Publications by authors named "Hannes Lohi"

167 Publications

Canine hyperactivity, impulsivity, and inattention share similar demographic risk factors and behavioural comorbidities with human ADHD.

Transl Psychiatry 2021 10 1;11(1):501. Epub 2021 Oct 1.

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder impairing the quality of life of the affected individuals. The domestic dog can spontaneously manifest high hyperactivity/impulsivity and inattention which are components of human ADHD. Therefore, a better understanding of demographic, environmental and behavioural factors influencing canine hyperactivity/impulsivity and inattention could benefit both humans and dogs. We collected comprehensive behavioural survey data from over 11,000 Finnish pet dogs and quantified their level of hyperactivity/impulsivity and inattention. We performed generalised linear model analyses to identify factors associated with these behavioural traits. Our results indicated that high levels of hyperactivity/impulsivity and inattention were more common in dogs that are young, male and spend more time alone at home. Additionally, we showed several breed differences suggesting a substantial genetic basis for these traits. Furthermore, hyperactivity/impulsivity and inattention had strong comorbidities with compulsive behaviour, aggressiveness and fearfulness. Multiple of these associations have also been identified in humans, strengthening the role of the dog as an animal model for ADHD.
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http://dx.doi.org/10.1038/s41398-021-01626-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486809PMC
October 2021

Whole Genome Sequencing Reveals Multiple Linked Genetic Variants on Canine Chromosome 12 Associated with Risk for Symmetrical Lupoid Onychodystrophy (SLO) in the Bearded Collie.

Genes (Basel) 2021 Aug 19;12(8). Epub 2021 Aug 19.

Department on Animal Science, University of California, Davis, CA 95616, USA.

In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association study of the Bearded Collie revealed two regions of association that conferred risk for disease: one on canine chromosome (CFA) 12 that encompasses the DLA genes, and one on CFA17. Case-control association was employed on whole genome sequencing data to uncover putative causative variants in SLO within the CFA12 and CFA17 associated regions. Genotype imputation was then employed to refine variants of interest. Although no SLO-associated protein-coding variants were identified on CFA17, multiple variants, many with predicted damaging effects, were identified within potential candidate genes on CFA12. Furthermore, many potentially damaging alleles were fully correlated with the presence of DLA class II risk haplotypes for SLO, suggesting that the variants may reflect DLA class II haplotype association with disease or vice versa. Strong linkage disequilibrium in the region precluded the ability to isolate and assess the individual or combined effect of variants on disease development. Nonetheless, all were predictive of risk for SLO and, with judicious assessment, their application in selective breeding may prove useful to reduce the incidence of SLO in the breed.
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http://dx.doi.org/10.3390/genes12081265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394396PMC
August 2021

A novel canine nuclear magnetic resonance spectroscopy-based metabolomics platform: Validation and sample handling.

Vet Clin Pathol 2021 Sep 24;50(3):410-426. Epub 2021 Aug 24.

PetBiomics Ltd, Helsinki, Finland.

Background: Metabolomics has been proven to be an invaluable research tool by providing comprehensive insight into systemic metabolism. However, the lack of scalable and quantitative methods with known reference intervals (RIs) and documented reproducibility has prevented the use of metabolomics in the clinical setting.

Objective: The objective of this study was to validate the developed quantitative nuclear magnetic resonance (NMR) spectroscopy-based metabolomics platform for canine serum and plasma samples and determine optimal sample handling conditions for its use.

Methods: Altogether, 8247 canine samples were analyzed using a Bruker's 500 MHz NMR spectrometer. Using statistical approaches derived from international guidelines, we studied method precision, measurand stability in various long- and short-term storage conditions, as well as the effect of prolonged contact with red blood cells (RBCs), and differences among blood collection tubes. We also screened interferences with lipemia, hemolysis, and bilirubinemia. The results were compared against routine clinical chemistry methods, and RIs were defined for all measurands.

Results: We determined RIs for 123 measurands, most of which were previously unpublished. The reproducibility of the results of the NMR platform appeared generally outstanding, and the integrity of the results can be ensured by following standard blood drawing and processing guidelines.

Conclusions: Owing to the advantages of quantitative results, high reproducibility, and scalability, this canine metabolomics platform holds great potential for numerous clinical and research applications to improve canine health and well-being.
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http://dx.doi.org/10.1111/vcp.12954DOI Listing
September 2021

Dog colour patterns explained by modular promoters of ancient canid origin.

Nat Ecol Evol 2021 Oct 12;5(10):1415-1423. Epub 2021 Aug 12.

Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Distinctive colour patterns in dogs are an integral component of canine diversity. Colour pattern differences are thought to have arisen from mutation and artificial selection during and after domestication from wolves but important gaps remain in understanding how these patterns evolved and are genetically controlled. In other mammals, variation at the ASIP gene controls both the temporal and spatial distribution of yellow and black pigments. Here, we identify independent regulatory modules for ventral and hair cycle ASIP expression, and we characterize their action and evolutionary origin. Structural variants define multiple alleles for each regulatory module and are combined in different ways to explain five distinctive dog colour patterns. Phylogenetic analysis reveals that the haplotype combination for one of these patterns is shared with Arctic white wolves and that its hair cycle-specific module probably originated from an extinct canid that diverged from grey wolves more than 2 million years ago. Natural selection for a lighter coat during the Pleistocene provided the genetic framework for widespread colour variation in dogs and wolves.
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http://dx.doi.org/10.1038/s41559-021-01524-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484016PMC
October 2021

Reliability and Validity of Seven Feline Behavior and Personality Traits.

