Thorough Investigation of a Canine Autoinflammatory Disease (AID) Confirms One Main Risk Locus and Suggests a Modifier Locus for Amyloidosis
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{"title"=>"Thorough Investigation of a Canine Autoinflammatory Disease (AID) Confirms One Main Risk Locus and Suggests a Modifier Locus for Amyloidosis", "type"=>"journal", "authors"=>[{"first_name"=>"Mia", "last_name"=>"Olsson", "scopus_author_id"=>"24338847800"}, {"first_name"=>"Linda", "last_name"=>"Tintle", "scopus_author_id"=>"6508250025"}, {"first_name"=>"Marcin", "last_name"=>"Kierczak", "scopus_author_id"=>"15124018000"}, {"first_name"=>"Michele", "last_name"=>"Perloski", "scopus_author_id"=>"24802440500"}, {"first_name"=>"Noriko", "last_name"=>"Tonomura", "scopus_author_id"=>"55962730100"}, {"first_name"=>"Andrew", "last_name"=>"Lundquist", "scopus_author_id"=>"56632653700"}, {"first_name"=>"Eva", "last_name"=>"Murén", "scopus_author_id"=>"6602454367"}, {"first_name"=>"Max", "last_name"=>"Fels", "scopus_author_id"=>"55875450100"}, {"first_name"=>"Katarina", "last_name"=>"Tengvall", "scopus_author_id"=>"45461440100"}, {"first_name"=>"Gerli", "last_name"=>"Pielberg", "scopus_author_id"=>"9234689700"}, {"first_name"=>"Caroline", "last_name"=>"Dufaure de Citres", "scopus_author_id"=>"55875868200"}, {"first_name"=>"Laetitia", "last_name"=>"Dorso", "scopus_author_id"=>"25027231200"}, {"first_name"=>"Jérôme", "last_name"=>"Abadie", "scopus_author_id"=>"7006745257"}, {"first_name"=>"Jeanette", "last_name"=>"Hanson", "scopus_author_id"=>"55753534500"}, {"first_name"=>"Anne", "last_name"=>"Thomas", "scopus_author_id"=>"19436643300"}, {"first_name"=>"Peter", "last_name"=>"Leegwater", "scopus_author_id"=>"6701835254"}, {"first_name"=>"Åke", "last_name"=>"Hedhammar", "scopus_author_id"=>"7004196747"}, {"first_name"=>"Kerstin", "last_name"=>"Lindblad-Toh", "scopus_author_id"=>"6603065092"}, {"first_name"=>"Jennifer R.S.", "last_name"=>"Meadows", "scopus_author_id"=>"8081315300"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84885155766", "doi"=>"10.1371/journal.pone.0075242", "issn"=>"19326203", "pui"=>"369979889", "sgr"=>"84885155766", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"24130694"}, "id"=>"3ae98db7-9c36-30a0-8894-0308c5c2eb28", "abstract"=>"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<2.6×10(-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.", "link"=>"http://www.mendeley.com/research/thorough-investigation-canine-autoinflammatory-disease-aid-confirms-one-main-risk-locus-suggests-mod", "reader_count"=>15, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>2, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2, "Other"=>2, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Agricultural and Biological Sciences"=>5, "Medicine and Dentistry"=>6, "Veterinary Science and Veterinary Medicine"=>3}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Unspecified"=>{"Unspecified"=>1}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>3}}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1230174"], "description"=>"1<p>Phased haplotypes are composed of the top eight SNP identified from the chromosome 14 and are estimated from the total population frequency (<i>n = </i>255).</p>2<p>Pairs observed at frequencies less than 10% in a sample set have been collapsed.</p>", "links"=>[], "tags"=>["chromosome", "14", "amyloidosis", "haplotype", "pairs", "shar-pei"], "article_id"=>818092, "categories"=>["Uncategorised"], "users"=>["Mia Olsson", "Linda Tintle", "Marcin Kierczak", "Michele Perloski", "Noriko Tonomura", "Andrew Lundquist", "Eva Murén", "Max Fels", "Katarina Tengvall", "Gerli Pielberg", "Caroline Dufaure de Citres", "Laetitia Dorso", "Jérôme Abadie", "Jeanette Hanson", "Anne Thomas", "Peter Leegwater", "Åke Hedhammar", "Kerstin Lindblad-Toh", "Jennifer R. S. Meadows"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0075242.t003", "stats"=>{"downloads"=>1, "page_views"=>44, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distribution_of_chromosome_14_Amyloidosis_haplotype_pairs_in_the_total_population_of_Shar_Pei_analysed_/818092", "title"=>"Distribution of chromosome 14 Amyloidosis haplotype pairs in the total population of Shar-Pei analysed.