Dataset Information

A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.

ABSTRACT: Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds--the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.

SUBMITTER: Bianchi M

PROVIDER: S-EPMC4532498 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.

Bianchi Matteo M Dahlgren Stina S Massey Jonathan J Dietschi Elisabeth E Kierczak Marcin M Lund-Ziener Martine M Sundberg Katarina K Thoresen Stein Istre SI Kämpe Olle O Andersson Göran G Ollier William E R WE Hedhammar Åke Å Leeb Tosso T Lindblad-Toh Kerstin K Kennedy Lorna J LJ Lingaas Frode F Rosengren Pielberg Gerli G

PloS one 20150811 8

Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds--the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 ...[more]

PMID: 26261983

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Project description:Recently, many genome-wide association studies (GWAS) have been conducted to understand the genetic architecture of economic important traits in farm animals. Pig is widely used as a biomedical animal model for its similarity with humans in terms of organ formation and disease mechanisms. Moreover, understanding the mechanisms that underlie the development of internal organs will impact the productive potential of pigs. Our aim was to uncover new single nucleotide polymorphisms (SNPs) associated with the weight of internal organs and carcass and also potential candidate genes.We performed GWAS for the weight of heart, liver, spleen, kidney and carcass on five pig populations (White Duroc × Erhualian F2 intercross, Sutai population, Laiwu population, Erhualian population and commercial population, for a total of 2650 individuals). Genotype data was produced using the PorcineSNP60 Beadchip array. After quality control, the data was used for association tests under a general linear mixed model. Population stratification was adjusted by including a random polygenic effect based on a matrix of genotypic relationships. A meta-analysis of our GWAS datasets was conducted by summing up the Chi square values across breeds, with the degrees of freedom of the Chi square distribution equal to the effective number of breeds.Thirty-nine quantitative trait loci (QTL) located on 15 chromosomes were identified by the single-population GWAS at the suggestive level. Among these, nine QTL surpassed the 5 % genome-wide significance threshold, including four for heart weight on SSC (Sus scrofa chromosome) 2, 4, 7 and 10, two for liver weight on SSC7, two for spleen weight on SSC5 and SSC7 and one for carcass weight on SSC11. The QTL on SSC7 showed pleiotropic effects for heart, liver and spleen weights in the F2 population. In addition, two QTL were detected in several populations, including one on SSC2 for heart weight in the F2 and Sutai populations and one on SSC7 for liver weight in the F2 and Laiwu populations. The meta-analysis detected four novel QTL on SSC1, 3, 8 and 16 for carcass weight.

Project description:BACKGROUND:Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. METHODS AND RESULTS:We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. CONCLUSIONS:We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).

Dataset Information

A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.

Publications

A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12.

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