Animals (Basel) 2021 Jul 2;11(7). Epub 2021 Jul 2.

Department of Veterinary Biosciences, University of Helsinki, 00014 Helsinki, Finland.

Domestic cats are popular pets, and they have personalities, with stable behavior differences between individuals. Lately, feline behavior and personality have been studied with different approaches, for example, with owner-completed questionnaires. The majority of these studies, however, lack a sufficient validation and reliability assessment of the questionnaires used. We designed an online feline behavior and personality questionnaire to collect cat behavior data from their owners. Then, we ran a factor analysis to study the structure of personality and behavior in a dataset of over 4300 cats. For validation, we studied the internal consistency, test-retest reliability, inter-rater reliability, convergent validity and discriminant validity of this questionnaire and extracted factors. In addition, we briefly examined breed differences in the seven discovered factors: fearfulness, activity/playfulness, aggression toward humans, sociability toward humans, sociability toward cats, excessive grooming and litterbox issues. Most of the rank ordering of breeds within each trait paralleled what has been found in previous studies. The validity and reliability of the questionnaire and factors were good, strengthening owner-completed questionnaires as a method to collect behavioral data from pet animals. Breed differences suggest a genetic background for personality. However, these differences should be studied further with multidimensional models, including environmental and biological variables.
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http://dx.doi.org/10.3390/ani11071991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300181PMC
July 2021

Reliable wolf-dog hybrid detection in Europe using a reduced SNP panel developed for non-invasively collected samples.

BMC Genomics 2021 Jun 25;22(1):473. Epub 2021 Jun 25.

Conservation Genetics Group, Senckenberg Research Institute and Natural History Museum Frankfurt, Gelnhausen, Germany.

Background: Understanding the processes that lead to hybridization of wolves and dogs is of scientific and management importance, particularly over large geographical scales, as wolves can disperse great distances. However, a method to efficiently detect hybrids in routine wolf monitoring is lacking. Microsatellites offer only limited resolution due to the low number of markers showing distinctive allele frequencies between wolves and dogs. Moreover, calibration across laboratories is time-consuming and costly. In this study, we selected a panel of 96 ancestry informative markers for wolves and dogs, derived from the Illumina CanineHD Whole-Genome BeadChip (174 K). We designed very short amplicons for genotyping on a microfluidic array, thus making the method suitable also for non-invasively collected samples.

Results: Genotypes based on 93 SNPs from wolves sampled throughout Europe, purebred and non-pedigree dogs, and suspected hybrids showed that the new panel accurately identifies parental individuals, first-generation hybrids and first-generation backcrosses to wolves, while second- and third-generation backcrosses to wolves were identified as advanced hybrids in almost all cases. Our results support the hybrid identity of suspect individuals and the non-hybrid status of individuals regarded as wolves. We also show the adequacy of these markers to assess hybridization at a European-wide scale and the importance of including samples from reference populations.

Conclusions: We showed that the proposed SNP panel is an efficient tool for detecting hybrids up to the third-generation backcrosses to wolves across Europe. Notably, the proposed genotyping method is suitable for a variety of samples, including non-invasive and museum samples, making this panel useful for wolf-dog hybrid assessments and wolf monitoring at both continental and different temporal scales.
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http://dx.doi.org/10.1186/s12864-021-07761-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235813PMC
June 2021

Clinical and Genetic Findings in 28 American Cocker Spaniels with Aural Ceruminous Gland Hyperplasia and Ectasia.

J Comp Pathol 2021 May 22;185:30-44. Epub 2021 Apr 22.

Department of Equine and Small Animal Medicine, Finland.

American Cocker Spaniels (ACSs) develop aural ceruminous gland hyperplasia and ectasia more often than dogs of other breeds. Data on the cause and development of these breed characteristic histopathological changes are lacking. We performed video-otoscopic examinations and dermatological work-up on 28 ACSs, obtained aural biopsies from each dog and assessed the statistical associations between the presence of ceruminous gland hyperplasia and ectasia and disease history, clinical or microbiological findings and underlying cause of otitis externa (OE). Histological lesions of ceruminous gland hyperplasia and ectasia were observed in aural biopsies from 6/13 clinically healthy ears and 13/15 ears with OE from 19/28 examined dogs. Nine of 28 dogs had histologically normal ceruminous glands (odds ratio [OR] 6.2, 95% confidence interval [CI] 1.1-36.6). Bacterial growth in microbiological culture of aural exudate (OR 14.1, 95% CI 2.1-95.3) was associated with ceruminous glandular changes, whereas previous history of OE, cutaneous findings or underlying allergies were not. Pedigree analysis and a genome-wide association study (GWAS) were performed on 18 affected and eight unaffected dogs based on histopathological diagnosis. While the GWAS indicated a tentative, but not statistically significant, association of ceruminous gland hyperplasia and ectasia with chromosome 31, a larger cohort is needed to confirm this preliminary result. Based on our results, ceruminous gland hyperplasia and ectasia may also precede clinical signs of OE in ACSs and a genetic aetiological component is likely Further studies with larger cohorts are warranted to verify our preliminary results.
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http://dx.doi.org/10.1016/j.jcpa.2021.03.005DOI Listing
May 2021

Serum NMR metabolomics uncovers multiple metabolic changes in phenobarbital-treated dogs.

Metabolomics 2021 06 2;17(6):54. Epub 2021 Jun 2.

PetBiomics Ltd., Helsinki, Finland.

