Publications by authors named "Jonathan Massey"

29 Publications

  • Page 1 of 1

Co-evolving wing spots and mating displays are genetically separable traits in Drosophila.

Evolution 2020 06 17;74(6):1098-1111. Epub 2020 May 17.

Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, 48109.

The evolution of sexual traits often involves correlated changes in morphology and behavior. For example, in Drosophila, divergent mating displays are often accompanied by divergent pigment patterns. To better understand how such traits co-evolve, we investigated the genetic basis of correlated divergence in wing pigmentation and mating display between the sibling species Drosophila elegans and Drosophila gunungcola. Drosophila elegans males have an area of black pigment on their wings known as a wing spot and appear to display this spot to females by extending their wings laterally during courtship. By contrast, D. gunungcola lost both of these traits. Using Multiplexed Shotgun Genotyping (MSG), we identified a ∼440 kb region on the X chromosome that behaves like a genetic switch controlling the presence or absence of male-specific wing spots. This region includes the candidate gene optomotor-blind (omb), which plays a critical role in patterning the Drosophila wing. The genetic basis of divergent wing display is more complex, with at least two loci on the X chromosome and two loci on autosomes contributing to its evolution. Introgressing the X-linked region affecting wing spot development from D. gunungcola into D. elegans reduced pigmentation in the wing spots but did not affect the wing display, indicating that these are genetically separable traits. Consistent with this observation, broader sampling of wild D. gunungcola populations confirmed that the wing spot and wing display are evolving independently: some D. gunungcola males performed wing displays similar to D. elegans despite lacking wing spots. These data suggest that correlated selection pressures rather than physical linkage or pleiotropy are responsible for the coevolution of these morphological and behavioral traits. They also suggest that the change in morphology evolved prior to the change in behavior.
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http://dx.doi.org/10.1111/evo.13990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494213PMC
June 2020

The gene influences male mating success through sex comb melanization.

Elife 2019 10 15;8. Epub 2019 Oct 15.

Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, United States.

males perform a series of courtship behaviors that, when successful, result in copulation with a female. For over a century, mutations in the gene, named for its effects on pigmentation, have been known to reduce male mating success. Prior work has suggested that influences mating behavior through effects on wing extension, song, and/or courtship vigor. Here, we rule out these explanations, as well as effects on the nervous system more generally, and find instead that the effects of on male mating success are mediated by its effects on pigmentation of male-specific leg structures called sex combs. Loss of expression in these modified bristles reduces their melanization, which changes their structure and causes difficulty grasping females prior to copulation. These data illustrate why the mechanical properties of anatomy, not just neural circuitry, must be considered to fully understand the development and evolution of behavior.
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http://dx.doi.org/10.7554/eLife.49388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794089PMC
October 2019

Author Correction: Genotypic variability-based genome-wide association study identifies non-additive loci HLA-C and IL12B for psoriasis.

J Hum Genet 2019 Aug;64(8):831

Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, M6 8HD, UK.

This article was originally published under a CC BY-NC-SA License, but has now been made available under a CC BY 4.0 License.
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http://dx.doi.org/10.1038/s10038-019-0605-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760575PMC
August 2019

Pleiotropic Effects of and on Pigmentation and Cuticular Hydrocarbon Composition in .

Front Physiol 2019 1;10:518. Epub 2019 May 1.

Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Japan.

Pleiotropic genes are genes that affect more than one trait. For example, many genes required for pigmentation in the fruit fly also affect traits such as circadian rhythms, vision, and mating behavior. Here, we present evidence that two pigmentation genes, and , which encode enzymes catalyzing reciprocal reactions in the melanin biosynthesis pathway, also affect cuticular hydrocarbon (CHC) composition in females. More specifically, we report that loss-of-function mutants have a CHC profile that is biased toward long (>25C) chain CHCs, whereas loss-of-function mutants have a CHC profile that is biased toward short (<25C) chain CHCs. Moreover, pharmacological inhibition of dopamine synthesis, a key step in the melanin synthesis pathway, reversed the changes in CHC composition seen in mutants, making the CHC profiles similar to those seen in mutants. These observations suggest that genetic variation affecting and/or activity might cause correlated changes in pigmentation and CHC composition in natural populations. We tested this possibility using the Genetic Reference Panel (DGRP) and found that CHC composition covaried with pigmentation as well as levels of and expression in newly eclosed adults in a manner consistent with the and mutant phenotypes. These data suggest that the pleiotropic effects of and might contribute to covariation of pigmentation and CHC profiles in .
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http://dx.doi.org/10.3389/fphys.2019.00518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504824PMC
May 2019

Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis.

