| 1. |
- Eriksson, Daniel, et al.
(författare)
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Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison’s disease in Sweden
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.
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| 2. |
- Eriksson, D, et al.
(författare)
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Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
- 2016
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10(-15) , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
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| 3. |
- Holmqvist, Anna S., et al.
(författare)
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Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma–identification of high-risk populations to guide surveillance : A report from the Late Effects Study Group
- 2019
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 125:8, s. 1373-1383
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Tidskriftsartikel (refereegranskat)abstract
- Background: Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations. Methods: The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years. Results: In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk. Conclusions: Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.
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| 4. |
- Jäderkvist Fegraeus, Kim, et al.
(författare)
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A potential regulatory region near the EDN3 gene may control both harness racing performance and coat color variation in horses
- 2018
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Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- The Swedish‐Norwegian Coldblooded trotter and the heavier North‐Swedish draught horse both descend from the North‐Swedish horse, but the Coldblooded trotters have been selected for racing performance while the North‐Swedish draught horse is mainly used for agricultural and forestry work. By comparing the genomes of Coldblooded trotters, North‐Swedish draught horses and Standardbreds for a large number of single‐nucleotide polymorphisms (SNPs), the aim of the study was to identify genetic regions that may be under selection for racing performance. We hypothesized that the selection for racing performance, in combination with unauthorized crossbreeding of Coldblooded trotters and Standardbreds, has created regions in the genome where the Coldblooded trotters and Standardbreds are similar, but differ from the North‐Swedish draught horse. A fixation index (Fst) analysis was performed and sliding window Delta Fst values were calculated across the three breeds. Five windows, where the average Fst between Coldblooded trotters and Standardbreds was low and the average Fst between Coldblooded trotters and North‐Swedish draught horses was high, were selected for further investigation. Associations between the most highly ranked SNPs and harness racing performance were analyzed in 400 raced Coldblooded trotters with race records. One SNP showed a significant association with racing performance, with the CC genotype appearing to be negatively associated. The SNP identified was genotyped in 1915 horses of 18 different breeds. The frequency of the TT genotype was high in breeds typically used for racing and show jumping while the frequency of the CC genotype was high in most pony breeds and draught horses. The closest gene in this region was the Endothelin3 gene (EDN3), a gene mainly involved in melanocyte and enteric neuron development. Both functional genetic and physiological studies are needed to fully understand the possible impacts of the gene on racing performance.
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| 5. |
- Kierczak, Marcin, et al.
(författare)
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cgmisc : Enhanced Genome-wide Association Analyses and Visualisation
- 2015
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 31:23, s. 3830-3831
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Tidskriftsartikel (refereegranskat)abstract
- SUMMARY:High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them.RESULTS: We present cgmisc, an R package that enables enhanced data analysis and visualisation of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualisation of genomic data and utilises the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data.AVAILABILITY: The package is operating system-independent and is available from: https://github.com/cgmisc-team/cgmisc CONTACT: cgmisc@imbim.uu.se.
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| 6. |
- Meadows, Jennifer, et al.
(författare)
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Dissecting evolution and disease using comparative vertebrate genomics
- 2017
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Ingår i: Nature reviews genetics. - : Springer Science and Business Media LLC. - 1471-0056 .- 1471-0064. ; 18:10, s. 624-636
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Forskningsöversikt (refereegranskat)abstract
- With the generation of more than 100 sequenced vertebrate genomes in less than 25 years, the key question arises of how these resources can be used to inform new or ongoing projects. In the past, this diverse collection of sequences from human as well as model and non-model organisms has been used to annotate the human genome and to increase the understanding of human disease. In the future, comparativevertebrate genomics in conjunction with additional genomic resources will yield insights into the processes of genome function, evolution, speciation, selection and adaptation, as well as the quantification of species diversity. In this Review, we discuss how the genomics of non-human organisms can provide insights into vertebrate biology and how this can contribute to the understanding of human physiology and health.
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| 7. |
- Nordin, Jessika
(författare)
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Human leukocyte antigen in sickness and in health : Ankylosing spondylitis and HLA in Sweden
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human leukocyte antigen (HLA) plays a major role in keeping us healthy, but some of the HLA alleles can contribute to disease susceptibility. One example is HLA-B*27, which confers increased susceptibility of ankylosing spondylitis and represents one of the strongest genetic associations found in any common human disease. Ankylosing spondylitis shows a strong sex ratio skew (2-3:1 male to female) and studies confirm the existence of sexual-dimorphism in the presentation of this disease. The genetic predisposition for this, however, has not previously been studied. A Swedish ankylosing spondylitis population was sequenced with a targeted array to investigate the existence of sex-specific associations. RUNX3 was revealed to be associated in males by a univariate test, while aggregate tests revealed the HLA gene MICB to be associated in females. Functional validation demonstrated that the risk variants in RUNX3 increase expression, and MICB changed the transcription factor binding sites. Interestingly, since the disease involves bone changes, both RUNX3 and one of the MICB variants had effect in the bone cell line, SaOS-2.In order to help researchers obtain more controls for HLA analysis, an HLA allele bioresource (SweHLA) was generated from 1,000 Swedish genomes. The alleles were typed with three to four HLA typing software programs and results were combined by an n-1methodology. This produced high quality alleles where the bias from each software program was diminished.The methodology from SweHLA was utilised to study HLA in ankylosing spondylitis. To investigate both sex-specific predisposition and HLA-B*27 independence, samples were subdivided into two populations (one population with mixed HLA-B*27 positive and negative samples and one with only HLA-B*27 positive samples) that in turn were grouped by sex. In the mixed population, several alleles were replicated from previous studies. This study also revealed three female-specific alleles, two of which were new and one that had previously been associated to the severity of radiological changes. The HLA-B*27 population revealed a previously unknown protective allele, HLA-A*24:02. Through deeper examination of the HLA-B*27 population, two amino acids in HLA-A, position 119 in the whole set and position 180 in the male set, were revealed to be protective.This thesis brings new insight into the genetic predisposition for a sex-skewed disease, demonstrating how sexual-dimorphism can be reflected in the genetic predisposition, hopefully leading to more similar studies. It also highlights the importance of methodology and demonstrate the drastic biases that can be imparted by software programs.