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-10-09 02:51:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1230172"], "description"=>"1<p>Number of markers from a genotyped set of 173,662 which passed two rounds of quality control.</p>2<p>The genomic inflation factor measured from the unadjusted qtscore GWAS.</p>3<p>The genomic inflation factor after the application of a polygenic mixed model encompassing the Identity By State (IBS) matrix.</p>4<p>Genomic position (<i>CanFam</i> 2.0, chromosome 13, bp) of the top SNP as ranked by <sup>5</sup>Significance of mixed model p-value.</p>6<p>Number of SNP which exceeded the Bonferroni 5% threshold for significance.</p>", "links"=>[], "tags"=>["GWAS", "conducted", "breed-subtype", "symptoms", "shar-pei", "autoinflammatory"], "article_id"=>818089, "categories"=>["Uncategorised"], "users"=>["Mia Olsson", "Linda Tintle", "Marcin Kierczak", "Michele Perloski", "Noriko Tonomura", "Andrew Lundquist", "Eva Murén", "Max Fels", "Katarina Tengvall", "Gerli Pielberg", "Caroline Dufaure de Citres", "Laetitia Dorso", "Jérôme Abadie", "Jeanette Hanson", "Anne Thomas", "Peter Leegwater", "Åke Hedhammar", "Kerstin Lindblad-Toh", "Jennifer R. S. Meadows"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0075242.t001", "stats"=>{"downloads"=>4, "page_views"=>33, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_the_separate_GWAS_analyses_conducted_on_breed_subtype_and_five_symptoms_of_Shar_Pei_autoinflammatory_disease_SPAID_/818089", "title"=>"Summary of the separate GWAS analyses conducted on breed-subtype and five symptoms of Shar-Pei autoinflammatory disease (SPAID).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-10-09 02:51:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1230170"], "description"=>"<p>. The genome wide association study of amyloidosis positive (<i>n</i> = 37) and negative (<i>n</i> = 14) individuals revealed a signal of association on chromosome 14 (14∶54948811, <i>p<sub>MM</sub></i> = 4.34×10<sup>−6</sup>) which was of slightly reduced strength to that observed on chromosome 13 (13∶27371905, <i>p<sub>MM</sub></i> = 3.0×10<sup>−6</sup>). <b>B</b>. A zoomed view of a subset of the genes across the chromosome 14 disease associated region, <b>C</b>. This region encompasses two peaks in moderate LD (<i>r<sup>2</sup></i> = 0.6) as indicated by heat colouring. A genome wide significant threshold (red dotted line) has been defined using as Bonferroni 5%. <b>D</b>. The scaled plots of genes demonstrating differential expression between amyloidosis negative (<i>n</i> = 7) and positive (<i>n</i> = 7) kidney biopsies. Samples are shown in the same order for each gene and also in order of phased H14 haplotypes (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0075242#pone.0075242.s005\" target=\"_blank\">Table S3</a>). Each sample registered expression, although in some cases it was negligible. p-values 0.05>0.01, *>**.