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1.
Hum Genomics ; 13(1): 37, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31429796

RESUMO

BACKGROUND: While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS). RESULTS: GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus. CONCLUSIONS: Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mieloma Múltiplo/genética , Transcriptoma/genética , Desaminase APOBEC-3G/genética , Aminoidrolases/genética , Citidina Desaminase/genética , Citosina Desaminase/genética , Perfilação da Expressão Gênica , Genótipo , Humanos , Mieloma Múltiplo/patologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
2.
Ann Hum Genet ; 83(4): 231-238, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30768683

RESUMO

Genomic regions of homozygosity (ROH), detectable in outbred populations, have been implicated as determinants of inherited risk. To examine whether ROH is associated with risk of multiple myeloma (MM), we performed whole-genome homozygosity analysis using single-nucleotide polymorphism genotype data from 2,282 MM cases and 5,197 controls, with replication in an additional 878 MM cases and 7,083 controls. Globally, the distribution of ROH between cases and controls was not significantly different. However, one ROH at chromosome 9q21, harboring the B-cell transcription factor gene KLF9, showed evidence of a consistent association and may therefore warrant further investigation as a candidate risk factor for MM. Overall, our analysis provides little support for a homozygosity signature being a significant factor in MM risk.


Assuntos
Alelos , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Idoso , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
4.
Nat Commun ; 15(1): 2637, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38527997

RESUMO

For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls. We complement this analysis by systematically mining the literature space for supporting evidence. In addition to providing supporting evidence for well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we also find sex steroid hormones, plasma lipids, and telomere length as determinants of cancer risk. A number of the molecular factors we identify may prove to be potential biomarkers. Our analysis, which highlights aetiological similarities and differences in common cancers, should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app to visualise findings.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Ovarianas , Masculino , Feminino , Humanos , Fatores de Risco , Fenômica , Fenótipo , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único
5.
Nat Commun ; 15(1): 6644, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39103364

RESUMO

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.


Assuntos
Antígeno de Maturação de Linfócitos B , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mieloma Múltiplo , Polimorfismo de Nucleotídeo Único , Mieloma Múltiplo/genética , Humanos , Antígeno de Maturação de Linfócitos B/genética , Análise da Randomização Mendeliana , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Masculino , Telômero/genética
6.
medRxiv ; 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-37066289

RESUMO

For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls. To derive a more comprehensive insight into disease aetiology we systematically mined the literature space for supporting evidence. We evaluated causal relationships for over 3,000 potential risk factors. In addition to identifying well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we provide evidence for specific factors, including dietary intake, sex steroid hormones, plasma lipids and telomere length as determinants of cancer risk. We also implicate molecular factors including plasma levels of IL-18, LAG-3, IGF-1, CT-1, and PRDX1 as risk factors. Our analyses highlight the importance of risk factors that are common to many cancer types but also reveal aetiological differences. A number of the molecular factors we identify have the potential to be biomarkers. Our findings should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app (https://mrcancer.shinyapps.io/mrcan/) to visualise findings.

7.
Res Sq ; 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36993383

RESUMO

For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls. To derive a more comprehensive insight into disease aetiology we systematically mined the literature space for supporting evidence. We evaluated causal relationships for over 3,000 potential risk factors. In addition to identifying well-established risk factors (smoking, alcohol, obesity, lack of physical activity), we provide evidence for specific factors, including dietary intake, sex steroid hormones, plasma lipids and telomere length as determinants of cancer risk. We also implicate molecular factors including plasma levels of IL-18, LAG-3, IGF-1, CT-1, and PRDX1 as risk factors. Our analyses highlight the importance of risk factors that are common to many cancer types but also reveal aetiological differences. A number of the molecular factors we identify have the potential to be biomarkers. Our findings should aid public health prevention strategies to reduce cancer burden. We provide a R/Shiny app (https://mrcancer.shinyapps.io/mrcan/) to visualise findings.

