Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Nat Commun. 2022 Jan 10;13(1):151. doi: 10.1038/s41467-021-27666-x.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Antineoplastic Combined Chemotherapy Protocols
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology*
  • Base Sequence
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / immunology
  • Chromatin / chemistry
  • Chromatin / immunology
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / immunology
  • DNA, Intergenic / genetics*
  • DNA, Intergenic / immunology
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / immunology
  • Humans
  • Inheritance Patterns
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / immunology
  • Multiple Myeloma / pathology
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Plasma Cells / immunology
  • Plasma Cells / pathology*
  • Polymorphism, Genetic
  • Primary Cell Culture
  • Quantitative Trait Loci
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology
  • Risk Assessment
  • Transcriptional Elongation Factors / genetics
  • Transcriptional Elongation Factors / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • CDCA7L protein, human
  • CEP120 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA, Intergenic
  • ELL2 protein, human
  • Guanine Nucleotide Exchange Factors
  • Neoplasm Proteins
  • PREX1 protein, human
  • Repressor Proteins
  • SMARCD3 protein, human
  • Transcriptional Elongation Factors
  • WAC protein, human