</p>", "links"=>[], "tags"=>["locus", "chromosome", "14", "shar-pei"], "article_id"=>818088, "categories"=>["Uncategorised"], "users"=>["Mia Olsson", "Linda Tintle", "Marcin Kierczak", "Michele Perloski", "Noriko Tonomura", "Andrew Lundquist", "Eva Murén", "Max Fels", "Katarina Tengvall", "Gerli Pielberg", "Caroline Dufaure de Citres", "Laetitia Dorso", "Jérôme Abadie", "Jeanette Hanson", "Anne Thomas", "Peter Leegwater", "Åke Hedhammar", "Kerstin Lindblad-Toh", "Jennifer R. S. Meadows"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0075242.g003", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_novel_locus_on_chromosome_14_is_associated_with_Shar_Pei_amyloidosis_A_/818088", "title"=>"A novel locus on chromosome 14 is associated with Shar-Pei amyloidosis. A", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-09 02:51:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1230184", "https://ndownloader.figshare.com/files/1230185", "https://ndownloader.figshare.com/files/1230186", "https://ndownloader.figshare.com/files/1230187", "https://ndownloader.figshare.com/files/1230188", "https://ndownloader.figshare.com/files/1230189", "https://ndownloader.figshare.com/files/1230190"], "description"=>"<div><p>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 (<i>p</i><2.6×10<sup>−8</sup>) 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 (<i>F</i><sub>ST</sub>) 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 (<i>p</i><0.05) renal differential expression in four genes previously implicated in kidney or immune health (<i>AOAH</i>, <i>ELMO1, HAS2</i> and <i>IL6</i>). 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.</p></div>", "links"=>[], "tags"=>["canine", "autoinflammatory", "confirms", "locus", "suggests", "modifier"], "article_id"=>818101, "categories"=>["Uncategorised"], "users"=>["Mia Olsson", "Linda Tintle", "Marcin Kierczak", "Michele Perloski", "Noriko Tonomura", "Andrew Lundquist", "Eva Murén", "Max Fels", "Katarina Tengvall", "Gerli Pielberg", "Caroline Dufaure de Citres", "Laetitia Dorso", "Jérôme Abadie", "Jeanette Hanson", "Anne Thomas", "Peter Leegwater", "Åke Hedhammar", "Kerstin Lindblad-Toh", "Jennifer R. S. Meadows"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0075242.s001", "https://dx.doi.org/10.1371/journal.pone.0075242.s002", "https://dx.doi.org/10.1371/journal.pone.0075242.s003", "https://dx.doi.org/10.1371/journal.pone.0075242.s004", "https://dx.doi.org/10.1371/journal.pone.0075242.s005", "https://dx.doi.org/10.1371/journal.pone.0075242.s006", "https://dx.doi.org/10.1371/journal.pone.0075242.s007"], "stats"=>{"downloads"=>8, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Thorough_Investigation_of_a_Canine_Autoinflammatory_Disease_AID_Confirms_One_Main_Risk_Locus_and_Suggests_a_Modifier_Locus_for_Amyloidosis_/818101", "title"=>"Thorough Investigation of a Canine Autoinflammatory Disease (AID) Confirms One Main Risk Locus and Suggests a Modifier Locus for Amyloidosis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-09 02:51:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1230168"], "description"=>"<p>The phenotypes of fever (<b>A</b>. <i>n</i> = 129), arthritis (<b>B</b>. <i>n</i> = 107), vesicular hyaluronosis (<b>C</b>. <i>n</i> = 46), and otitis (<b>D</b>. <i>n</i> = 27) were compared to a subset of healthy controls at least 7 years old (<i>n</i> = 24). The phenotype of amyloidosis (<b>E</b>) required individuals to undergo renal biopsy screening to be declared positive (<i>n</i> = 37) or negative (<i>n</i> = 14) for the deposits. In each panel the top genome-wide significant SNP has been highlighted with an open circle and linkage disequilibrium (<i>r<sup>2</sup></i>) between this marker and the others in the region coloured according to strength. A genome wide significant threshold (red dotted line) has been defined using an analysis specific Bonferroni 5% limit.</p>", "links"=>[], "tags"=>["investigated", "signs", "shar-pei", "autoinflammatory", "overlapping"], "article_id"=>818086, "categories"=>["Uncategorised"], "users"=>["Mia Olsson", "Linda Tintle", "Marcin Kierczak", "Michele Perloski", "Noriko Tonomura", "Andrew Lundquist", "Eva Murén", "Max Fels", "Katarina Tengvall", "Gerli Pielberg", "Caroline Dufaure de Citres", "Laetitia Dorso", "Jérôme Abadie", "Jeanette Hanson", "Anne Thomas", "Peter Leegwater", "Åke Hedhammar", "Kerstin Lindblad-Toh", "Jennifer R. S. Meadows"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0075242.g002", "stats"=>{"downloads"=>2, "page_views"=>36, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_five_investigated_signs_of_Shar_Pei_autoinflammatory_disease_share_overlapping_association_signals_/818086", "title"=>"The five investigated signs of Shar-Pei autoinflammatory disease share overlapping association signals.