Introduction: Phenobarbital is a commonly used anticonvulsant for the treatment of canine epileptic seizures. In addition to its central nervous system (CNS) depressing effects, long-term phenobarbital administration affects liver function. However, broader metabolic consequences of phenobarbital treatment are poorly characterized.

Objectives: To identify metabolic changes in the sera of phenobarbital-treated dogs and to investigate the relationship between serum phenobarbital concentration and metabolite levels.

Methods: Leftovers of clinical samples were used: 58 cases with phenobarbital concentrations ranging from 7.8 µg/mL to 50.8 µg/mL, and 25 controls. The study design was cross-sectional. The samples were analyzed by a canine-specific H NMR metabolomics platform. Differences between the case and control groups were evaluated by logistic regression. The linear relationship between metabolite and phenobarbital concentrations was evaluated using linear regression.

Results: Increasing concentrations of glycoprotein acetyls, LDL particle size, palmitic acid, and saturated fatty acids, and decreasing concentrations of albumin, glutamine, histidine, LDL particle concentration, multiple HDL measures, and polyunsaturated fatty acids increased the odds of the sample belonging to the phenobarbital-treated group, having a p-value < .0033, and area under the curve (AUC) > .7. Albumin and glycoprotein acetyls had the best discriminative ability between the groups (AUC: .94). No linear associations between phenobarbital and metabolite concentrations were observed.

Conclusion: The identified metabolites are known to associate with, for example, liver and CNS function, inflammatory processes and drug binding. The lack of a linear association to phenobarbital concentration suggests that other factors than the blood phenobarbital concentration contribute to the magnitude of metabolic changes.
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http://dx.doi.org/10.1007/s11306-021-01803-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172515PMC
June 2021

Seizure frequency discrepancy between subjective and objective ictal electroencephalography data in dogs.

J Vet Intern Med 2021 Jul 18;35(4):1819-1825. Epub 2021 May 18.

Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.

Background: Many studies of epilepsy in veterinary medicine use subjective data (eg, caregiver-derived histories) to determine seizure frequency. Conversely, in people, objective data from electroencephalography (EEG) are mainly used to diagnose epilepsy, measure seizure frequency and evaluate efficacy of antiseizure drugs. These EEG data minimize the possibility of the underreporting of seizures, a known phenomenon in human epileptology.

Objective: To evaluate the correlation between reported seizure frequency and EEG frequency of ictal paroxysmal discharges (PDs) and to determine whether seizure underreporting phenomenon exists in veterinary epileptology.

Animals: Thirty-three ambulatory video-EEG recordings in dogs showing ≥1 ictal PD, excluding dogs with status epilepticus.

Methods: Retrospective observational study. Ictal PDs were counted manually over the entire recording to obtain the frequency of EEG seizures. Caregiver-reported seizure frequency from the medical record was categorized into weekly, daily, hourly, and per minute seizure groupings. The Spearman rank test was used for correlation analysis.

Results: The coefficient value (r ) comparing reported seizure to EEG-confirmed ictal PD frequencies was 0.39 (95% confidence interval [CI] = 0.048-0.64, P = .03). Other r values comparing history against various seizure types were: 0.36 for motor seizures and 0.37 for nonmotor (absence) seizures.

Conclusions And Clinical Importance: A weak correlation was found between the frequency of reported seizures from caregivers (subjective data) and ictal PDs on EEG (objective data). Subjective data may not be reliable enough to determine true seizure frequency given the discrepancy with EEG-confirmed seizure frequency. Confirmation of the seizure underreporting phenomenon in dogs by prospective study should be carried out.
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http://dx.doi.org/10.1111/jvim.16158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295668PMC
July 2021

Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss.

Hum Genet 2021 May 13. Epub 2021 May 13.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Hearing loss is a common sensory deficit in both humans and dogs. In canines, the genetic basis is largely unknown, as genetic variants have only been identified for a syndromic form of hearing impairment. We observed a congenital or early-onset sensorineural hearing loss in a Rottweiler litter. Assuming an autosomal recessive inheritance, we used a combined approach of homozygosity mapping and genome sequencing to dissect the genetic background of the disorder. We identified a fully segregating missense variant in LOXHD1, a gene that is known to be essential for cochlear hair cell function and associated with nonsyndromic hearing loss in humans and mice. The canine LOXHD1 variant was specific to the Rottweiler breed in our study cohorts of pure-bred dogs. However, it also was present in some mixed-breed dogs, of which the majority showed Rottweiler ancestry. Low allele frequencies in these populations, 2.6% and 0.04%, indicate a rare variant. To summarize, our study describes the first genetic variant for canine nonsyndromic hearing loss, which is clinically and genetically similar to human LOXHD1-related hearing disorder, and therefore, provides a new large animal model for hearing loss. Equally important, the affected breed will benefit from a genetic test to eradicate this LOXHD1-related hearing disorder from the population.
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http://dx.doi.org/10.1007/s00439-021-02286-zDOI Listing
May 2021

Aggressive behaviour is affected by demographic, environmental and behavioural factors in purebred dogs.