Pharmacogenomics J 2018 09 31;18(5):657-664. Epub 2018 Aug 31.

Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.

Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation. Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate. We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months. The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 × 10). Capture Hi-C data show chromatin interactions in GM12878 cells between rs2540767, in high linkage disequilibrium with rs7195994 (R = 0.9) and IRX3, a neighbouring gene of FTO. IRX3 encodes a transcription factor involved in adipocyte remodelling and is regarded as the obesity gene at the FTO locus. Importantly, the rs7195994 association remained significantly associated following adjustment for BMI. In addition, using capture Hi-C data we showed interactions between TNFi-response associated variants and 16 RA susceptibility variants.
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http://dx.doi.org/10.1038/s41397-018-0040-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150911PMC
September 2018

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

Pharmacogenomics J 2018 07 25;18(4):528-538. Epub 2018 May 25.

Leeds Institute of Cancer and Pathology, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.
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http://dx.doi.org/10.1038/s41397-018-0025-5DOI Listing
July 2018

Evaluation of metrics for benchmarking antimicrobial use in the UK dairy industry.

Vet Rec 2018 03 23;182(13):379. Epub 2018 Feb 23.

Bristol Veterinary School, University of Bristol, Bristol, UK.

The issue of antimicrobial resistance is of global concern across human and animal health. In 2016, the UK government committed to new targets for reducing antimicrobial use (AMU) in livestock. Although a number of metrics for quantifying AMU are defined in the literature, all give slightly different interpretations. This paper evaluates a selection of metrics for AMU in the dairy industry: total mg, total mg/kg, daily dose and daily course metrics. Although the focus is on their application to the dairy industry, the metrics and issues discussed are relevant across livestock sectors. In order to be used widely, a metric should be understandable and relevant to the veterinarians and farmers who are prescribing and using antimicrobials. This means that clear methods, assumptions (and possible biases), standardised values and exceptions should be published for all metrics. Particularly relevant are assumptions around the number and weight of cattle at risk of treatment and definitions of dose rates and course lengths; incorrect assumptions can mean metrics over-represent or under-represent AMU. The authors recommend that the UK dairy industry work towards the UK-specific metrics using the UK-specific medicine dose and course regimens as well as cattle weights in order to monitor trends nationally.
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http://dx.doi.org/10.1136/vr.104701DOI Listing
March 2018

Genotypic variability-based genome-wide association study identifies non-additive loci HLA-C and IL12B for psoriasis.

J Hum Genet 2018 Mar 19;63(3):289-296. Epub 2017 Dec 19.

Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, M6 8HD, UK.

Genome-wide association studies (GWASs) have identified a number of loci for psoriasis but largely ignored non-additive effects. We report a genotypic variability-based GWAS (vGWAS) that can prioritize non-additive loci without requiring prior knowledge of interaction types or interacting factors in two steps, using a mixed model to partition dichotomous phenotypes into an additive component and non-additive environmental residuals on the liability scale and then the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups genome widely. The vGWAS identified two genome-wide significant (P < 5.0e-08) non-additive loci HLA-C and IL12B that were also genome-wide significant in an accompanying GWAS in the discovery cohort. Both loci were statistically replicated in vGWAS of an independent cohort with a small sample size. HLA-C and IL12B were reported in moderate gene-gene and/or gene-environment interactions in several occasions. We found a moderate interaction with age-of-onset of psoriasis, which was replicated indirectly. The vGWAS also revealed five suggestive loci (P < 6.76e-05) including FUT2 that was associated with psoriasis with environmental aspects triggered by virus infection and/or metabolic factors. Replication and functional investigation are needed to validate the suggestive vGWAS loci.
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http://dx.doi.org/10.1038/s10038-017-0350-6DOI Listing
March 2018

CD4+ and B Lymphocyte Expression Quantitative Traits at Rheumatoid Arthritis Risk Loci in Patients With Untreated Early Arthritis: Implications for Causal Gene Identification.

Arthritis Rheumatol 2018 03 30;70(3):361-370. Epub 2018 Jan 30.

NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, and Newcastle University, Newcastle upon Tyne, UK.

Objective: Rheumatoid arthritis (RA) is a genetically complex disease of immune dysregulation. This study sought to gain further insight into the genetic risk mechanisms of RA by conducting an expression quantitative trait locus (eQTL) analysis of confirmed genetic risk loci in CD4+ T cells and B cells from carefully phenotyped patients with early arthritis who were naive to therapeutic immunomodulation.

