Systematic fine-mapping and functional studies of prostate cancer risk variants

Yuyang Qian; Jianhua Wang; Bo Wang; Wenbin Wang; Peng Li; Zhenhao Zhao; Yuan Jiang; He Ren; Dandan Huang; Yang Yang; Zhongfang Zhao; Lei Zhang; Jiandang Shi; Mulin Jun Li; Wange Lu

doi:10.1016/j.isci.2023.106497

Systematic fine-mapping and functional studies of prostate cancer risk variants

iScience. 2023 Mar 25;26(4):106497. doi: 10.1016/j.isci.2023.106497. eCollection 2023 Apr 21.

Authors

Yuyang Qian¹, Jianhua Wang², Bo Wang¹, Wenbin Wang¹, Peng Li¹, Zhenhao Zhao¹, Yuan Jiang¹, He Ren³, Dandan Huang², Yang Yang¹, Zhongfang Zhao¹, Lei Zhang¹, Jiandang Shi¹, Mulin Jun Li², Wange Lu¹

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.
² Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
³ Center for GI Cancer Diagnosis and Treatment, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Huangdao District, Qingdao 266000, China.

Abstract

To date, genome-wide association studies (GWAS) have revealed over 200 genetic risk loci associated with prostate cancer; yet, true disease-causing variants remain elusive. Identification of causal variants and their targets from association signals is complicated by high linkage disequilibrium and limited availability of functional genomics data for specific tissue/cell types. Here, we integrated statistical fine-mapping and functional annotation from prostate-specific epigenomic profiles, 3D genome features, and quantitative trait loci data to distinguish causal variants from associations and identify target genes. Our fine-mapping analysis yielded 3,395 likely causal variants, and multiscale functional annotation linked them to 487 target genes. We prioritized rs10486567 as a genome-wide top-ranked SNP and predicted HOTTIP as its target. Deletion of the rs10486567-associated enhancer in prostate cancer cells decreased their capacity for invasive migration. HOTTIP overexpression in enhancer-KO cell lines rescued defective invasive migration. Furthermore, we found that rs10486567 regulates HOTTIP through allele-specific long-range chromatin interaction.

Keywords: Cancer; Genetics; Genomics.