Sci Rep 2021 05 3;11(1):9433. Epub 2021 May 3.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Aggressive behaviour is an unwanted and serious problem in pet dogs, negatively influencing canine welfare, management and public acceptance. We aimed to identify demographic and environmental factors associated with aggressive behaviour toward people in Finnish purebred pet dogs. We collected behavioural data from 13,715 dogs with an owner-completed online questionnaire. Here we used a dataset of 9270 dogs which included 1791 dogs with frequent aggressive behaviour toward people and 7479 dogs without aggressive behaviour toward people. We studied the effect of several explanatory variables on aggressive behaviour with multiple logistic regression. Several factors increased the probability of aggressive behaviour toward people: older age, being male, fearfulness, small body size, lack of conspecific company, and being the owner's first dog. The probability of aggressive behaviour also differed between breeds. These results replicate previous studies and suggest that improvements in the owner education and breeding practices could alleviate aggressive behaviour toward people while genetic studies could reveal associated hereditary factors.
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http://dx.doi.org/10.1038/s41598-021-88793-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093277PMC
May 2021

Reliability and Validity of a Dog Personality and Unwanted Behavior Survey.

Animals (Basel) 2021 Apr 24;11(5). Epub 2021 Apr 24.

Department of Veterinary Biosciences, University of Helsinki, 00014 Helsinki, Finland.

Dogs have distinct, consistent personalities, but the structure of dog personality is still unclear. Dog personality and unwanted behavior are often studied with behavioral questionnaires. Even though many questionnaires are reliable and valid measures of behavior, all new questionnaire tools should be extensively validated. Here, we examined the structure of personality and six unwanted behavior questionnaire sections: noise sensitivity, fearfulness, aggression, fear of surfaces and heights, separation anxiety and impulsivity/inattention with factor analyses. Personality consisted of seven factors: Insecurity, Training focus, Energy, Aggressiveness/dominance, Human sociability, Dog sociability and Perseverance. Most unwanted behavior sections included only one factor, but the impulsivity/inattention section divided into two factors (Hyperactivity/impulsivity and Inattention) and the aggression section into four factors (Barking, Stranger directed aggression, Owner directed aggression and Dog directed aggression). We also examined the internal consistency, test-retest reliability, inter-rater reliability and convergent validity of the 17 personality and unwanted behavior traits and discovered excellent reliability and validity. Finally, we investigated the discriminant validity of the personality traits, which was good. Our findings indicate that this personality and unwanted behavior questionnaire is a reliable and valid tool that can be used to study personality and behavior extensively.
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http://dx.doi.org/10.3390/ani11051234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147106PMC
April 2021

In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration.

Hum Genet 2021 Apr 9. Epub 2021 Apr 9.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

We investigated the clinical, genetic, and pathological characteristics of a previously unknown severe juvenile brain disorder in several litters of Parson Russel Terriers. The disease started with epileptic seizures at 6-12 weeks of age and progressed rapidly to status epilepticus and death or euthanasia. Histopathological changes at autopsy were restricted to the brain. There was severe acute neuronal degeneration and necrosis diffusely affecting the grey matter throughout the brain with extensive intraneuronal mitochondrial crowding and accumulation of amyloid-β (Aβ). Combined homozygosity mapping and genome sequencing revealed an in-frame 6-bp deletion in the nuclear-encoded pitrilysin metallopeptidase 1 (PITRM1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. The 6-bp deletion results in the loss of two amino acid residues in the N-terminal part of PITRM1, potentially affecting protein folding and function. Assessment of the mitochondrial function in the affected brain tissue showed a significant deficiency in respiratory chain function. The functional consequences of the mutation were modeled in yeast and showed impaired growth in permissive conditions and an impaired respiration capacity. Loss-of-function variants in human PITRM1 result in a childhood-onset progressive amyloidotic neurological syndrome characterized by spinocerebellar ataxia with behavioral, psychiatric and cognitive abnormalities. Homozygous Pitrm1-knockout mice are embryonic lethal, while heterozygotes show a progressive, neurodegenerative phenotype characterized by impairment in motor coordination and Aβ deposits. Our study describes a novel early-onset PITRM1-related neurodegenerative canine brain disorder with mitochondrial dysfunction, Aβ accumulation, and lethal epilepsy. The findings highlight the essential role of PITRM1 in neuronal survival and strengthen the connection between mitochondrial dysfunction and neurodegeneration.
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http://dx.doi.org/10.1007/s00439-021-02279-yDOI Listing
April 2021

A hypomyelinating leukodystrophy in German Shepherd dogs.

J Vet Intern Med 2021 May 18;35(3):1455-1465. Epub 2021 Mar 18.

Centre for Clinical Veterinary Medicine, Faculty of Veterinary Medicine, LMU Munich, Munich, Germany.

Background: Shaking puppy syndrome is commonly attributed to abnormal myelination of the central nervous system.

Hypothesis/objectives: To report the long-term clinical course and the imaging characteristics of hypomyelinating leukodystrophy in German Shepherd dogs.

Animals And Methods: Three related litters with 11 affected dogs.

Results: The 11 affected dogs experienced coarse, side-to-side tremors of the head and trunk, which interfered with normal goal-oriented movements and disappeared at rest. Signs were noticed shortly after birth. Nine dogs were euthanized, 3 dogs underwent pathological examination, and 2 littermates were raised by their breeder. Tremors improved gradually until 6 to 7 months of age. Adult dogs walked with severe residual pelvic limb ataxia. One dog developed epilepsy with tonic-clonic seizures at 15 months of age. Conventional magnetic resonance imaging (MRI) disclosed homogenous hyperintense signal of the entire subcortical white matter in 3 affected 7-week-old dogs and a hypointense signal in a presumably unaffected littermate. Subcortical white matter appeared isointense to gray matter at 15 and 27 weeks of age on repeated MRI. Abnormal white matter signal with failure to display normal gray-white matter contrast persisted into adulthood. Cerebellar arbor vitae was not visible at any time point. Clinical signs, MRI findings, and pathological examinations were indicative of a hypomyelinating leukodystrophy. All parents of the affected litters shared a common ancestor and relatedness of the puppies suggested an autosomal recessive mode of inheritance.

