microirradiated and filmed at maximum acquisition speed. (MOV)

Seckel syndrome is a recessively inherited dwarfism disorder characterized by microcephaly and a unique head profile. Genetically, it constitutes a heterogeneous condition, with several loci mapped (SCKL1-5) but only three disease genes identified: the ATR, CENPJ, and CEP152 genes that control cellular responses to DNA damage. We previously mapped...