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Kierczak, M., Jablonska, J., Forsberg, S. K., Bianchi, M., Tengvall, K., Pettersson, M., . . . Lindblad-Toh, K. (2015). cgmisc: Enhanced Genome-wide Association Analyses and Visualisation. Bioinformatics, 31(23), 3830-3831
Open this publication in new window or tab >>cgmisc: Enhanced Genome-wide Association Analyses and Visualisation
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2015 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 31, no 23, p. 3830-3831Article in journal (Refereed) Published
Abstract [en]

SUMMARY:

High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them.

RESULTS: We present cgmisc, an R package that enables enhanced data analysis and visualisation of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualisation of genomic data and utilises the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data.

AVAILABILITY: The package is operating system-independent and is available from: https://github.com/cgmisc-team/cgmisc CONTACT: cgmisc@imbim.uu.se.

National Category
Bioinformatics and Systems Biology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-259684 (URN)10.1093/bioinformatics/btv426 (DOI)000366378400016 ()6249815 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish Research Council FormasSwedish Research CouncilEU, European Research CouncilEU, European Research Council
Available from: 2015-08-10 Created: 2015-08-10 Last updated: 2018-01-11Bibliographically approved
Tengvall, K. (2015). Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Genetic Studies in Dogs Implicate Novel Genes Involved in Atopic Dermatitis and IgA Deficiency
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents genetic studies of atopic dermatitis (AD) and IgA deficiency in dogs.

AD is a chronic inflammatory and pruritic skin disorder caused by allergic reactions against environmental allergens. Both genetic and environmental factors are involved in the development of Canine AD (CAD) and human AD. In Paper I, we performed genome-wide association studies (GWAS) and identified a locus on chromosome 27 significantly associated with CAD in German shepherd dogs (GSDs). The locus contains several genes and fine-mapping indicated strongest association close to the candidate gene PKP2. In Paper II, we performed additional fine-mapping and identified four highly associated SNPs located in regions with transcriptional regulatory potential in epithelial and immune cells. The risk alleles were associated with increased transcriptional activity and the effect on expression was cell-type dependent. These data indicate that multiple cell-type specific enhancers regulate the expression of PKP2, and/or the neighboring genes YARS2, DNM1L and FGD4, and predispose GSDs to CAD.

IgA deficiency is the most common primary immune deficiency disorder in both humans and dogs, characterized by a higher risk of recurrent mucosal tract infections, allergic and other immune-mediated diseases. In Paper III, we performed the widest screening (to date) of serum IgA levels in dog breeds (Ndogs=1267, Nbreeds=22) and defined eight breeds as predisposed to low IgA levels. In Paper IV, we performed GWAS in four of the breeds defined as prone to low IgA levels. We used a novel percentile groups-approach to establish breed-specific cut-offs to perform analyses in a close to continuous manner. In total, 35 genomic loci were suggestively associated (p<0.0005) to IgA levels, and three genomic regions (including the genes KIRREL3 and SERPINA9) were genome-wide significantly associated with IgA levels in GSDs. A ~20kb long haplotype on chromosome 28, significantly associated to IgA levels in Shar-Pei dogs, was positioned within the first intron of the gene SLIT1 overlapping with a possible dog domestication sweep.

This thesis suggests novel candidate genes involved in two immune-mediated disorders in the dog. Hopefully, these results will become an important resource for the genetic research of the corresponding human diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 88
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1128
Keywords
GWAS, canine model, genetic association, immunogenetics, atopic dermatitis, IgA deficiency
National Category
Medical Genetics
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-259606 (URN)978-91-554-9304-2 (ISBN)
Public defence
2015-10-06, B22, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2015-09-11 Created: 2015-08-10 Last updated: 2018-01-11
Olsson, M., Tengvall, K., Frankowiack, M., Kierczak, M., Bergvall, K., Axelsson, E., . . . Lindblad-Toh, K. (2015). Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency. PLoS ONE, 10(7), Article ID e0133844.
Open this publication in new window or tab >>Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133844Article in journal (Refereed) Published
Abstract [en]

Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.

Keywords
Genome-wide association studies, Dogs, IgA, immunodeficieny, B-cell
National Category
Medical Genetics Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-259595 (URN)10.1371/ journal.pone.0133844 (DOI)000358837700039 ()26225558 (PubMedID)
Funder
Swedish Research Council, 521-2012-2826, 521-2011-3515Swedish Research Council Formas, 221-2009-1689EU, European Research Council, 310203EU, FP7, Seventh Framework Programme, GA-201370
Available from: 2015-08-10 Created: 2015-08-10 Last updated: 2018-01-11Bibliographically approved
Olsson, M., Frankowiack, M., Tengvall, K., Roosje, P., Fall, T., Ivansson, E., . . . Hammarstrom, L. (2014). The dog as a genetic model for immunoglobulin A (IgA) deficiency: Identification of several breeds with low serum IgA concentrations. Veterinary Immunology and Immunopathology, 60(3-4), 255-259
Open this publication in new window or tab >>The dog as a genetic model for immunoglobulin A (IgA) deficiency: Identification of several breeds with low serum IgA concentrations
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2014 (English)In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 60, no 3-4, p. 255-259Article in journal (Refereed) Published
Abstract [en]