8.
Sci Rep ; 12(1): 12696, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-35882937

RESUMO

Despite recent advances in therapy, multiple myeloma essentially remains an incurable malignancy. Targeting tumour-specific essential genes, which constitute a druggable dependency, potentially offers a strategy for developing new therapeutic agents to treat MM and overcome drug resistance. To explore this possibility, we analysed DepMap project data identifying 23 MM essential genes and examined the relationship between their expression and patient outcome in three independent series totalling 1503 cases. The expression of TCF3 and FLVCR1 were both significantly associated with progression-free survival. IKBKB is already a drug target in other diseases, offering the prospect of repurposing to treat MM, while PIM2 is currently being investigated as a treatment for the disease. Our analysis supports the rationale of using large-scale genetic perturbation screens to guide the development of new therapeutic agents for MM.


Assuntos
Antineoplásicos , Mieloma Múltiplo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia
9.
Nat Commun ; 13(1): 151, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013207

RESUMO

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.


Assuntos
Linfócitos B/patologia , DNA Intergênico/genética , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Proteínas de Neoplasias/genética , Plasmócitos/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica , Linfócitos B/imunologia , Sequência de Bases , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Cromatina/química , Cromatina/imunologia , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/imunologia , DNA Intergênico/imunologia , Regulação Neoplásica da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Padrões de Herança , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/imunologia , Plasmócitos/imunologia , Polimorfismo Genético , Cultura Primária de Células , Locos de Características Quantitativas , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Medição de Risco , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/imunologia
10.
Blood Cancer J ; 11(4): 76, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33875642

RESUMO

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.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Mieloma Múltiplo/genética , Idoso , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único
11.
Leukemia ; 34(3): 697-708, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31913320

RESUMO

Multiple myeloma (MM) is the second most common blood malignancy. Epidemiological family studies going back to the 1920s have provided evidence for familial aggregation, suggesting a subset of cases have an inherited genetic background. Recently, studies aimed at explaining this phenomenon have begun to provide direct evidence for genetic predisposition to MM. Genome-wide association studies have identified common risk alleles at 24 independent loci. Sequencing studies of familial cases and kindreds have begun to identify promising candidate genes where variants with strong effects on MM risk might reside. Finally, functional studies are starting to give insight into how identified risk alleles promote the development of MM. Here, we review recent findings in MM predisposition field, and highlight open questions and future directions.


Assuntos
Predisposição Genética para Doença , Mieloma Múltiplo/genética , Alelos , Ensaios Clínicos como Assunto , Variação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Mieloma Múltiplo/epidemiologia , Polimorfismo de Nucleotídeo Único , Risco , Análise de Sequência de DNA
12.
Blood Adv ; 4(10): 2172-2179, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32433745

RESUMO

The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed.


Assuntos
Estudo de Associação Genômica Ampla , Mieloma Múltiplo , Humanos , Análise da Randomização Mendeliana , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
14.
Neuro Oncol ; 21(8): 1039-1048, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31102405

RESUMO

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL. METHODS: We performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data. RESULTS: We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis. CONCLUSION: To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/genética , Estudo de Associação Genômica Ampla , Humanos , Linfoma Difuso de Grandes Células B/genética
15.
Nat Commun ; 10(1): 213, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631080

RESUMO

The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

16.
Nat Commun ; 9(1): 3707, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30213928

RESUMO

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.


Assuntos
Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único , Teorema de Bayes , Cromatina/química , Imunoprecipitação da Cromatina , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Regiões Promotoras Genéticas , Controle de Qualidade , Locos de Características Quantitativas , Risco , População Branca/genética
17.
Blood Cancer J ; 9(1): 1, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30602759

RESUMO

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Mieloma Múltiplo/genética , Alelos , Estudos de Casos e Controles , Bases de Dados Genéticas , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
18.
Cell Rep ; 20(11): 2556-2564, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28903037

RESUMO

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.


Assuntos
Cromossomos Humanos Par 5/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Mieloma Múltiplo/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Elongação da Transcrição/genética , Alelos , Diploide , Epigênese Genética , Epigenômica , Loci Gênicos , Humanos , Proteínas Nucleares/metabolismo , Mapeamento Físico do Cromossomo , Prognóstico , Ligação Proteica , Fatores de Risco , Elongação da Transcrição Genética , Resposta a Proteínas não Dobradas/genética
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