Conclusion: We describe a novel hypomyelinating leukodystrophy in German Shepherd dogs with a suspected inherited origin.
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http://dx.doi.org/10.1111/jvim.16085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163122PMC
May 2021

A missense variant in IFT122 associated with a canine model of retinitis pigmentosa.

Hum Genet 2021 Feb 19. Epub 2021 Feb 19.

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Retinitis pigmentosa (RP) is a blinding eye disease affecting nearly two million people worldwide. Dogs are affected with a similar illness termed progressive retinal atrophy (PRA). Lapponian herders (LHs) are affected with several types of inherited retinal dystrophies, and variants in PRCD and BEST1 genes have been associated with generalized PRA and canine multifocal retinopathy 3 (cmr3), respectively. However, all retinal dystrophy cases in LHs are not explained by these variants, indicating additional genetic causes of disease in the breed. We collected DNA samples from 10 PRA affected LHs, with known PRCD and BEST1 variants excluded, and 34 unaffected LHs. A genome-wide association study identified a locus on CFA20 (p = 2.4 × 10, p = 0.035), and subsequent whole-genome sequencing of an affected LH revealed a missense variant, c.3176G>A, in the intraflagellar transport 122 (IFT122) gene. The variant was also found in Finnish Lapphunds, in which its clinical relevancy needs to be studied further. The variant interrupts a highly conserved residue, p.(R1059H), in IFT122 and likely impairs its function. Variants in IFT122 have not been associated with retinal degeneration in mammals, but the loss of ift122 in zebrafish larvae impaired opsin transport and resulted in progressive photoreceptor degeneration. Our study establishes a new spontaneous dog model to study the role of IFT122 in RP biology, while the affected breed will benefit from a genetic test for a recessive condition.
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http://dx.doi.org/10.1007/s00439-021-02266-3DOI Listing
February 2021

Canine DVL2 variant contributes to brachycephalic phenotype and caudal vertebral anomalies.

Hum Genet 2021 Feb 18. Epub 2021 Feb 18.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

A frameshift deletion variant in the Wnt pathway gene dishevelled 2 (DVL2) is associated with a truncated, kinked tail ("screw tail") in English Bulldogs, French Bulldogs and Boston Terriers. These breeds are also characterized by distinctive morphological traits, including a wide head, flat face and short-limbed dwarfism, which are characteristic of Robinow syndrome in humans, caused by defects in genes such as DVL1 and DVL3. Based on these phenotypic and genetic similarities, it has previously been hypothesized that the canine DVL2 variant results in a syndromic phenotype called the Robinow-like syndrome. In our study, we investigated the distribution of the DVL2 variant in 1954 dogs from 15 breeds, identifying breeds with allele variation and enabling the dissection of the genotype-phenotype correlation for the first time. With CT examinations in American Staffordshire Terriers, we confirmed that the DVL2 allele is associated with caudal vertebral malformations and a brachycephalic phenotype. We also hypothesize that the variant may be linked to additional health conditions, including brachycephalic obstructive airway syndrome and congenital heart defects. Altogether, our study strengthens the role of DVL2 as one of the contributors to the "bulldog type" morphology and features on the spectrum of human Robinow syndrome.
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http://dx.doi.org/10.1007/s00439-021-02261-8DOI Listing
February 2021

Intronic variant in POU1F1 associated with canine pituitary dwarfism.

Hum Genet 2021 Feb 6. Epub 2021 Feb 6.

Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

The anterior pituitary gland secretes several endocrine hormones, essential for growth, reproduction and other basic physiological functions. Abnormal development or function of the pituitary gland leads to isolated or combined pituitary hormone deficiency (CPHD). At least 30 genes have been associated with human CPHD, including many transcription factors, such as POU1F1. CPHD occurs spontaneously also in mice and dogs. Two affected breeds have been reported in dogs: German Shepherds with a splice defect in the LHX3 gene and Karelian Bear Dogs (KBD) with an unknown genetic cause. We obtained samples from five KBDs presenting dwarfism and abnormal coats. A combined analysis of genome-wide association and next-generation sequencing mapped the disease to a region in chromosome 31 and identified a homozygous intronic variant in the fourth exon of the POU1F1 gene in the affected dogs. The identified variant, c.605-3C>A, resided in the splice region and was predicted to affect splicing. The variant's screening in three new prospective cases, related breeds, and ~ 8000 dogs from 207 breeds indicated complete segregation in KBDs with a carrier frequency of 8%, and high breed-specificity as carriers were found at a low frequency only in Lapponian Herders, a related breed. Our study establishes a novel canine model for CPHD with a candidate POU1F1 defect.
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http://dx.doi.org/10.1007/s00439-021-02259-2DOI Listing
February 2021

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

BMC Genomics 2021 Jan 21;22(1):68. Epub 2021 Jan 21.

Department of Veterinary Biosciences, University of Helsinki, P.O. BOX 66 (Agnes Sjöbergin katu 2), 00014, Helsinki, Finland.

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.
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http://dx.doi.org/10.1186/s12864-021-07375-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818755PMC
January 2021

Effect of prior general anesthesia or sedation and antiseizure drugs on the diagnostic utility of wireless video electroencephalography in dogs.

J Vet Intern Med 2020 Sep 13;34(5):1967-1974. Epub 2020 Jul 13.

Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.

Background: Ambulatory wireless video electroencephalography (AEEG) is the method of choice to discriminate epileptic seizures from other nonepileptic episodes. However, the influence of prior general anesthesia (GA), sedation, or antiseizure drug (ASD) on the diagnostic ability of AEEG is unknown.

Hypothesis/objectives: The use of sedation/GA or ASD treatment before AEEG recording may affect the diagnostic ability of AEEG and the time to first abnormality on AEEG.

Animals: A total of 108 client-owned dogs undergoing ambulatory AEEG for paroxysmal episodes.

Methods: Retrospective cohort study. Proportions of diagnostic AEEG and time to first abnormality were compared between dogs that received sedation/GA or neither for instrumentation as well as dogs receiving at least 1 ASD and untreated dogs.

Results: Ambulatory EEG was diagnostic in 60.2% of all dogs including 49% of the sedation/GA dogs and 68% of dogs that received neither (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.02-5.00; P = .05). The AEEG was diagnostic in 51% of dogs receiving at least 1 ASD and 66% of untreated dogs (OR, 1.95; 95% CI, 0.9-4.3; P = .11). No difference was found in time to first abnormality between sedation/GA or neither or ASD-treated or untreated dogs (P = .1 and P = .3 respectively). Ninety-five percent of dogs had at least 1 abnormality within 277 minutes.

Conclusion And Clinical Importance: Sedation/GA and concurrent ASD administration were not identified as confounding factors for decreasing AEEG diagnostic capability nor did they delay the time to first abnormality. A 4-hour minimal recording period is recommended.
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http://dx.doi.org/10.1111/jvim.15856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517491PMC
September 2020

Correction to: Genetic characterization of Addison's disease in Bearded Collies.

BMC Genomics 2020 Dec 30;21(1):898. Epub 2020 Dec 30.

Department of Animal Science, University of California-Davis, Davis, CA, 95616, USA.

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http://dx.doi.org/10.1186/s12864-020-07328-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772898PMC
December 2020

High serum creatinine concentration is associated with metabolic perturbations in dogs.

J Vet Intern Med 2021 Jan 21;35(1):405-414. Epub 2020 Dec 21.

PetMeta Labs Ltd, Helsinki, Finland.

Background: The kidneys have many essential metabolic functions, and metabolic disturbances during decreased renal function have not been studied extensively.

Objectives: To identify metabolic changes in blood samples with increased serum creatinine concentration, indicating decreased glomerular filtration.

Animals: Clinical samples analyzed using a nuclear magnetic resonance (NMR) based metabolomics platform. The case group consisted of 23 samples with serum creatinine concentration >125 μmol/L, and the control group of 873 samples with serum creatinine concentration within the reference interval.

Methods: Biomarker association with increased serum creatinine concentration was evaluated utilizing 3 statistical approaches: Wilcoxon rank-sum test, logistic regression analysis (false discovery rate (FDR)-corrected P-values), and random forest classification. Medians of the biomarkers were compared to reference intervals. A heatmap and box plots were used to represent the differences.

Results: All 3 statistical approaches identified similar analytes associated with increased serum creatinine concentrations. The percentages of citrate, tyrosine, branched-chain amino acids, valine, leucine, albumin, linoleic acid and the ratio of phenylalanine to tyrosine differed significantly using all statistical approaches, acetate differed using the Wilcoxon test and random forest, docosapentaenoic acid percentage only using logistic regression (P < .05), and alanine only using random forest.

Conclusions And Clinical Importance: We identified several metabolic changes associated with increased serum creatinine concentrations, including prospective diagnostic markers and therapeutic targets. Further research is needed to verify the association of these changes with the clinical state of the dog. The NMR metabolomics test is a promising tool for improving diagnostic testing and management of renal diseases in dogs.
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http://dx.doi.org/10.1111/jvim.16011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848334PMC
January 2021

Simultaneous allergic traits in dogs and their owners are associated with living environment, lifestyle and microbial exposures.

Sci Rep 2020 12 15;10(1):21954. Epub 2020 Dec 15.

Research Programs Unit, Molecular Neurology, University of Helsinki, 00014, Helsinki, Finland.

Both humans and pet dogs are more prone to develop allergies in urban than in rural environments, which has been associated with the differing microbial exposures between areas. However, potential similarities in the microbiota, that associate with environmental exposures, in allergic dogs and owners has not been investigated. We evaluated skin and gut microbiota, living environment, and lifestyle in 168 dog-owner pairs. Due to partly different manifestations of allergies between species, we focused on aeroallergen sensitized humans and dogs with owner-reported allergic symptoms. Our results agree with previous studies: dog-owner pairs suffered simultaneously from these allergic traits, higher risk associated with an urban environment, and the skin, but not gut, microbiota was partly shared by dog-owner pairs. We further discovered that urban environment homogenized both dog and human skin microbiota. Notably, certain bacterial taxa, which were associated with living environment and lifestyle, were also related with allergic traits, but these taxa differed between dogs and humans. Thus, we conclude that dogs and humans can be predisposed to allergy in response to same risk factors. However, as shared predisposing or protective bacterial taxa were not discovered, other factors than environmental microbial exposures can mediate the effect or furry dog and furless human skin select different taxa.
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http://dx.doi.org/10.1038/s41598-020-79055-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738549PMC
December 2020

Genetic characterization of Addison's disease in Bearded Collies.

BMC Genomics 2020 Nov 26;21(1):833. Epub 2020 Nov 26.

