| 11. |
- Broderick, Peter, et al.
(författare)
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Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:1, s. 58-83
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Tidskriftsartikel (refereegranskat)abstract
- To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 x 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 x 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 x 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights.
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| 12. |
- Law, Philip J., et al.
(författare)
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Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 10-9). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.
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| 13. |
- Lenz, Tobias L., et al.
(författare)
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Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
- 2015
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Ingår i: Nature Genetics. - : Macmillan Publishers Ltd.. - 1061-4036 .- 1546-1718. ; 47:9, s. 1085-1090
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Tidskriftsartikel (refereegranskat)abstract
- Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (n(cases) = 5,337), type 1 diabetes (T1D; n(cases) = 5,567), psoriasis vulgaris (n(cases) = 3,089), idiopathic achalasia (n(cases) = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 x 10(-12); T1D, P = 2.4 x 10(-10); psoriasis, P = 5.9 x 10(-6); celiac disease, P = 1.2 x 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 x 10(-3); T1D, P = 8.6 x 10(-27); celiac disease, P = 6.0 x 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.
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| 14. |
- Malhotra, Rajeev, et al.
(författare)
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HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:11, s. 1580-
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Tidskriftsartikel (refereegranskat)abstract
- Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10−8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein–deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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| 15. |
- Migliorini, Gabriele, et al.
(författare)
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Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 122:19, s. 3298-3307
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Tidskriftsartikel (refereegranskat)abstract
- Acute lymphoblastic leukemia (ALL) is the major pediatric cancer diagnosed in economically developed countries with B-cell precursor (BCP)-ALL, accounting for approximately 70% of ALL. Recent genome-wide association studies (GWAS) have provided the first unambiguous evidence for common inherited susceptibility to BCP-ALL, identifying susceptibility loci at 7p12.2, 9p21.3, 10q21.2, and 14q11.2. To identify additional BCP-ALL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1658 cases and 4723 controls, with validation in 1449 cases and 1488 controls. Combined analysis identified novel loci mapping to 10p12.2 (rs10828317, odds ratio [OR] = 1.23; P = 2.30 x 10(-9)) and 10p14marked by rs3824662(OR = 1.31; P = 8.62 x 10(-12)). The single nucleotide polymorphism rs10828317 is responsible for the N215S polymorphism in exon 7 of PIP4K2A, and rs3824662 localizes to intron 3 of the transcription factor and putative tumor suppressor gene GATA3. The rs10828317 association was shown to be specifically associated with hyperdiploid ALL, whereas the rs3824662-associated risk was confined to nonhyperdiploid non-TEL-AML1 + ALL. The risk allele of rs3824662 was correlated with older age at diagnosis (P < .001) and significantly worse event-free survivorship (P < .0001). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to BCP-ALL and the influence of constitutional genotype on disease development.
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| 16. |
- Stuart, Philip E., et al.
(författare)
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Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture
- 2015
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 97:6, s. 816-836
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 x 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 x 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.
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| 17. |
- Thanassoulis, George, et al.
(författare)
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Genetic Associations with Valvular Calcification and Aortic Stenosis
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 368:6, s. 503-512
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Tidskriftsartikel (refereegranskat)abstract
- Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P = 9.0x10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5x10(-8) and P = 1.8x10(-8), respectively), but the findings were not replicated consistently. Conclusions Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
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| 18. |
- Weinhold, Niels, et al.
(författare)
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The CCND1 c.870G > A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:5, s. 522-525
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Tidskriftsartikel (refereegranskat)abstract
- A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 x 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.
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| 19. |
- Dand, Nick, et al.
(författare)
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Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling
- 2017
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Ingår i: Human Molecular Genetics. - : OXFORD UNIV PRESS. - 0964-6906 .- 1460-2083. ; 26:21, s. 4301-4313
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.
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| 20. |
- Disney-Hogg, Linden, et al.
(författare)
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Impact of atopy on risk of glioma : a Mendelian randomisation study
- 2018
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Ingår i: BMC Medicine. - : BioMed Central. - 1741-7015. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.Methods: Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis.Results: Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194).Conclusions: Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.
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