[Show abstract][Hide abstract] ABSTRACT: Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity—multiple homozygous SNPs in a row—to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003–0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium.
The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM.
This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.
Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2015-208119 · 10.38 Impact Factor
[Show abstract][Hide abstract] 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 characterisa-tion 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.
PLoS ONE 09/2015; 10(8). DOI:10.1371/journal.pone.0134720 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.Genes and Immunity advance online publication, 20 August 2015; doi:10.1038/gene.2015.28.
Genes and immunity 08/2015; DOI:10.1038/gene.2015.28 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Administration of insulin for treatment of diabetes mellitus in dogs can stimulate an immune response, with a proportion of animals developing anti-insulin antibodies (AIA). For an IgG antibody response to occur, this would require B cell presentation of insulin peptides by major histocompatibility complex (MHC) class II molecules, encoded by dog leukocyte antigen (DLA) genes, in order to receive T-cell help for class switching. DLA genes are highly polymorphic in the dog population and vary from breed to breed. The aim of the present study was to evaluate AIA reactivity in diabetic dogs of different breeds and to investigate whether DLA genes influence AIA status.
Veterinary Immunology and Immunopathology 08/2015; DOI:10.1016/j.vetimm.2015.07.014 · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.Genes and Immunity advance online publication, 23 July 2015; doi:10.1038/gene.2015.27.
Genes and immunity 07/2015; 16(6). DOI:10.1038/gene.2015.27 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Beagles are commonly used in vaccine trials as part of the regulatory approval process. Genetic restriction within this breed and the impact this might have on vaccine responses is rarely considered. This study was designed to characterise diversity of dog leucocyte antigen (DLA) class II genes in a breeding colony of laboratory Beagles, whose offspring are used in vaccine studies. DLA haplotypes were determined by PCR and sequence-based typing from genomic DNA extracted from blood. Breeding colony Beagles demonstrated significantly different DLA haplotype frequencies in comparison with pet Beagles and both groups showed limited DLA diversity. Restricted DLA class II genetic variability within Beagles might result in selective antigen presentation and vaccine responses that are not necessarily representative of those seen in other dog breeds.
The Veterinary Journal 01/2015; 203(3). DOI:10.1016/j.tvjl.2014.12.032 · 1.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives/HypothesisAge-related hearing loss has a genetic component, but there have been limited genetic studies in this field. Both N-acetyltransferase 2 and apolipoprotein E genes have previously been associated. However, these studies have either used small sample sizes, examined a limited number of polymorphisms, or have produced conflicting results. Here we use a haplotype tagging approach to determine association with age-related hearing loss and investigate epistasis between these two genes.Study DesignCandidate gene association study of a continuous phenotype.Methods
We investigated haplotype tagging single nucleotide polymorphisms in the N-acetyltransferase 2 gene and the presence/absence of the apolipoprotein E ε4 allele for association with age-related hearing loss in a cohort of 265 Caucasian elderly volunteers from Greater Manchester, United Kingdom. Hearing phenotypes were generated using principal component analysis of the hearing threshold levels for the better ear (severity, slope, and concavity). Genotype data for the N-acetyltransferase 2 gene was obtained from existing genome-wide association study data from the Illumina 610-Quadv1 chip. Apolipoprotein E genotyping was performed using Sequenom technology. Linear regression analysis was performed using Plink and Stata software.ResultsNo significant associations (P value, > 0.05) were observed between the N-acetyltransferase 2 or apolipoprotein E gene polymorphisms and any hearing factor. No significant association was observed for epistasis analysis of apolipoprotein E ε4 and the N-acetyltransferase 2 single nucleotide polymorphism rs1799930 (NAT2*6A).Conclusion
We found no evidence to support that either N-acetyltransferase 2 or apolipoprotein E gene polymorphisms are associated with age-related hearing loss in a cohort of 265 elderly volunteers.Level of EvidenceN/A. Laryngoscope, 2014
The Laryngoscope 01/2015; 125(1). DOI:10.1002/lary.24898 · 2.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
The focus of this investigation was to elucidate molecular mimicry as a plausible model for idiopathic inflammatory myopathy (IIM) aetiology through systematic, computational experimentation using a previously developed molecular mimicry identification pipeline package.
The investigation found no direct association between molecular mimicry and IIM, however, the investigation successfully identified a catalogue of mimicry candidates possessed by bacterial, protist and viral infectious agent which can provide a platform for further analysis, not only for IIM, but for a range of diseases associated with these infectious agents where molecular mimicry is a theorised pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status, and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) - the ability to reason in novel situations - and general crystallized intelligence (gC) - the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.
[Show abstract][Hide abstract] ABSTRACT: Background Idiopathic inflammatory myopathies (IIM) may present as a primary disorder, or may overlap with connective tissue diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis. The aetiology of IIM is largely unknown, but is thought to include a combination of genetic and environmental factors. To generate ethnically homogeneous IIM cohorts of sufficient size given its rarity, one of the largest European IIM initiatives has enabled Europe wide ascertainment of cases with EUMYONET. Numerous genome-wide association studies (GWAS) have identified many genetic variants associated with autoimmune disorders, several common to multiple disorders. This is supported by our recent dermatomyositis (DM) GWAS, suggesting genetic overlap with other autoimmune disorders1.
Objectives We sought to identify additional novel genetic risk factors in adult and juvenile polymyositis (PM) and DM (not previously identified by DM GWAS), shared with other autoimmune disorders.
Methods SNPs significantly associated with SLE, RA, juvenile idiopathic arthritis, coeliac disease, Crohn's disease, ulcerative colitis, psoriasis, type 1 diabetes, multiple sclerosis or systemic sclerosis were identified from published Caucasian GWAS and from the national human genome research institute catalogue of published GWAS. 233 unique SNPs were identified (p <5×10-8), of which 99 had not been directly genotyped or captured through our MYOGEN GWAS1. SNPs were genotyped by Sequenom in a sample of 1001 European Caucasian individuals with definite or probable adult or juvenile PM or DM. 83 SNPs passed quality control criteria. GWAS data from EU contributors was imputed to the 1000G_phase1integrated_v3 reference panel. Association tests for IIM subgroups and random-effects meta-analysis of the individual country datasets were performed.
Results Samples with >5% missing genotype data were excluded, resulting in 1149 cases and 3572 controls. Outside the MHC region, a non-synonymous SNP rs2304256 in the TYK2 gene was identified reaching Bonferroni-corrected significance in IIM and DM (β= -0.21, p value=0.00027; β= -0.25, p value=0.00020 respectively). Two further SNPs within the BLK gene and 2335bp 5' of BLK were associated with DM (rs2618476, β=0.24, p value=0.00062; rs13277113, β=0.25 p value=0.00045 respectively) but not with PM, supporting the results of our DM GWAS.
Conclusions We have identified TYK2 as a novel association for DM, suggesting genetic overlap of DM with other autoimmune disorders, and indicating genetic heterogeneity between PM and DM. TYK2 has been associated previously with SLE, type 1 diabetes and multiple sclerosis. Further associations of the BLK gene with DM, suggests a role of B cells in its development.
Acknowledgements Funding: Arthritis Research UK (grants 18474; 14518), Intramural Research Program of the NIH, Wellcome Trust (076113; 085860). We thank all other members of the EUMYONET and Myositis Genetics Consortium (MYOGEN).
Disclosure of Interest None declared
Annals of the Rheumatic Diseases 06/2014; 73(Suppl 2):151-151. DOI:10.1136/annrheumdis-2014-eular.2877 · 10.38 Impact Factor