Department of Animal Science, University of California-Davis, Davis, CA, 95616, USA.

Background: Primary hypoadrenocorticism (or Addison's disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies.

Results: Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility.

Conclusion: Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.
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http://dx.doi.org/10.1186/s12864-020-07243-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690126PMC
November 2020

Formal commentary.

PLoS Genet 2020 11 5;16(11):e1009059. Epub 2020 Nov 5.

School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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http://dx.doi.org/10.1371/journal.pgen.1009059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643992PMC
November 2020

Altered Basal Autophagy Affects Extracellular Vesicle Release in Cells of Lagotto Romagnolo Dogs With a Variant .

Vet Pathol 2020 11 5;57(6):926-935. Epub 2020 Oct 5.

3835University of Helsinki, Helsinki, Finland.

Lagotto Romagnolo breed dogs develop a progressive neurological disease with intracellular vacuolar storage when homozygous for a variant in the autophagy-related gene 4D (). A lysosomal enzyme deficiency has not been proven in this disease, despite its overlapping morphology with lysosomal storage diseases. Instead, basal autophagy was altered in fibroblasts from affected dogs. The aim of this study was to clarify the origin of the limiting membrane of the accumulating vacuoles and determine whether altered basal autophagy affects the extracellular release of vesicles in cells from diseased dogs. When assessed by immunoelectron microscopy, the membrane of the cytoplasmic vacuoles in affected tissues contained ATG4D, markers for autolysosomes (microtubule-associated protein 1A/B light chain 3 and lysosome-associated membrane protein 2) and for recycling endosomes (transferrin receptor 2), indicating that the vacuoles are hybrid organelles between endocytic and autophagic pathways. Ultracentrifugation, nanoparticle tracking analysis, and mass spectrometry were used to analyze the vesicles released from cultured fibroblasts of affected and control dogs. The amount of extracellular vesicles (EVs) released from affected fibroblasts was significantly increased during basal conditions in comparison to controls. This difference disappeared during starvation. The basal EV proteome of affected cells was enriched with cytosolic, endoplasmic reticulum, and mitochondrial proteins. Heat shock proteins and chaperones, some of which are known substrates of basal autophagy, were identified among the proteins unique to EVs of affected cells. An increased release of extracellular vesicles may serve as a compensatory mechanism in disposal of intracellular proteins during dysfunctional basal autophagy in this spontaneous disease.
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http://dx.doi.org/10.1177/0300985820959243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747043PMC
November 2020

Metabolome of canine and human saliva: a non-targeted metabolomics study.

Metabolomics 2020 08 25;16(9):90. Epub 2020 Aug 25.

Institute of Public Health and Clinical Nutrition, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.

Introduction: Saliva metabolites are suggested to reflect the health status of an individual in humans. The same could be true with the dog (Canis lupus familiaris), an important animal model of human disease, but its saliva metabolome is unknown. As a non-invasive sample, canine saliva could offer a new alternative material for research to reveal molecular mechanisms of different (patho)physiological stages, and for veterinary medicine to monitor dogs' health trajectories.

Objectives: To investigate and characterize the metabolite composition of dog and human saliva in a non-targeted manner.

Methods: Stimulated saliva was collected from 13 privately-owned dogs and from 14 human individuals. We used a non-targeted ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qTOF-MS) method to measure metabolite profiles from saliva samples.

Results: We identified and classified a total of 211 endogenous and exogenous salivary metabolites. The compounds included amino acids, amino acid derivatives, biogenic amines, nucleic acid subunits, lipids, organic acids, small peptides as well as other metabolites, like metabolic waste molecules and other chemicals. Our results reveal a distinct metabolite profile of dog and human saliva as 25 lipid compounds were identified only in canine saliva and eight dipeptides only in human saliva. In addition, we observed large variation in ion abundance within and between the identified saliva metabolites in dog and human.

Conclusion: The results suggest that non-targeted metabolomics approach utilizing UHPLC-qTOF-MS can detect a wide range of small compounds in dog and human saliva with partially overlapping metabolite composition. The identified metabolites indicate that canine saliva is potentially a versatile material for the discovery of biomarkers for dog welfare. However, this profile is not complete, and dog saliva needs to be investigated in the future with other analytical platforms to characterize the whole canine saliva metabolome. Furthermore, the detailed comparison of human and dog saliva composition needs to be conducted with harmonized study design.
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http://dx.doi.org/10.1007/s11306-020-01711-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447669PMC
August 2020

Active and social life is associated with lower non-social fearfulness in pet dogs.

Sci Rep 2020 08 13;10(1):13774. Epub 2020 Aug 13.

Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.

Behavioural problems are leading welfare issues in domestic dogs. In particular, anxiety-related behavioural problems, such as fearfulness and noise sensitivity are highly prevalent conditions that cause distress to fearful dogs. To better understand the environmental factors associated with non-social fear, including noise sensitivity, fear of novel situations, and fear of surfaces and heights, a large online survey including data on 13,700 Finnish pet dogs was performed by the dog owners. After fulfilling inclusion criteria, this data consisted of 9,613 dogs with fear of fireworks, 9,513 dogs with fear of thunder, 6,945 dogs with fear of novel situations, and 2,932 dogs with fear of surfaces and heights. Logistic regression analyses revealed that dogs with frequent non-social fear had experienced less socialisation during puppyhood, were more often neutered, had inexperienced owners, lived without conspecifics, participated less frequently in activities or training, and lived in more urban environments. In addition, we identified several breed differences, and a tendency of more common non-social fear in small dog breeds, which suggests a genetic background. Non-social fearfulness has a negative effect on well-being of the dogs. Our findings suggest that the socialisation and the living environment and the value of other dogs' company and owner interaction via activities and training may improve the well-being of the dogs.
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http://dx.doi.org/10.1038/s41598-020-70722-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426946PMC
August 2020

Assessment of databases to determine the validity of β- and γ-carbonic anhydrase sequences from vertebrates.

