A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus
Abstract
To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 23, 2023
- Source ID
- 10.1038/s41467-023-40616-z
Entities
People
- Alan H. Bartels
- Alexander Gusev
- Anamay Shetty
- Bálint Pataki
- Connor Bell
- David R. Stillman
- Dezső Ribli
- Forough Abbasi
- István Csabai
- Ji-Heui Seo
- Kate Lawrenson
- Mark Pomerantz
- Matthew L Freedman
- Mersedeh Rohanizadegan
- Márton Papp
- Norbert Solymosi
- Pier Vitale Nuzzo
- Sarah Abou Alaiwi
- Simon A Gayther
- Sylvan C. Baca
- Sándor Spisák
- Viktoria Tisza
- Xianzhi Lin
- Zoltán Szállási
- Zsófia Sztupinszki
Organizations
- United States Department of Defense