Methods: RNA and DNA were isolated from purified B and/or CD4+ T cells obtained from the peripheral blood of 344 patients with early arthritis. Genotyping and global gene expression measurements were carried out using Illumina BeadChip microarrays. Variants in linkage disequilibrium (LD) with non-HLA RA single-nucleotide polymorphisms (defined as r ≥ 0.8) were analyzed, seeking evidence of cis- or trans-eQTLs according to whether the associated probes were or were not within 4 Mb of these LD blocks.

Results: Genes subject to cis-eQTL effects that were common to both CD4+ and B lymphocytes at RA risk loci were FADS1, FADS2, BLK, FCRL3, ORMDL3, PPIL3, and GSDMB. In contrast, those acting on METTL21B, JAZF1, IKZF3, and PADI4 were unique to CD4+ lymphocytes, with the latter candidate risk gene being identified for the first time in this cell subset. B lymphocyte-specific eQTLs for SYNGR1 and CD83 were also found. At the 8p23 BLK-FAM167A locus, adjacent genes were subject to eQTLs whose activity differed markedly between cell types; in particular, the FAM167A effect displayed striking B lymphocyte specificity. No trans-eQTLs approached experiment-wide significance, and linear modeling did not identify a significant influence of biologic covariates on cis-eQTL effect sizes.

Conclusion: These findings further refine the understanding of candidate causal genes in RA pathogenesis, thus providing an important platform from which downstream functional studies, directed toward particular cell types, may be prioritized.
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http://dx.doi.org/10.1002/art.40393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888199PMC
March 2018

Analysis of SNP-SNP interactions and bone quantitative ultrasound parameter in early adulthood.

BMC Med Genet 2017 10 3;18(1):107. Epub 2017 Oct 3.

Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK.

Background: Osteoporosis individual susceptibility is determined by the interaction of multiple genetic variants and environmental factors. The aim of this study was to conduct SNP-SNP interaction analyses in candidate genes influencing heel quantitative ultrasound (QUS) parameter in early adulthood to identify novel insights into the mechanism of disease.

Methods: The study population included 575 healthy subjects (mean age 20.41; SD 2.36). To assess bone mass QUS was performed to determine Broadband ultrasound attenuation (BUA, dB/MHz). A total of 32 SNPs mapping to loci that have been characterized as genetic markers for QUS and/or BMD parameters were selected as genetic markers in this study. The association of all possible SNP pairs with QUS was assessed by linear regression and a SNP-SNP interaction was defined as a significant departure from additive effects.

Results: The pairwise SNP-SNP analysis showed multiple interactions. The interaction comprising SNPs rs9340799 and rs3736228 that map in the ESR1 and LRP5 genes respectively, revealed the lowest p value after adjusting for confounding factors (p-value = 0.001, β (95% CI) = 14.289 (5.548, 23.029). In addition, our model reported others such as TMEM135-WNT16 (p = 0.007, β(95%CI) = 9.101 (2.498, 15.704), ESR1-DKK1 (p = 0.012, β(95%CI) = 13.641 (2.959, 24.322) or OPG-LRP5 (p = 0.012, β(95%CI) = 8.724 (1.936, 15.512). However, none of the detected interactions remain significant considering the Bonferroni significance threshold for multiple testing (p<0.0001).

Conclusion: Our analysis of SNP-SNP interaction in candidate genes of QUS in Caucasian young adults reveal several interactions, especially between ESR1 and LRP5 genes, that did not reach statistical significance. Although our results do not support a relevant genetic contribution of SNP-SNP epistatic interactions to QUS in young adults, further studies in larger independent populations would be necessary to support these preliminary findings.
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http://dx.doi.org/10.1186/s12881-017-0468-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627468PMC
October 2017

HLA-A 31:01 is not associated with the development of methotrexate pneumonitis in the UK population: results from a genome-wide association study.

Ann Rheum Dis 2017 12 12;76(12):e51. Epub 2017 May 12.

Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.

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http://dx.doi.org/10.1136/annrheumdis-2017-211512DOI Listing
December 2017

Identifying Causal Genes at the Multiple Sclerosis Associated Region 6q23 Using Capture Hi-C.

PLoS One 2016 18;11(11):e0166923. Epub 2016 Nov 18.

Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Siences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.

Background: The chromosomal region 6q23 has been found to be associated with multiple sclerosis (MS) predisposition through genome wide association studies (GWAS). There are four independent single nucleotide polymorphisms (SNPs) associated with MS in this region, which spans around 2.5 Mb. Most GWAS variants associated with complex traits, including these four MS associated SNPs, are non-coding and their function is currently unknown. However, GWAS variants have been found to be enriched in enhancers and there is evidence that they may be involved in transcriptional regulation of their distant target genes through long range chromatin looping.