BMC Genomics 2020 May 11;21(1):352. Epub 2020 May 11.

Faculty of Medicine and Health Technology, Tampere University, FI-33520, Tampere, Finland.

Background: The inaccuracy of DNA sequence data is becoming a serious problem, as the amount of molecular data is multiplying rapidly and expectations are high for big data to revolutionize life sciences and health care. In this study, we investigated the accuracy of DNA sequence data from commonly used databases using carbonic anhydrase (CA) gene sequences as generic targets. CAs are ancient metalloenzymes that are present in all unicellular and multicellular living organisms. Among the eight distinct families of CAs, including α, β, γ, δ, ζ, η, θ, and ι, only α-CAs have been reported in vertebrates.

Results: By an in silico analysis performed on the NCBI and Ensembl databases, we identified several β- and γ-CA sequences in vertebrates, including Homo sapiens, Mus musculus, Felis catus, Lipotes vexillifer, Pantholops hodgsonii, Hippocampus comes, Hucho hucho, Oncorhynchus tshawytscha, Xenopus tropicalis, and Rhinolophus sinicus. Polymerase chain reaction (PCR) analysis of genomic DNA persistently failed to amplify positive β- or γ-CA gene sequences when Mus musculus and Felis catus DNA samples were used as templates. Further BLAST homology searches of the database-derived "vertebrate" β- and γ-CA sequences revealed that the identified sequences were presumably derived from gut microbiota, environmental microbiomes, or grassland ecosystems.

Conclusions: Our results highlight the need for more accurate and fast curation systems for DNA databases. The mined data must be carefully reconciled with our best knowledge of sequences to improve the accuracy of DNA data for publication.
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http://dx.doi.org/10.1186/s12864-020-6762-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216627PMC
May 2020

Genome wide association study of 40 clinical measurements in eight dog breeds.

Sci Rep 2020 04 16;10(1):6520. Epub 2020 Apr 16.

Unit of Animal Genomics, GIGA Institute, University of Liège, Liège, Belgium.

The domestic dog represents an ideal model for identifying susceptibility genes, many of which are shared with humans. In this study, we investigated the genetic contribution to individual differences in 40 clinically important measurements by a genome-wide association study (GWAS) in a multinational cohort of 472 healthy dogs from eight breeds. Meta-analysis using the binary effects model after breed-specific GWAS, identified 13 genome-wide significant associations, three of them showed experimental-wide significant associations. We detected a signal at chromosome 13 for the serum concentration of alanine aminotransferase (ALT) in which we detected four breed-specific signals. A large proportion of the variance of ALT (18.1-47.7%) was explained by this locus. Similarly, a single SNP was also responsible for a large proportion of the variance (6.8-78.4%) for other measurements such as fructosamine, stress during physical exam, glucose, and morphometric measurements. The genetic contribution of single variant was much larger than in humans. These findings illustrate the importance of performing meta-analysis after breed-specific GWAS to reveal the genetic contribution to individual differences in clinically important measurements, which would lead to improvement of veterinary medicine.
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http://dx.doi.org/10.1038/s41598-020-63457-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162946PMC
April 2020

webGQT: A Shiny Server for Genotype Query Tools for Model-Based Variant Filtering.

Front Genet 2020 3;11:152. Epub 2020 Mar 3.

Department of Veterinary Biosciences, Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.

Summary: Genotype Query Tools (GQT) were developed to discover disease-causing variations from billions of genotypes and millions of genomes, processes data at substantially higher speed over other existing methods. While GQT has been available to a wide audience as command-line software, the difficulty of constructing queries among non-IT or non-bioinformatics researchers has limited its applicability. To overcome this limitation, we developed webGQT, an easy-to-use tool with a graphical user interface. With pre-built queries across three modules, webGQT allows for pedigree analysis, case-control studies, and population frequency studies. As a package, webGQT allows researchers with less or no applied bioinformatics/IT experience to mine potential disease-causing variants from billions.

Results: webGQT offers a flexible and easy-to-use interface for model-based candidate variant filtering for Mendelian diseases from thousands to millions of genomes at a reduced computation time. Additionally, webGQT provides adjustable parameters to reduce false positives and rescue missing genotypes across all modules. Using a case study, we demonstrate the applicability of webGQT to query non-human genomes. In addition, we demonstrate the scalability of webGQT on large data sets by implementing complex population-specific queries on the 1000 Genomes Project Phase 3 data set, which includes 8.4 billion variants from 2504 individuals across 26 different populations. Furthermore, webGQT supports filtering single-nucleotide variants, short insertions/deletions, copy number or any other variant genotypes supported by the VCF specification. Our results show that webGQT can be used as an online web service, or deployed on personal computers or local servers within research groups.

Availability: webGQT is made available to the users in three forms: 1) as a webserver available at https://vm1138.kaj.pouta.csc.fi/webgqt/, 2) as an R package to install on personal computers, and 3) as part of the same R package to configure on the user's own servers. The application is available for installation at https://github.com/arumds/webgqt.
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http://dx.doi.org/10.3389/fgene.2020.00152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063093PMC
March 2020
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