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 (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.
Highlights
Chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) are both B-cell malignancies, which arise from the clonal expansion of progenitor cells at different stages of B-cell maturity[1,2,3]
Linkage disequilibrium (LD) score regression is a method which exploits the feature of a test statistic for a given single nucleotide polymorphism (SNP), whereby that test statistic will incorporate the effects of correlated SNPs15
Genetic correlation and heritability We performed cross-trait LD-score regression using summary statistics from two recent genome-wide association studies (GWAS) meta-analyses based on 7717 MM cases and 21,587 controls and 4017 CLL cases and 7881 controls (Fig. 1, Supplementary Table 1-4)
Summary
Chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) are both B-cell malignancies, which arise from the clonal expansion of progenitor cells at different stages of B-cell maturity[1,2,3]. Epidemiological observations on familial cancer risks across the different B-cell malignancies suggest an element of shared inherited susceptibility, especially between CLL and MM4. Conventional LD score regression regresses trait χ2 statistics against the LD score for a given SNP, with the coefficient of the regression line providing an estimate of trait heritability This method can be modified by instead regressing the product of SNP Z-scores from two traits against the SNP LD score, with the slope providing an estimate of genetic covariance between the two traits[16]. This method can be applied to summary statistics, is not biased by sample overlap and does not require multiple traits to be measured for each individual
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