Aim: The aim of this work is to identify causal disease genes in the 6q23 locus by studying long range chromatin interactions, using the recently developed Capture Hi-C method in human T and B-cell lines. Interactions involving four independent associations unique to MS, tagged by rs11154801, rs17066096, rs7769192 and rs67297943 were analysed using Capture Hi-C Analysis of Genomic Organisation (CHiCAGO).

Results: We found that the pattern of chromatin looping interactions in the MS 6q23 associated region is complex. Interactions cluster in two regions, the first involving the rs11154801 region and a second containing the rs17066096, rs7769192 and rs67297943 SNPs. Firstly, SNPs located within the AHI1 gene, tagged by rs11154801, are correlated with expression of AHI1 and interact with its promoter. These SNPs also interact with other potential candidate genes such as SGK1 and BCLAF1. Secondly, the rs17066096, rs7769192 and rs67297943 SNPs interact with each other and with immune-related genes such as IL20RA, IL22RA2, IFNGR1 and TNFAIP3. Finally, the above-mentioned regions interact with each other and therefore, may co-regulate these target genes.

Conclusion: These results suggest that the four 6q23 variants, independently associated with MS, are involved in the regulation of several genes, including immune genes. These findings could help understand mechanisms of disease and suggest potential novel therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166923PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115837PMC
June 2017

Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23.

Genome Biol 2016 11 1;17(1):212. Epub 2016 Nov 1.

Arthritis Research UK Centre for Genetics and Genomics, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.

Background: The identification of causal genes from genome-wide association studies (GWAS) is the next important step for the translation of genetic findings into biologically meaningful mechanisms of disease and potential therapeutic targets. Using novel chromatin interaction detection techniques and allele specific assays in T and B cell lines, we provide compelling evidence that redefines causal genes at the 6q23 locus, one of the most important loci that confers autoimmunity risk.

Results: Although the function of disease-associated non-coding single nucleotide polymorphisms (SNPs) at 6q23 is unknown, the association is generally assigned to TNFAIP3, the closest gene. However, the DNA fragment containing the associated SNPs interacts through chromatin looping not only with TNFAIP3, but also with IL20RA, located 680 kb upstream. The risk allele of the most likely causal SNP, rs6927172, is correlated with both a higher frequency of interactions and increased expression of IL20RA, along with a stronger binding of both the NFκB transcription factor and chromatin marks characteristic of active enhancers in T-cells.

Conclusions: Our results highlight the importance of gene assignment for translating GWAS findings into biologically meaningful mechanisms of disease and potential therapeutic targets; indeed, monoclonal antibody therapy targeting IL-20 is effective in the treatment of rheumatoid arthritis and psoriasis, both with strong GWAS associations to this region.
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http://dx.doi.org/10.1186/s13059-016-1078-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5088679PMC
November 2016

Previously reported PDE3A-SLCO1C1 genetic variant does not correlate with anti-TNF response in a large UK rheumatoid arthritis cohort.

Pharmacogenomics 2016 05 16;17(7):715-20. Epub 2016 May 16.

Arthritis Research UK, Centre for Genetics & Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK.

Aim: A genetic variant has recently reached genome-wide significance for association with TNF-inhibitor response in rheumatoid arthritis patients. Here we undertake a replication study in a UK Caucasian population to test for association with TNF-inhibitor response.

Materials & Methods: The genetic variant, rs3794271, located within the PDE3A-SLCO1C1 locus was analyzed for correlation with treatment response using both the EULAR classification criteria and absolute change in (Δ)DAS28 scores as outcome measures.

Results: Genotype data were available from 1750 TNF-inhibitor treated individuals. However, no evidence for association was observed (EULAR: p = 0.91 and ΔDAS28: p = 0.93). Furthermore, no significant associations were observed upon stratification by the anti-TNF received (p > 0.05).

Conclusion: In the largest replication cohort conducted to date, no evidence for association was observed.
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http://dx.doi.org/10.2217/pgs.16.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996314PMC
May 2016

Major histocompatibility complex harbors widespread genotypic variability of non-additive risk of rheumatoid arthritis including epistasis.

Sci Rep 2016 04 25;6:25014. Epub 2016 Apr 25.