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-09 02:51:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1230165"], "description"=>"<p>Individuals representing the extremes of physical appearance (Meatmouth, heavily wrinkled thickened skin, <i>n</i> = 123; Bonemouth, few wrinkles left into adulthood, <i>n</i> = 33) were compared. <b>A</b>. Pairwise <i>F</i><sub>ST</sub> was calculated between the two groups for 126,206 SNP and plotted in chromosomal order. Smoothed values in bins of 100 SNP are superimposed to better illustrate the peak of association (red line). <b>B</b>. A zoomed view of a subset of the genes from the chromosome region in relation to the peak of <i>F</i><sub>ST</sub> (based on most divergent SNP and a 5% threshold, red box). <b>C</b>. The plot of a mixed model association test for breed subtype. The top genome-wide significant SNP (13∶23180227, <i>p<sub>MM</sub></i> = 2.63×10<sup>−9</sup>) has been highlighted with an open circle and linkage disequilibrium (<i>r<sup>2</sup></i>) between this marker and the others in the region are coloured according to strength. A genome wide significant threshold (red dotted line) has been defined using an analysis specific Bonferroni 5% limit.</p>", "links"=>[], "tags"=>["breed", "sub-type", "chromosome"], "article_id"=>818083, "categories"=>["Uncategorised"], "users"=>["Mia Olsson", "Linda Tintle", "Marcin Kierczak", "Michele Perloski", "Noriko Tonomura", "Andrew Lundquist", "Eva Murén", "Max Fels", "Katarina Tengvall", "Gerli Pielberg", "Caroline Dufaure de Citres", "Laetitia Dorso", "Jérôme Abadie", "Jeanette Hanson", "Anne Thomas", "Peter Leegwater", "Åke Hedhammar", "Kerstin Lindblad-Toh", "Jennifer R. S. Meadows"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0075242.g001", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_genetic_signature_of_within_breed_sub_type_on_chromosome_13_/818083", "title"=>"The genetic signature of within breed sub-type on chromosome 13.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-09 02:51:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/1230173"], "description"=>"1<p>Phased haplotypes are composed of the top SNP identified in each GWAS where genome-wide significance was reached and estimated from the total population frequency.</p>2<p>Haplotype pairs observed at frequencies less than 10% in a sample set have been collapsed.</p>", "links"=>[], "tags"=>["haplotype", "pairs", "observed", "chromosome", "13", "defined", "GWAS"], "article_id"=>818091, "categories"=>["Uncategorised"], "users"=>["Mia Olsson", "Linda Tintle", "Marcin Kierczak", "Michele Perloski", "Noriko Tonomura", "Andrew Lundquist", "Eva Murén", "Max Fels", "Katarina Tengvall", "Gerli Pielberg", "Caroline Dufaure de Citres", "Laetitia Dorso", "Jérôme Abadie", "Jeanette Hanson", "Anne Thomas", "Peter Leegwater", "Åke Hedhammar", "Kerstin Lindblad-Toh", "Jennifer R. S. Meadows"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0075242.t002", "stats"=>{"downloads"=>4, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Major_haplotype_pairs_observed_across_chromosome_13_as_defined_by_GWAS_significant_SNP_/818091", "title"=>"Major haplotype pairs observed across chromosome 13 as defined by GWAS significant SNP.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-10-09 02:51:09"}

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Relative Metric

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