Candidate gene studies in human anxiety disorders

Anxiety disorders, such as panic disorder (PD), obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and phobias are common psychiatric disorders, characterized by exaggerated, prolonged and debilitating levels of anxiety. They are complex diseases with onset influenced by both environmental and genetic factors, but so far little progress has been made in identifying solid susceptibility genes. The aim of this study was to shed light on the genetic basis of human anxiety disorders by genetic analyses of putative susceptibility genes. Altogether, 333 single nucleotide polymorphism markers from 30 genes were tested for genetic association to anxiety disorders in a sample (N = 974) derived from the Finnish population-based Health 2000 cohort. Three other samples from Spain (N = 503), Sweden (N = 2020) and USA (N = 1128) were used for replication attempts or meta-analyses. The studied genes were 1) selected based on a mouse model of anxiety-like behavior; 2) an asthma-linked receptor (neuropeptide S receptor 1; NPSR1) and its neuropeptide ligand (neuropeptide S; NPS); and 3) selected based on previous findings in anxiety disorders or anxiety-related personality traits. We also evaluated whether any of the studied genes modulate probability for anxiety disorders in interaction with childhood adverse life events, which are strong environmental risk factors for anxiety disorders. First, with a cross-species approach, we discovered that six of the murine candidate genes associated with specific human anxiety disorders. The implicated genes link novel biological pathways to anxiety susceptibility. Second, NPSR1 and NPS associated with PD in adults, and symptoms of anxiety/depression in children. Our findings suggest that NPS-NPSR1 signaling modulates predisposition not only to asthma, but also to anxiety. Third, of the putative susceptibility genes examined based on previous studies, the strongest associations were for glutamate decarboxylase 1 (GAD1) with phobias. Our results, together with previous findings in the gene, support the role of GAD1 as a risk factor for anxiety- and mood disorders, and neuroticism. Fourth, the neuropeptide Y (NPY) gene modulated the effects of the number of experienced childhood adversities on anxiety susceptibility. NPY may therefore influence individual variation in stress resilience. In conclusion, we identified altogether ten potential susceptibility genes for anxiety disorders. They should be further evaluated in independent study samples, and studied functionally to understand how they may regulate behavior. Such future studies will be essential for evaluating their therapeutic potential in treatment of anxiety disorders. Our findings also support the notion that understanding of the interplay between environmental risk factors and genetic variants is important for understanding predisposition to psychiatric disorders.Ahdistuneisuushäiriöt, kuten paniikkihäiriö, pakko-oireinen häiriö, traumaperäinen stressihäiriö, yleistynyt ahdistuneisuushäiriö ja fobiat, ovat yleisiä psykiatrisia häiriöitä, joiden tunnusmerkki on liiallinen, pitkittynyt ja toimintakykyä alentava ahdistuneisuus. Niiden puhkeamiseen vaikuttavat sekä ympäristö- että geneettiset tekijät, mutta vankkoja alttiusgeenejä tunnetaan toistaiseksi heikosti. Tämän tutkimuksen tavoitteena oli selvittää ahdistuneisuushäiriöiden perinnöllistä taustaa geneettisillä analyyseillä, joissa tutkittiin mahdollisia alttiusgeenejä. ----- Arvioimme yhteensä 30 geenin yhteyttä ahdistuneisuushäiriöihin näytteessä, joka oli peräisin suomalaisesta Terveys 2000 väestötutkimuksesta. Käytimme myös kolmea muuta aineistoa Espanjasta, Ruotsista ja Yhdysvalloista replikaatioaineistona tai meta-analyyseissä. Tutkitut geenit olivat: 1) valittu perustuen hiiren ahdistuneisuuskäyttäytymistä mittaavaan eläinmalliin; 2) astmaan yhdistetty reseptori (neuropeptidi S reseptori 1; NPSR1) ja sen ligandi, neuropeptidi S (NPS); sekä 3) valittu perustuen aikaisempiin löydöksiin ahdistuneisuudessa. Selvitimme myös muokkaavatko jotkut tutkituista geeneistä alttiutta ahdistuneisuushäiriöille yhdessä lapsuusiän vastoinkäymisten kanssa, jotka ovat vahvoja ympäristöllisiä riskitekijöitä ahdistuneisuushäiriöille. Lajeja yhdistävän lähestymistavan avulla havaitsimme, että kuusi hiirimallin perusteella valittua ehdokasgeeniä assosioituivat spesifisiin ahdistuneisuushäiriöihin. Löydöksemme yhdistävät uusia biologisia reittejä ahdistuneisuusalttiuteen. NPS ja NPSR1 assosioituivat paniikkihäiriöön aikuisilla sekä ahdistuneisuuden/masennuksen oireisiin lapsilla. NPS-NPSR1 signalointi näyttäisi muuntelevan altiutta paitsi astmalle myös ahdistuneisuudelle. Aikaisemmin ahdistuneisuuteen yhdistetyistä geeneistä merkitsevimmät löydöksemme olivat glutamaattidekarboksylaasi 1 (GAD1) geenistä, joka lisäsi riskiä sairastua fobioihin. Analyysimme, yhdessä aikaisempien löydösten kanssa, tukee GAD1:n merkitystä riskitekijänä ahdistuneisuus- ja mielialahäiriöille sekä neuroottisuudelle. Neuropeptidi Y (NPY) geeni muunteli koettujen lapsuusiän vastoinkäymisten määrän vaikutusta ahdistuneisuusalttiuteen. NPY:llä sattaa olla rooli yksilöllisen stressinsietokyvyn muuntelussa. Yhteenvetona tunnistimme yhteensä kymmenen potentiaalista alttiusgeeniä ahdistuneisuushäiriöille. Niitä tulisi jatkossa tutkia riippumattomissa näytteissä sekä toiminnallisin kokein, jotta voimme ymmärtää miten ne säätelevät käyttäytymistä. On myös syytä arvioida voisivatko tunnistetut geenit olla sopivia kohteita ahdistuneisuushäiriöiden lääkehoidossa. Löydöksemme tukevat myös käsitystä, että ympäristöllisten riskitekijöiden ja geenien vuorovaikutusten tunteminen on tärkeää psykiatristen tautien alttiuden ymmärtämisessä