Arthritis Research UK Centre for Genetics and Genomics, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

Genotypic variability based genome-wide association studies (vGWASs) can identify potentially interacting loci without prior knowledge of the interacting factors. We report a two-stage approach to make vGWAS applicable to diseases: firstly using a mixed model approach to partition dichotomous phenotypes into additive risk and non-additive environmental residuals on the liability scale and secondly using the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups per marker. We found widespread significant (P < 2.5e-05) vGWAS signals within the major histocompatibility complex (MHC) across all three study cohorts of rheumatoid arthritis. We further identified 10 epistatic interactions between the vGWAS signals independent of the MHC additive effects, each with a weak effect but jointly explained 1.9% of phenotypic variance. PTPN22 was also identified in the discovery cohort but replicated in only one independent cohort. Combining the three cohorts boosted power of vGWAS and additionally identified TYK2 and ANKRD55. Both PTPN22 and TYK2 had evidence of interactions reported elsewhere. We conclude that vGWAS can help discover interacting loci for complex diseases but require large samples to find additional signals.
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http://dx.doi.org/10.1038/srep25014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842957PMC
April 2016

Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti-Cyclic Citrullinated Peptide-Negative Rheumatoid Arthritis.

Arthritis Rheumatol 2016 07;68(7):1603-13

NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Arthritis Research UK Centre for Genetics and Genomics, Manchester Academic Health Science Centre, and University of Manchester, Manchester, UK.

Objective: Genetic polymorphisms within the HLA region explain only a modest proportion of anti-cyclic citrullinated peptide (anti-CCP)-negative rheumatoid arthritis (RA) heritability. However, few non-HLA markers have been identified so far. This study was undertaken to replicate the associations of anti-CCP-negative RA with non-HLA genetic polymorphisms demonstrated in a previous study.

Methods: The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune-related regions in 3,339 anti-CCP-negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case-control replication study of the anti-CCP-negative markers with the strongest associations in that discovery study, in an independent cohort of anti-CCP-negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome-wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel.

Results: After genotyping and imputation quality control procedures, data were available for 15 non-HLA single-nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta-analysis odds ratio [OR] 0.80; P = 2.8 × 10(-13) ) and BLK (OR 1.13; P = 7.0 × 10(-6) ) and identified new and specific markers of anti-CCP-negative RA (prolactin [PRL] [OR 1.13; P = 2.1 × 10(-6) ] and NFIA [OR 0.85; P = 2.5 × 10(-6) ]). Neither of these loci is associated with other common, complex autoimmune diseases.

Conclusion: Anti-CCP-negative RA and anti-CCP-positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti-CCP-negative RA.
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http://dx.doi.org/10.1002/art.39619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924598PMC
July 2016

A role for HLA-DRB1*1101 and DRB1*0801 in cognitive ability and its decline with age.

Am J Med Genet B Neuropsychiatr Genet 2016 Mar 16;171B(2):209-14. Epub 2015 Oct 16.

Centre for Clinical and Cognitive Neuroscience, Institute of Brain Behaviour and Mental Health, Salford Royal NHS Hospital, The University of Manchester, Manchester, UK.

Cognitive abilities (memory, processing speed, vocabulary, and fluid intelligence) are correlated with educational attainment and occupational status, as well as physical and mental health. The variation in cognitive abilities observed within a population has a substantial genetic contribution (heritability ∼50%) and yet the identification of genetic polymorphisms from both genome-wide association and candidate studies have to date only uncovered a limited number of genetic variants that exert small genetic effects. Here we impute human leukocyte antigens (HLA) using existing genome-wide association data from 1,559 non-pathological elderly volunteers who have been followed for changes in cognitive functioning between a 12- and 18-year period. Specifically, we investigate DRB1*05 (*11/*12) and DRB1*01, which have previously been associated with cognitive ability. We also analyze DRB1*0801, which shares close sequence homology with DRB1*1101. Together with DRB1*1101, DRB1*0801 has been associated with several diseases including multiple sclerosis and primary biliary cirrhosis, which themselves are associated with cognitive impairment. We observed that both DRB1*0801 and DRB1*1101 were significantly associated with vocabulary ability (cross-sectional and longitudinal scores) and that the effects were in opposite directions with DRB1*0801 associated with lower score and faster decline. This opposing affect is similar to that reported by other groups in systemic lupus erythematosus, type 1 diabetes, and primary biliary cirrhosis. DRB1*0801 was also significantly associated with reduced memory ability. We observed no associations between cognitive abilities and DRB1*01 or DRB1*12.
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http://dx.doi.org/10.1002/ajmg.b.32393DOI Listing
March 2016

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

PLoS One 2015 11;10(8):e0134720. Epub 2015 Aug 11.

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134720PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532498PMC
May 2016

Social evolution. Genomic signatures of evolutionary transitions from solitary to group living.

Science 2015 Jun 14;348(6239):1139-43. Epub 2015 May 14.

China National GeneBank, BGI-Shenzhen, Shenzhen, 518083, China. Centre for Social Evolution, Department of Biology, Universitetsparken 15, University of Copenhagen, DK-2100 Copenhagen, Denmark.

