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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

ABSTRACT: 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 (R_g = 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.

SUBMITTER: Went M

PROVIDER: S-EPMC6315026 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

Went Molly M Sud Amit A Speedy Helen H Sunter Nicola J NJ Försti Asta A Law Philip J PJ Johnson David C DC Johnson David C DC Mirabella Fabio F Holroyd Amy A Li Ni N Orlando Giulia G Weinhold Niels N van Duin Mark M Chen Bowang B Mitchell Jonathan S JS Mansouri Larry L Juliusson Gunnar G Smedby Karin E KE Jayne Sandrine S Majid Aneela A Dearden Claire C Allsup David J DJ Bailey James R JR Pratt Guy G Pepper Chris C Fegan Chris C Rosenquist Richard R Kuiper Rowan R Stephens Owen W OW Bertsch Uta U Broderick Peter P Einsele Hermann H Gregory Walter M WM Hillengass Jens J Hoffmann Per P Jackson Graham H GH Jöckel Karl-Heinz KH Nickel Jolanta J Nöthen Markus M MM da Silva Filho Miguel Inacio MI Thomsen Hauke H Walker Brian A BA Broyl Annemiek A Davies Faith E FE Hansson Markus M Goldschmidt Hartmut H Dyer Martin J S MJS Kaiser Martin M Sonneveld Pieter P Morgan Gareth J GJ Hemminki Kari K Nilsson Björn B Catovsky Daniel D Allan James M JM Houlston Richard S RS

Blood cancer journal 20181221 1

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 (R<sub>g</sub> = 0.4, P = 0.0046). Furthermore, four of the 4 ...[more]

PMID: 30602759

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Project description:BackgroundSchizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology.MethodsWe used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology.ResultsWe found evidence for weak genome-wide negative correlation of schizophrenia with T2D (rg = -0.07; 95% C.I., -0.03,0.12; P = .002) and BMI (rg = -0.09; 95% C.I., -0.06, -0.12; P = 1.83 × 10-5). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (BDNF); rs8192675 (SLC2A2); rs3800229 (FOXO3); rs17514846 (FURIN)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways.ConclusionsLDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders.

Dataset Information

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

Publications

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

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