| 1. |
- Halvarsson, Britt-Marie, et al.
(författare)
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Direct evidence for a polygenic etiology in familial multiple myeloma
- 2017
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:10, s. 619-623
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Tidskriftsartikel (refereegranskat)abstract
- Although common risk alleles for multiple myeloma have been identified, their contribution to familial MM is unknown. We demonstrate an enrichment of common MM risk alleles in familial cases, providing the first direct evidence for a polygenic contribution.
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| 2. |
- Halvarsson, Britt-Marie
(författare)
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Genetic Predisposition to Sporadic and Familial Multiple Myeloma
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple Myeloma (MM) is the second most common hematological malignancy. It is defined by an uncontrolled growth of plasma cells, usually in the bone marrow. Clinically it is complicated by hypercalcemia, renal failure, anaemia, and bone pain. Although recent advances in the treatment have extended survival and quality-of-life considerably, MM remains a fatal disease.Since the 1920’s MM has been reported to aggregate in families (famililial MM). In first-degree relatives of MM patients there is a two to four-fold increased risk in developing MM, pointing at a possible inherited genetic aetiology in at least a subset of MM patients.The overall aim of this thesis is to identify germline DNA sequence variants that predispose for Multiple Myeloma (MM), and it is based on four Papers.In Paper I, II and IV, we performed case-control genome-wide association studies (GWASs) to identify germline single nucleotide polymorphisms (SNPs) and small insertions/deletions (INDELs) that associate with MM risk. In Paper I, we identified a novel significant association with ELL2, and a border-line suggestive association with TOM1.In Paper II and IV we collaborated internationally in GWAS meta-analyses and identified eight and six variants, respectively, in or near the genes JARID2 (at 6p22.3), ATG5 (6q21), SMARCD3, (7q36.1), CCAT1 (8q24.21), CDKN2A (9p21.3), WAC (10p12.1), RFWD3 (16q23.1), PREX1 (20q13.13), CEP120 (5q23.2), POT1 (7q31.33), CCDC71L (7q22.3), SP3 (2q31.1), KLF2 (19p13.11) and PRR14/RNF40 (16p11.2). The TOM1 variant in Paper I replicated in these studies. The identified MM risk loci is estimated to explain a 20% of MM heritability.In Paper III, we performed SNP microarray and whole-exome sequencing analysis on 38 cases of familial MM. Constructing polygenic risk scores, we found direct evidence for a polygenic aetiology in familial MM, and estimated that about one-third of familial MM cases were associated with an enrichment of common risk variants identified by GWAS. In Paper IV, we extended our polygenic risk scores with newly identified risk variants, and again observed an enrichment of risk variants in familial cases.
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| 3. |
- Mitchell, Jonathan S., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P = 1.31 x 10(-8)), 6q21 (rs9372120, P = 9.09 x 10(-15)), 7q36.1 (rs7781265, P = 9.71 x 10(-9)), 8q24.21 (rs1948915, P = 4.20 x 10(-11)), 9p21.3 (rs2811710, P = 1.72 x 10(-13)), 10p12.1 (rs2790457, P = 1.77 x 10(-8)), 16q23.1 (rs7193541, P = 5.00 x 10(-12)) and 20q13.13 (rs6066835, P = 1.36 x 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
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| 4. |
- Swaminathan, Bhairavi, et al.
(författare)
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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).
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| 5. |
- Went, M, et al.
(författare)
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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 3707-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.
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