The evolution of eusociality is one of the major transitions in evolution, but the underlying genomic changes are unknown. We compared the genomes of 10 bee species that vary in social complexity, representing multiple independent transitions in social evolution, and report three major findings. First, many important genes show evidence of neutral evolution as a consequence of relaxed selection with increasing social complexity. Second, there is no single road map to eusociality; independent evolutionary transitions in sociality have independent genetic underpinnings. Third, though clearly independent in detail, these transitions do have similar general features, including an increase in constrained protein evolution accompanied by increases in the potential for gene regulation and decreases in diversity and abundance of transposable elements. Eusociality may arise through different mechanisms each time, but would likely always involve an increase in the complexity of gene networks.
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http://dx.doi.org/10.1126/science.aaa4788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471836PMC
June 2015

Clinical features of idiopathic inflammatory polymyopathy in the Hungarian Vizsla.

BMC Vet Res 2015 Apr 21;11:97. Epub 2015 Apr 21.

Fitzpatrick Referrals, Halfway Lane, Eashing, Godalming, GU7 2QQ, Surrey, UK.

Background: A retrospective study of the clinicopathological features of presumed and confirmed cases of idiopathic inflammatory polymyopathy in the Hungarian Vizsla dog and guidelines for breeding.

Results: 369 medical records were reviewed (1992-2013) and 77 Hungarian Vizslas were identified with a case history consistent with idiopathic inflammatory polymyopathy. Inclusion criteria were: group 1 (confirmed diagnosis); histopathology and clinical findings compatible with an inflammatory polymyopathy and group 2 (probable diagnosis); clinical findings compatible with a polymyopathy including dysphagia, sialorrhea, temporal muscle atrophy, elevated serum creatine kinase (CK) activity, and sufficient clinical history to suggest that other neuromuscular disorders could be ruled out. Some group 2 dogs had muscle biopsy, which suggested muscle disease but did not reveal an inflammatory process. The mean age of onset was 2.4 years; male dogs were slightly overrepresented. Common presenting signs were dysphagia, sialorrhea, masticatory muscle atrophy, and regurgitation. Common muscle histopathological findings included degenerative and regenerative changes, with multifocal mononuclear cell infiltration with lymphoplasmacytic myositis of variable severity. A positive response to immunosuppressive treatment supported an immune-mediated aetiology. The mean age at death and survival time were 6.4 and 3.9 years, respectively. Recurrence of clinical signs and aspiration pneumonia were common reasons for euthanasia.

Conclusions: Diagnosis of Vizsla idiopathic inflammatory polymyopathy can be challenging due to lack of specific tests, however the presence of dysphagia, regurgitation and masticatory muscle atrophy in this breed with negative serological tests for masticatory muscle myositis and myasthenia gravis, along with muscle biopsies suggesting an inflammatory process, support the diagnosis. However, there is an urgent need for a more specific diagnostic test. The average of inbreeding coefficient (CoI) of 16.3% suggests an increased expression of a Dog Leukocyte Antigen Class II haplotype, leading to an increased disease risk. The prognosis remains guarded, as treatment can only manage the disease. Recurrence of clinical signs and perceived poor quality of life are the most common reasons for humane euthanasia.
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http://dx.doi.org/10.1186/s12917-015-0408-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414416PMC
April 2015

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis.

Nat Commun 2015 Feb 5;6:6046. Epub 2015 Feb 5.

1] Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester M13 9PT, UK [2] NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust and University of Manchester, Manchester Academy of Health Sciences, Manchester M13 9WU, UK.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case-control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8(+) memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.
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http://dx.doi.org/10.1038/ncomms7046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327416PMC
February 2015

Socially responsive effects of brain oxidative metabolism on aggression.

Proc Natl Acad Sci U S A 2014 Aug 4;111(34):12533-7. Epub 2014 Aug 4.

Department of Entomology, Institute for Genomic Biology, and Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801; and

Despite ongoing high energetic demands, brains do not always use glucose and oxygen in a ratio that produces maximal ATP through oxidative phosphorylation. In some cases glucose consumption exceeds oxygen use despite adequate oxygen availability, a phenomenon known as aerobic glycolysis. Although metabolic plasticity seems essential for normal cognition, studying its functional significance has been challenging because few experimental systems link brain metabolic patterns to distinct behavioral states. Our recent transcriptomic analysis established a correlation between aggression and decreased whole-brain oxidative phosphorylation activity in the honey bee (Apis mellifera), suggesting that brain metabolic plasticity may modulate this naturally occurring behavior. Here we demonstrate that the relationship between brain metabolism and aggression is causal, conserved over evolutionary time, cell type-specific, and modulated by the social environment. Pharmacologically treating honey bees to inhibit complexes I or V in the oxidative phosphorylation pathway resulted in increased aggression. In addition, transgenic RNAi lines and genetic manipulation to knock down gene expression in complex I in fruit fly (Drosophila melanogaster) neurons resulted in increased aggression, but knockdown in glia had no effect. Finally, honey bee colony-level social manipulations that decrease individual aggression attenuated the effects of oxidative phosphorylation inhibition on aggression, demonstrating a specific effect of the social environment on brain function. Because decreased neuronal oxidative phosphorylation is usually associated with brain disease, these findings provide a powerful context for understanding brain metabolic plasticity and naturally occurring behavioral plasticity.
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http://dx.doi.org/10.1073/pnas.1412306111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151721PMC
August 2014