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| 8. |
- Olsson, M., et al.
(författare)
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Absolute quantification reveals the stable transmission of a high copy number variant linked to autoinflammatory disease
- 2016
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Ingår i: BMC Genomics. - : BioMed Central (BMC). - 1471-2164. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dissecting the role copy number variants (CNVs) play in disease pathogenesis is directly reliant on accurate methods for quantification. The Shar-Pei dog breed is predisposed to a complex autoinflammatory disease with numerous clinical manifestations. One such sign, recurrent fever, was previously shown to be significantly associated with a novel, but unstable CNV (CNV_16.1). Droplet digital PCR (ddPCR) offers a new mechanism for CNV detection via absolute quantification with the promise of added precision and reliability. The aim of this study was to evaluate ddPCR in relation to quantitative PCR (qPCR) and to assess the suitability of the favoured method as a genetic test for Shar-Pei Autoinflammatory Disease (SPAID). Results: One hundred and ninety-six individuals were assayed using both PCR methods at two CNV positions (CNV_14.3 and CNV_16.1). The digital method revealed a striking result. The CNVs did not follow a continuum of alleles as previously reported, rather the alleles were stable and pedigree analysis showed they adhered to Mendelian segregation. Subsequent analysis of ddPCR case/control data confirmed that both CNVs remained significantly associated with the subphenotype of fever, but also to the encompassing SPAID complex (p < 0.001). In addition, harbouring CNV_16.1 allele five (CNV_16.1 vertical bar 5) resulted in a four-fold increase in the odds for SPAID (p < 0.001). The inclusion of a genetic marker for CNV_16.1 in a genome-wide association test revealed that this variant explained 9.7 % of genetic variance and 25.8 % of the additive genetic heritability of this autoinflammatory disease. Conclusions: This data shows the utility of the ddPCR method to resolve cryptic copy number inheritance patterns and so open avenues of genetic testing. In its current form, the ddPCR test presented here could be used in canine breeding to reduce the number of homozygote CNV_16.1 broken vertical bar 5 individuals and thereby to reduce the prevalence of disease in this breed.
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| 9. |
- Sakthikumar, Sharadha, et al.
(författare)
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SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma
- 2018
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Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 78:13, s. 3421-3431
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Tidskriftsartikel (refereegranskat)abstract
- Osteosarcoma is a debilitating bone cancer that affects humans, especially children and adolescents. A homologous form of osteosarcoma spontaneously occurs in dogs, and its differential incidence observed across breeds allows for the investigation of tumor mutations in the context of multiple genetic backgrounds. Using whole-exome sequencing and dogs from three susceptible breeds (22 golden retrievers, 21 Rottweilers, and 23 greyhounds), we found that osteosarcoma tumors show a high frequency of somatic copy-number alterations (SCNA), affecting key oncogenes and tumor-suppressor genes. The across-breed results are similar to what has been observed for human osteosarcoma, but the disease frequency and somatic mutation counts vary in the three breeds. For all breeds, three mutational signatures (one of which has not been previously reported) and 11 significantly mutated genes were identified. TP53 was the most frequently altered gene (83% of dogs have either mutations or SCNA in TP53), recapitulating observations in human osteosarcoma. The second most frequently mutated gene, histone methyltransferase SETD2, has known roles in multiple cancers, but has not previously been strongly implicated in osteosarcoma. This study points to the likely importance of histone modifications in osteosarcoma and highlights the strong genetic similarities between human and dog osteosarcoma, suggesting that canine osteosarcoma may serve as an excellent model for developing treatment strategies in both species. Significance: Canine osteosarcoma genomics identify SETD2 as a possible oncogenic driver of osteosarcoma, and findings establish the canine model as a useful comparative model for the corresponding human disease.
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| 10. |
- Sepulveda, Jorge I. Ramirez, et al.
(författare)
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Long-term follow-up in primary Sjögren's syndrome reveals differences in clinical presentation between female and male patients
- 2017
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Ingår i: Biology of Sex Differences. - : BioMed Central. - 2042-6410. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjogren's syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS. Methods: Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 +/- 7.6 for women and 8.5 +/- 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women. Results: Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB (p = 0. 02), and ANA (p = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease (p = 0. 008), lymphadenopathy (p = 0.04) and lymphoma (p = 0.007). Conversely, concomitant hypothyroidism was more common among female patients (p = 0.009). Conclusions: We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS.
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