| 1. |
- Ajore, Ram, et al.
(författare)
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Functional dissection of inherited non-coding variation influencing multiple myeloma risk
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
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| 2. |
- Duran Lozano, Laura
(författare)
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Genetic predisposition for Multiple Myeloma. Identification and functional characterization of risk variants
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is a blood malignancy originating from plasma cells. First-degree relatives of patients with MM have two- to four-fold higher risk of MM. However, the molecular basis remains largely unknown. This Ph.D. project aims to identify novel DNA sequence variants predisposing to MM through genome-wide association studies (GWAS) and, subsequently, characterize identified variants functionally.Article I describes a systematic study where we screened for causal gene-regulatory variants at 21 MM risk loci. Article II describes a Nordic GWAS identifying the SOHLH2 (13q13.3) as a novel MM risk locus. Article III describes a novel international meta-analysis of GWAS data totalling 10 906 cases and 366 221 controls, identifying twelve new risk variants for MM accounted for by nine loci: 5q35.2 CPEB4, 6p22.2 BTN3A2, 9q21.33 DAPK1, 10q24.33 STN1, 10q25.2 MXI1, 19p13.3 NFIC, 21q11.2, SAMSN1 and a rare variant at 13q13.1 BRCA2. Finally, in Article IV, we explore the possibility of identifying transcription factors that mediate allele-specific gene-regulatory effects through combined use of CRISPR/Cas9 screening and epistasis analysis of gene expression data.The work presented in this thesis provides new insight into the mechanisms underlying genetic predisposition for multiple myeloma.
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| 3. |
- Duran-Lozano, Laura, et al.
(författare)
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Germline variants at SOHLH2 influence multiple myeloma risk
- 2021
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.
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