An across-breed validation study of 46 genetic markers in canine hip dysplasia

BackgroundCanine hip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants.ResultsWe execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Federation Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation.ConclusionsOur study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis.Peer reviewe

Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs

Neonatal interstitial lung diseases due to abnormal surfactant biogenesis are rare in humans and have never been reported as a spontaneous disorder in animals. We describe here a novel lung disorder in Airedale Terrier (AT) dogs with clinical symptoms and pathology similar to the most severe neonatal forms of human surfactant deficiency. Lethal hypoxic respiratory distress and failure occurred within the first days or weeks of life in the affected puppies. Transmission electron microscopy of the affected lungs revealed maturation arrest in the formation of lamellar bodies (LBs) in the alveolar epithelial type II (AECII) cells. The secretory organelles were small and contained fewer lamellae, often in combination with small vesicles surrounded by an occasionally disrupted common limiting membrane. A combined approach of genome-wide association study and whole exome sequencing identified a recessive variant, c.1159G>A, p.(E387K), in LAMP3, a limiting membrane protein of the cytoplasmic surfactant organelles in AECII cells. The substitution resides in the LAMP domain adjacent to a conserved disulfide bond. In summary, this study describes a novel interstitial lung disease in dogs, identifies a new candidate gene for human surfactant dysfunction and brings important insights into the essential role of LAMP3 in the process of the LB formation. Author summary We have characterized a lethal lung disease in neonatal Airedale Terrier dogs. The pathological features of the disease resemble those of the surfactant dysfunction in newborn babies. Surfactant is essential for lung function and we observed a maturation defect in the surfactant producing organelles of the lung epithelial type II cells. Genetic analyses revealed a recessive variant in the lysosome associated membrane LAMP3 gene. LAMP3 is a structural, limiting membrane protein of the surfactant organelles. This study provides an excellent candidate gene for human surfactant disorders as well as new insights into LAMP3 biology and pathophysiology while the affected breed will benefit from genetic testing to eradicate this severe disease.Peer reviewe