Rare variants and autoimmune disease.

Brief Funct Genomics 2014 Sep 9;13(5):392-7. Epub 2014 May 9.

The study of rare variants in monogenic forms of autoimmune disease has offered insight into the aetiology of more complex pathologies. Research in complex autoimmune disease initially focused on sequencing candidate genes, with some early successes, notably in uncovering low-frequency variation associated with Type 1 diabetes mellitus. However, other early examples have proved difficult to replicate, and a recent study across six autoimmune diseases, re-sequencing 25 autoimmune disease-associated genes in large sample sizes, failed to find any associated rare variants. The study of rare and low-frequency variation in autoimmune diseases has been made accessible by the inclusion of such variants on custom genotyping arrays (e.g. Immunochip and Exome arrays). Whole-exome sequencing approaches are now also being utilised to uncover the contribution of rare coding variants to disease susceptibility, severity and treatment response. Other sequencing strategies are starting to uncover the role of regulatory rare variation.
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http://dx.doi.org/10.1093/bfgp/elu011DOI Listing
September 2014

Genetics of canine anal furunculosis in the German shepherd dog.

Immunogenetics 2014 May 14;66(5):311-24. Epub 2014 Mar 14.

Centre for Integrated Genomic Medical Research (CIGMR), Institute of Population Health, Faculty of Medical and Human Sciences, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK,

Canine anal furunculosis (AF) is characterised by ulceration and fistulation of perianal tissue and is a disease that particularly affects German shepherd dogs (GSDs). There are some similarities between AF and perianal Crohn's disease (CD) in man. An immune-mediated aetiopathogenesis for AF has been suggested due to tissue pathology, a major histocompatibility complex (MHC) association and clinical response to ciclosporin. Genome-wide association studies (GWAS) can be conducted in dogs with fewer markers and individuals than would be required in a human study. A discovery GWAS was performed on 21 affected and 25 control GSDs from the UK. No SNPs reached genome-wide significance levels at this stage. However, 127 nominally associated SNPs were genotyped in further 76 cases and 191 controls from the UK and Finland. Sequencing of these regions was undertaken to discover novel genetic variation. Association testing of these variants in the UK and Finnish cohorts revealed nine significantly associated SNPs, six of which cause non-synonymous changes in protein sequence. The ADAMTS16 and CTNND2 gene regions were most significantly associated with disease. Members of the butyrophilin protein family, important in intestinal inflammatory regulation, were also associated with disease, but their independence from the MHC region remains to be established. The CTNND2 gene region is also interesting as this locus was implicated in human ulcerative colitis and CD, albeit at a different candidate gene: DAP. We suggest that this represents a common association between inflammatory bowel disease-related conditions in both species and believe that future studies will strengthen this link.
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http://dx.doi.org/10.1007/s00251-014-0766-5DOI Listing
May 2014

Searching for "monogenic diabetes" in dogs using a candidate gene approach.

Canine Genet Epidemiol 2014 7;1. Epub 2014 Jul 7.

Centre for Integrated Genomic Medical Research, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT UK.

Background: Canine diabetes is a common endocrine disorder with an estimated breed-related prevalence ranging from 0.005% to 1.5% in pet dogs. Increased prevalence in some breeds suggests that diabetes in dogs is influenced by genetic factors and similarities between canine and human diabetes phenotypes suggest that the same genes might be associated with disease susceptibility in both species. Between 1-5% of human diabetes cases result from mutations in a single gene, including maturity onset diabetes of the adult (MODY) and neonatal diabetes mellitus (NDM). It is not clear whether monogenic forms of diabetes exist within some dog breeds. Identification of forms of canine monogenic diabetes could help to resolve the heterogeneity of the condition and lead to development of breed-specific genetic tests for diabetes susceptibility.

Results: Seventeen dog breeds were screened for single nucleotide polymorphisms (SNPs) in eighteen genes that have been associated with human MODY/NDM. Six SNP associations were found from five genes, with one gene (ZFP57) being associated in two different breeds.

