DOI: 10.5281/zenodo.15464477
title: GWAS summary statistics "Clustering of lymphoid neoplasms by cell of origin, somatic mutation and drug usage profiles: A multi-trait genome-wide association study"

description: 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