An across-breed validation study of 46 genetic markers in canine hip dysplasia

Abstract Background Canine hip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants. Results We execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Fédération Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation. Conclusions Our study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis

Genetic epidemiology of blood type, disease and trait variants, and genome-wide genetic diversity in over 11,000 domestic cats

In the largest DNA-based study of domestic cats to date, 11,036 individuals (10,419 pedigreed cats and 617 non-pedigreed cats) were genotyped via commercial panel testing elucidating the distribution and frequency of known disease, blood type, and physical trait associated genetic variants across cat breeds. This study provides allele frequencies for many disease-associated variants for the first time and provides updates on previously reported information with evidence suggesting that DNA testing has been effectively used to reduce disease associated variants within certain pedigreed cat populations over time. We identified 13 disease-associated variants in 47 breeds or breed types in which the variant had not previously been documented, highlighting the relevance of comprehensive genetic screening across breeds. Three disease-associated variants were discovered in non-pedigreed cats only. To investigate the causality of nine disease-associated variants in cats of different breed backgrounds our veterinarians conducted owner interviews, reviewed clinical records, and invited cats to have follow-up clinical examinations. Additionally, genetic variants determining blood types A, B and AB, which are relevant clinically and in cat breeding, were genotyped. Appearance-associated genetic variation in all cats is also discussed. Lastly, genome-wide SNP heterozygosity levels were calculated to obtain a comparable measure of the genetic diversity in different cat breeds. This study represents the first comprehensive exploration of informative Mendelian variants in felines by screening over 10,000 pedigreed cats. The results qualitatively contribute to the understanding of feline variant heritage and genetic diversity and demonstrate the clinical utility and importance of such information in supporting breeding programs and the research community. The work also highlights the crucial commitment of pedigreed cat breeders and registries in supporting the establishment of large genomic databases, that when combined with phenotype information can advance scientific understanding and provide insights that can be applied to improve the health and welfare of cats. Author summaryDomestic cats are one of the world's most popular companion animals, of which pedigreed cats represent small unique subpopulations. Genetic research on pedigreed cats has facilitated discoveries of heritable conditions resulting in the availability of DNA testing for studying and managing inherited disorders and traits in specific cat breeds. We have explored an extensive study cohort of 11,036 domestic cat samples representing pedigreed cats of 90 breeds and breed types. This work provided insight into the heritage of feline disease and trait alleles. We gained knowledge on the most common and relevant genetic markers for inherited disorders and physical traits, and the genetic determinants of the clinically relevant AB blood group system. We also used a measure of genetic diversity to compare inbreeding levels within and between breeds. This information can help support sustainable breeding goals within the cat fancy. Direct-to-consumer genetic tests help to raise awareness of various inherited single gene conditions in cats and provide information that owners can share with their veterinarians. In due course, ventures of this type will enable the genetics of common complex feline disease to be deciphered, paving the way for precision healthcare with the potential to ultimately improve welfare for all cats.Peer reviewe

Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders

Background The growing number of identified genetic disease risk variants across dog breeds challenges the current state-of-the-art of population screening, veterinary molecular diagnostics, and genetic counseling. Multiplex screening of such variants is now technologically feasible, but its practical potential as a supportive tool for canine breeding, disease diagnostics, pet care, and genetics research is still unexplored. Results To demonstrate the utility of comprehensive genetic panel screening, we tested nearly 7000 dogs representing around 230 breeds for 93 disease-associated variants using a custom-designed genotyping microarray (the MyDogDNA1panel test). In addition to known breed disease-associated mutations, we discovered 15 risk variants in a total of 34 breeds in which their presence was previously undocumented. We followed up on seven of these genetic findings to demonstrate their clinical relevance. We report additional breeds harboring variants causing factor VII deficiency, hyperuricosuria, lens luxation, von Willebrand's disease, multifocal retinopathy, multidrug resistance, and rod-cone dysplasia. Moreover, we provide plausible molecular explanations for chondrodysplasia in the Chinook, cerebellar ataxia in the Norrbottenspitz, and familiar nephropathy in the Welsh Springer Spaniel. Conclusions These practical examples illustrate how genetic panel screening represents a comprehensive, efficient and powerful diagnostic and research discovery tool with a range of applications in veterinary care, disease research, and breeding. We conclude that several known disease alleles are more widespread across different breeds than previously recognized. However, careful follow up studies of any unexpected discoveries are essential to establish genotype-phenotype correlations, as is readiness to provide genetic counseling on their implications for the dog and its breed.Peer reviewe

Towards practical reinforcement learning for tokamak magnetic control

Reinforcement learning (RL) has shown promising results for real-time control systems, including the domain of plasma magnetic control. However, there are still significant drawbacks compared to traditional feedback control approaches for magnetic confinement. In this work, we address key drawbacks of the RL method; achieving higher control accuracy for desired plasma properties, reducing the steady-state error, and decreasing the required time to learn new tasks. We build on top of \cite{degrave2022magnetic}, and present algorithmic improvements to the agent architecture and training procedure. We present simulation results that show up to 65\% improvement in shape accuracy, achieve substantial reduction in the long-term bias of the plasma current, and additionally reduce the training time required to learn new tasks by a factor of 3 or more. We present new experiments using the upgraded RL-based controllers on the TCV tokamak, which validate the simulation results achieved, and point the way towards routinely achieving accurate discharges using the RL approach

Disruption of Rolandic Gamma-Band Functional Connectivity by Seizures is Associated with Motor Impairments in Children with Epilepsy

Although children with epilepsy exhibit numerous neurological and cognitive deficits, the mechanisms underlying these impairments remain unclear. Synchronization of oscillatory neural activity in the gamma frequency range (>30 Hz) is purported to be a mechanism mediating functional integration within neuronal networks supporting cognition, perception and action. Here, we tested the hypothesis that seizure-induced alterations in gamma synchronization are associated with functional deficits. By calculating synchrony among electrodes and performing graph theoretical analysis, we assessed functional connectivity and local network structure of the hand motor area of children with focal epilepsy from intracranial electroencephalographic recordings. A local decrease in inter-electrode phase synchrony in the gamma bands during ictal periods, relative to interictal periods, within the motor cortex was strongly associated with clinical motor weakness. Gamma-band ictal desychronization was a stronger predictor of deficits than the presence of the seizure-onset zone or lesion within the motor cortex. There was a positive correlation between the magnitude of ictal desychronization and impairment of motor dexterity in the contralateral, but not ipsilateral hand. There was no association between ictal desynchronization within the hand motor area and non-motor deficits. This study uniquely demonstrates that seizure-induced disturbances in cortical functional connectivity are associated with network-specific neurological deficits

Intercomparison of NO2, O4, O3 and HCHO slant column measurements by MAX-DOAS and zenith-sky UV¿visible spectrometers during CINDI-2