Conclusions: Some of the genes that have been associated with susceptibility to MODY and NDM in humans appear to also be associated with canine diabetes, although the limited number of associations identified in this study indicates canine diabetes is a heterogeneous condition and is most likely to be a polygenic trait in most dog breeds.
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http://dx.doi.org/10.1186/2052-6687-1-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579387PMC
September 2015

A candidate gene analysis of canine hypoadrenocorticism in 3 dog breeds.

J Hered 2013 Nov-Dec;104(6):807-20. Epub 2013 Aug 31.

the Centre for Integrated Genomic Medical Research, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK.

Canine hypoadrenocorticism is believed to be an immune-related condition. It is rare in the overall dog population but shows a breed-related predisposition with Standard poodles and Portuguese water dogs having a greater prevalence of the condition. It shares many similarities with human primary adrenal insufficiency and is believed to be a naturally occurring, spontaneous model for the human condition. Short haplotype blocks and low levels of linkage disequilibrium in the human genome mean that the identification of genetic contributors to the condition requires large sample numbers. Pedigree dogs have high linkage disequilibrium and long haplotypes within a breed, increasing the potential of identifying novel genes that contribute to canine genetic disease. We investigated 222 SNPs from 42 genes that have been associated or may be implicated in human Addison's disease. We conducted case-control analyses in 3 pedigree dog breeds (Labrador retriever: affected n = 30, unaffected = 76; Cocker Spaniel: affected n = 19, unaffected = 53; Springer spaniel: affected n = 26, unaffected = 46) and identified 8 associated alleles in genes COL4A4, OSBPL9, CTLA4, PTPN22, and STXBP5 in 3 pedigree breeds. Association with immune response genes PTPN22 and CTLA4 in certain breeds suggests an underlying immunopathogenesis of the disease. These results suggest that canine hypoadrenocorticism could be a useful model for studying comparative genetics relevant to human Addison's disease.
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http://dx.doi.org/10.1093/jhered/est051DOI Listing
May 2014

Association of an MHC class II haplotype with increased risk of polymyositis in Hungarian Vizsla dogs.

PLoS One 2013 14;8(2):e56490. Epub 2013 Feb 14.

Centre for Integrated Genomic Medical Research (CIGMR), Institute of Population Health, Faculty of Medical and Human Sciences, The University of Manchester, Manchester, United Kingdom.

A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 "graded" controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0056490PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572995PMC
August 2013

MHC class II association study in eight breeds of dog with hypoadrenocorticism.

Immunogenetics 2013 Apr 29;65(4):291-7. Epub 2013 Jan 29.

Centre for Integrated Genomic Medical Research (CIGMR), School of Medicine, University of Manchester, 2.722 Stopford Building, Oxford Road, Manchester, M13 9PT, UK.

Canine hypoadrenocorticism is an endocrine disorder characterised by inadequate secretion of steroid hormones from the adrenal glands. Pathology results from immune-mediated destruction of the adrenal cortex, which is similar to that seen in the human Addison's disease. Both the canine and human diseases have similar clinical presentation, with the diagnosis based on performing a dynamic adrenocorticotropic hormone stimulation test. MHC class II has previously been associated with the human and canine diseases. In the current study, we conducted an MHC class II association study in eight breeds of dog with diagnoses of hypoadrenocorticism. We demonstrated significant differences in dog leukocyte antigen (DLA) haplotype frequencies in six of these breeds: Cocker spaniel, Springer spaniel, Labrador, West Highland white terrier (WHWT), Bearded collie, and Standard poodle. In the Springer spaniel, the DLA-DRB1*015:01--DQA1*006:01--DQB1*023:01 haplotype was significantly associated with disease risk (p = 0.014, odds ratio (OR) = 5.14) and showed a similar trend in the Cocker spaniel. This haplotype is related to one associated with hypoadrenocorticism in the Nova Scotia duck tolling retriever. Similar haplotypes shared between breeds were demonstrated, with DLA-DRB1*001:01--DQA1*001:01--DQB1*002:01 more prevalent in both affected Labrador (p = 0.0002, OR = 3.06) and WHWT (p = 0.01, OR = 2.11). Other haplotypes that have not previously been associated with the disease were identified. The inter-breed differences in DLA haplotypes associated with susceptibility to canine hypoadrenocorticism could represent divergent aetiologies. This could have implications for clinical diagnosis and future comparative studies. Alternatively, it may suggest that the gene of interest is closely linked to the MHC.
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http://dx.doi.org/10.1007/s00251-013-0680-2DOI Listing
April 2013