Immunoglobulin A (IgA) serves as the basis of the secretory immune system by protecting the lining of mucosal sites from pathogens. In both humans and dogs, IgA deficiency (IgAD) is associated with recurrent infections of mucosal sites and immune-mediated diseases. Low concentrations of serum IgA have previously been reported to occur in a number of dog breeds but no generally accepted cut-off value has been established for canine IgAD. The current study represents the largest screening to date of IgA in dogs in terms of both number of dogs (n = 1267) and number of breeds studied (n = 22). Serum IgA concentrations were quantified by using capture ELISA and were found to vary widely between breeds. We also found IgA to be positively correlated with age (p < 0.0001). Apart from the two breeds previously reported as predisposed to low IgA (Shar-Pei and German shepherd), we identified six additional breeds in which > 10% of all tested dogs had very low (<0.07 g/l) IgA concentrations (Hovawart, Norwegian elkhound, Nova Scotia duck tolling retriever, Bullterrier, Golden retriever and Labrador retriever). In addition, we discovered low IgA concentrations to be significantly associated with canine atopic dermatitis (CAD, p < 0.0001) and pancreatic acinar atrophy (PAA, p = 0.04) in German shepherds.

Keywords
Immunoglobulin A (IgA) deficiency, Immunodeficiency, Dog, German shepherd
National Category
Immunology in the medical area Veterinary Science
Identifiers
urn:nbn:se:uu:diva-230943 (URN)10.1016/j.vetimm.2014.05.010 (DOI)000340221400014 ()
Available from: 2014-09-03 Created: 2014-09-01 Last updated: 2018-01-11Bibliographically approved
Jagannathan, V., Bannoehr, J., Plattet, P., Hauswirth, R., Droegemueller, C., Droegemueller, M., . . . Leeb, T. (2013). A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation. PLOS Genetics, 9(10), e1003848
Open this publication in new window or tab >>A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation
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2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 10, p. e1003848-Article in journal (Refereed) Published
Abstract [en]

Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (p(raw) = 4.4x10(-14)). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38x coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220001 (URN)10.1371/journal.pgen.1003848 (DOI)000330367200028 ()
Available from: 2014-03-09 Created: 2014-03-09 Last updated: 2017-12-05Bibliographically approved
Tengvall, K., Kierczak, M., Bergvall, K., Olsson, M., Frankowiack, M., Farias, F. H. G., . . . Lindblad-Toh, K. (2013). Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis. PLOS Genetics, 9(5), e1003475
Open this publication in new window or tab >>Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
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2013 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 5, p. e1003475-Article in journal (Refereed) Published
Abstract [en]

Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-205345 (URN)10.1371/journal.pgen.1003475 (DOI)000320030000005 ()
Note

Correction in: PLoS Genetics, vol. 11(12):e1005740. doi:10.1371/journal.pgen.1005740

Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2018-01-11Bibliographically approved
Frankowiack, M., Hellman, L., Zhao, Y., Arnemo, J. M., Lin, M., Tengvall, K., . . . Hammarstrom, L. (2013). IgA deficiency in wolves. Developmental and Comparative Immunology, 40(2), 180-184
Open this publication in new window or tab >>IgA deficiency in wolves
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2013 (English)In: Developmental and Comparative Immunology, ISSN 0145-305X, E-ISSN 1879-0089, Vol. 40, no 2, p. 180-184Article in journal (Refereed) Published
Abstract [en]

Low mean concentrations of serum immunoglobulin A (IgA) and an increased frequency of overt IgA deficiency (IgAD) in certain dog breeds raises the question whether it is a breeding-enriched phenomenon or a legacy from the dog's ancestor, the gray wolf (Canis lupus). The IgA concentration in 99 serum samples from 58 free-ranging and 13 captive Scandinavian wolves, was therefore measured by capture ELISA. The concentrations were markedly lower in the wolf serum samples than in the dog controls. Potential differences in the IgA molecule between dogs and wolves were addressed by sequencing the wolf IgA heavy chain constant region encoding gene (IGHA). Complete amino acid sequence homology was found. Detection of wolf and dog IgA was ascertained by showing identity using double immunodiffusion. We suggest that the vast majority of wolves, the ancestor of the dog, are IgA deficient.