40 pags., 22 figs., 13 tabs.In September 2016, 36 spectrometers from 24 institutes measured a number of key atmospheric pollutants for a period of 17¿d during the Second Cabauw Intercomparison campaign for Nitrogen Dioxide measuring Instruments (CINDI-2) that took place at Cabauw, the Netherlands (51.97¿¿N, 4.93¿¿E). We report on the outcome of the formal semi-blind intercomparison exercise, which was held under the umbrella of the Network for the Detection of Atmospheric Composition Change (NDACC) and the European Space Agency (ESA). The three major goals of CINDI-2 were (1) to characterise and better understand the differences between a large number of multi-axis differential optical absorption spectroscopy (MAX-DOAS) and zenith-sky DOAS instruments and analysis methods, (2) to define a robust methodology for performance assessment of all participating instruments, and (3) to contribute to a harmonisation of the measurement settings and retrieval methods. This, in turn, creates the capability to produce consistent high-quality ground-based data sets, which are an essential requirement to generate reliable long-term measurement time series suitable for trend analysis and satellite data validation. The data products investigated during the semi-blind intercomparison are slant columns of nitrogen dioxide (NO2), the oxygen collision complex (O4) and ozone (O3) measured in the UV and visible wavelength region, formaldehyde (HCHO) in the UV spectral region, and NO2 in an additional (smaller) wavelength range in the visible region. The campaign design and implementation processes are discussed in detail including the measurement protocol, calibration procedures and slant column retrieval settings. Strong emphasis was put on the careful alignment and synchronisation of the measurement systems, resulting in a unique set of measurements made under highly comparable air mass conditions. The CINDI-2 data sets were investigated using a regression analysis of the slant columns measured by each instrument and for each of the target data products. The slope and intercept of the regression analysis respectively quantify the mean systematic bias and offset of the individual data sets against the selected reference (which is obtained from the median of either all data sets or a subset), and the rms error provides an estimate of the measurement noise or dispersion. These three criteria are examined and for each of the parameters and each of the data products, performance thresholds are set and applied to all the measurements. The approach presented here has been developed based on heritage from previous intercomparison exercises. It introduces a quantitative assessment of the consistency between all the participating instruments for the MAX-DOAS and zenith-sky DOAS techniques.CINDI-2 received funding from the Netherlands Space Office (NSO). Funding for this study was provided by ESA through the CINDI-2 (ESA contract no. 4000118533/16/ISbo) and FRM4DOAS (ESA contract no. 4000118181/16/I-EF) projects and partly within the EU 7th Framework Programme QA4ECV project (grant agreement no. 607405). The BOKU MAX-DOAS instrument was funded and the participation of Stefan F. Schreier was supported by the Austrian Science Fund (FWF): I 2296-N29. The participation of the University of Toronto team was supported by the Canadian Space Agency (through the AVATARS project) and the Natural Sciences and Engineering Research Council (through the PAHA project). The instrument was primarily funded by the Canada Foundation for Innovation and is usually operated at the Polar Environment Atmospheric Research Laboratory (PEARL) by the Canadian Network for the Detection of Atmospheric Change (CANDAC). Funding for CISC was provided by the UVAS (“Ultraviolet and Visible Atmospheric Sounder”) projects SEOSAT/INGENIO, ESP2015-71299- R, MINECO-FEDER and UE. The activities of the IUP-Heidelberg were supported by the DFG project RAPSODI (grant no. PL 193/17-1). SAOZ and Mini-SAOZ instruments are supported by the Centre National de la Recherche Scientifique (CNRS) and the Centre National d’Etudes Spatiales (CNES). INTA recognises support from the National funding projects HELADO (CTM2013-41311-P) and AVATAR (CGL2014-55230-R). AMOIAP recognises support from the Russian Science Foundation (grant no. 16-17-10275) and the Russian Foundation for Basic Research (grant nos. 16-05- 01062 and 18-35-00682). Ka L. Chan received transnational access funding from ACTRIS-2 (H2020 grant agreement no. 654109). Rainer Volkamer recognises funding from NASA’s Atmospheric Composition Program (NASA-16-NUP2016-0001) and the US National Science Foundation (award AGS-1620530). Henning Finkenzeller is the recipient of a NASA graduate fellowship. Mihalis Vrekoussis recognises support from the University of Bremen and the DFG Research Center/Cluster of Excellence “The Ocean in the Earth System-MARUM”. Financial support through the University of Bremen Institutional Strategy in the framework of the DFG Excellence Initiative is gratefully appreciated for Anja Schönhardt. Pandora instrument deployment was supported by Luftblick through the ESA Pandonia Project and NASA Pandora Project at the Goddard Space Flight Center under NASA Headquarters’ Tropospheric Composition Program. The article processing charges for this open-access publication were covered by BK Scientific

Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1)

Peer reviewe