GWAS summary statistics "Clustering of lymphoid neoplasms by cell of origin, somatic mutation and drug usage profiles: A multi-trait genome-wide association study"

Lymphoid neoplasms (LNs) are heterogeneous malignancies arising from lymphoid cells, displaying diverse clinical and molecular features. Although LNs are collectively frequent, individual subtypes are rare, posing challenges for genetic association studies. Indeed, genome-wide association studies (GWAS) explained only a fraction of the heritability. Shared genetic susceptibility and overlapping risk factors suggest a partially common etiology across subtypes. We employed a multi-trait GWAS strategy to improve discovery power by leveraging pleiotropy among LN subtypes. We defined LN phenoclusters based on cell of origin, somatic mutation profiles, and approved therapeutic agents. Using data from three large cohorts—the UK Biobank, Million Veteran Program, and FinnGen—we analyzed 31,937 LN cases and 1.2 million controls across 8 individual subtypes and 7 phenoclusters. We replicated the novel associations in two independent cohorts (All of Us and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) with 2,892 LN cases and 165,791 controls. We identified 65 genome-wide significant loci for individual subtypes, including 20 novel associations. Through phenocluster- and subset-based analyses, we discovered 50 and 52 additional loci, respectively. We identified the subtypes contributing to each locus, putative candidate causal variants and genes underlying the associations, and found enrichment of specific cell types, biological processes, and drugs associated with LN risk genes. Overall, this study identified new LN genetic risk loci and candidate genes, providing insights that may inform novel therapeutic approaches. Citation: Güler, M., Canzian, F. Clustering of lymphoid neoplasms by cell of origin, somatic mutation and drug usage profiles: a multi-trait genome-wide association study. Blood Cancer J. 15, 147 (2025). https://doi.org/10.1038/s41408-025-01351-4 Column description for single and phenocluster: Column Description SNP SNP name in format CHR:POS:REF:ALT CHR Chromosome POS Position (GRCh37) REF Reference allele ALT Alternative allele (test allele) BETA Effect size (for ALT allele) SE Standard error of BETA PVAL P-value of association Final_Direction Direction of effects in individual studies (order: U:UKB, M:MVP, F:FinnGEN) HetISq I² heterogeneity statistic HetChiSq Chi-squared value of heterogeneity test HetDf Degrees of freedom (= number of studies − 1) HetPVal P-value of heterogeneity test ASSET column descriptions: Column Description SNP SNP ID Pvalue_meta Meta-analysis p-value OR_meta Meta-analysis odds ratio CI.low_meta Lower bound of 95% confidence interval for OR_meta CI.high_meta Upper bound of 95% confidence interval for OR_meta Pvalue_1sided One-sided ASSET p-value OR_1sided Odds ratio from one-sided ASSET analysis CI.low_1sided Lower bound of confidence interval for OR_1sided CI.high_1sided Upper bound of confidence interval for OR_1sided Pheno_1sided Phenotypes contributing to the one-sided ASSET signal Pvalue_2sided Two-sided ASSET p-value Pvalue.1_2sided P-value for subset 1 in two-sided ASSET analysis Pvalue.2_2sided P-value for subset 2 in two-sided ASSET analysis OR.1_2sided Odds ratio for subset 1 in two-sided ASSET CI.low.1_2sided Lower bound of confidence interval for OR.1_2sided CI.high.1_2sided Upper bound of confidence interval for OR.1_2sided OR.2_2sided Odds ratio for subset 2 in two-sided ASSET CI.low.2_2sided Lower bound of confidence interval for OR.2_2sided CI.high.2_2sided Upper bound of confidence interval for OR.2_2sided Pheno.1_2sided Phenotypes contributing to subset 1 in two-sided ASSET Pheno.2_2sided Phenotypes contributing to subset 2 in two-sided ASSET