Keywords
Serum IgA concentrations, IgA deficiency, Dog, Wolf
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-204119 (URN)10.1016/j.dci.2013.01.005 (DOI)000320491100011 ()
Available from: 2013-07-22 Created: 2013-07-22 Last updated: 2017-12-06Bibliographically approved
Olsson, M., Tintle, L., Kierczak, M., Perloski, M., Tonomura, N., Lindquist, A., . . . Meadows, J. R. S. (2013). Thorough investigation of a canine autoinflammatory disease (AID) syndrome confirms one main risk factor and suggests a modifier locus for amyloidosis. PLoS ONE, 8(10), e75242
Open this publication in new window or tab >>Thorough investigation of a canine autoinflammatory disease (AID) syndrome confirms one main risk factor and suggests a modifier locus for amyloidosis
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e75242-Article in journal (Refereed) Published
Abstract [en]

Autoinflammatory disease (AID) manifests from the dysregulation of the innate immune system and is characterised by systemic and persistent inflammation. Clinical heterogeneity leads to patients presenting with one or a spectrum of phenotypic signs, leading to difficult diagnoses in the absence of a clear genetic cause. We used separate genome-wide SNP analyses to investigate five signs of AID (recurrent fever, arthritis, breed specific secondary dermatitis, otitis and systemic reactive amyloidosis) in a canine comparative model, the pure bred Chinese Shar-Pei. Analysis of 255 DNA samples revealed a shared locus on chromosome 13 spanning two peaks of association. A three-marker haplotype based on the most significant SNP (p<2.6x10(-8)) from each analysis showed that one haplotypic pair (H13-11) was present in the majority of AID individuals, implicating this as a shared risk factor for all phenotypes. We also noted that a genetic signature (F-ST) distinguishing the phenotypic extremes of the breed specific Chinese Shar-Pei thick and wrinkled skin, flanked the chromosome 13 AID locus; suggesting that breed development and differentiation has played a parallel role in the genetics of breed fitness. Intriguingly, a potential modifier locus for amyloidosis was revealed on chromosome 14, and an investigation of candidate genes from both this and the chromosome 13 regions revealed significant (p<0.05) renal differential expression in four genes previously implicated in kidney or immune health (AOAH, ELMO1, HAS2 and IL6). These results illustrate that phenotypic heterogeneity need not be a reflection of genetic heterogeneity, and that genetic modifiers of disease could be masked if syndromes were not first considered as individual clinical signs and then as a sum of their component parts.

Keywords
autoinflammatory disease (AID), amyloidosis, canine model, genetic association
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Genetics
Identifiers
urn:nbn:se:uu:diva-183651 (URN)10.1371/journal.pone.0075242 (DOI)000325810900025 ()
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2017-12-07Bibliographically approved
Lauber, B., Molitor, V., Meury, S., Doherr, M. G., Favrot, C., Tengvall, K., . . . Marti, E. (2012). Total IgE and allergen-specific IgE and IgG antibody levels in sera of atopic dermatitis affected and non-affected Labrador- and Golden retrievers. Veterinary Immunology and Immunopathology, 149(1-2), 112-118
Open this publication in new window or tab >>Total IgE and allergen-specific IgE and IgG antibody levels in sera of atopic dermatitis affected and non-affected Labrador- and Golden retrievers
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2012 (English)In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 149, no 1-2, p. 112-118Article in journal (Refereed) Published
Abstract [en]

Canine atopic dermatitis (CAD) is an allergic skin disease associated with IgE and IgG antibodies (Ab) to environmental allergens. The aim of this study was to determine which other factors influence serum Ab levels in CAD-affected and non-affected dogs as this has only been poorly investigated in dogs so far. Total and allergen-specific IgE levels and Dermatophagoides farinae (DF)-specific IgG1 and IgG4 were measured by ELISA in sera of 145 CAD-affected and 271 non-affected Labrador- and Golden retrievers. A multivariable logistic regression analysis including the factors age, breed, gender, castration, clinical CAD status and allergen-specific immunotherapy (ASIT) was performed. Golden retrievers had more frequently total (OR=1.87, 95% CI=1.26-2.87, p<0.01) and specific IgE levels above the threshold value than Labrador retrievers, suggesting that genetic factors influence IgE levels in dogs. Castration was generally associated with low Ab levels (OR=0.43-0.65, p<0.05). Surprisingly, dogs with CAD did not have increased odds for high IgE against any of the allergens tested. ASIT with DF was associated with high DF-specific IgG1 (OR=4.32, 95% CI 1.46-12.8, p<0.01) but was not associated with DF-specific IgG4 or decreased IgE levels. Further studies are needed to understand the role of allergen-specific IgE in CAD and of IgG1 in ASIT.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-176992 (URN)10.1016/j.vetimm.2012.05.018 (DOI)000308831300017 ()22739207 (PubMedID)
Available from: 2012-06-29 Created: 2012-06-29 Last updated: 2017-12-07Bibliographically approved
Owczarek-Lipska, M., Lauber, B., Molitor, V., Meury, S., Kierczak, M., Tengvall, K., . . . Leeb, T. (2012). Two Loci on Chromosome 5 Are Associated with Serum IgE Levels in Labrador Retrievers. PLoS ONE, 7(6), e39176
Open this publication in new window or tab >>Two Loci on Chromosome 5 Are Associated with Serum IgE Levels in Labrador Retrievers
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39176-Article in journal (Refereed) Published
Abstract [en]

Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-176991 (URN)10.1371/journal.pone.0039176 (DOI)000305350000046 ()22720065 (PubMedID)
Available from: 2012-06-29 Created: 2012-06-29 Last updated: 2017-12-07Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-0424-3571

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