title: Comprehensively evaluating cis-regulatory variation in the human prostate transcriptome by using gene-level allele-specific expression.
abstract: The identification of cis-acting regulatory variation in primary tissues has the potential to elucidate the genetic basis of complex traits and further our understanding of transcriptomic diversity across cell types. Expression quantitative trait locus (eQTL) association analysis using RNA sequencing (RNA-seq) data can improve upon the detection of cis-acting regulatory variation by leveraging allele-specific expression (ASE) patterns in association analysis. Here, we present a comprehensive evaluation of cis-acting eQTLs by analyzing RNA-seq gene-expression data and genome-wide high-density genotypes from 471 samples of normal primary prostate tissue. Using statistical models that integrate ASE information, we identified extensive cis-eQTLs across the prostate transcriptome and found that approximately 70% of expressed genes corresponded to a significant eQTL at a gene-level false-discovery rate of 0.05. Overall, cis-eQTLs were heavily concentrated near the transcription start and stop sites of affected genes, and effects were negatively correlated with distance. We identified multiple instances of cis-acting co-regulation by using phased genotype data and discovered 233 SNPs as the most strongly associated eQTLs for more than one gene. We also noted significant enrichment (25/50, p = 2E-5) of previously reported prostate cancer risk SNPs in prostate eQTLs. Our results illustrate the benefit of assessing ASE data in cis-eQTL analyses by showing better reproducibility of prior eQTL findings than of eQTL mapping based on total expression alone. Altogether, our analysis provides extensive functional context of thousands of SNPs in prostate tissue, and these results will be of critical value in guiding studies examining disease of the human prostate.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: larson.nicholas@mayo.edu.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Larson
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: McDonnell
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Zach
authors.initials: Z
authors.lastname: Fogarty
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: John
authors.initials: J
authors.lastname: Cheville
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Riska
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Baheti
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Asha A
authors.initials: AA
authors.lastname: Nair
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
mesh_terms: D019295:Computational Biology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D058977:Molecular Sequence Annotation / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011467:Prostate / Q000378:metabolism*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA / Q000379:methods; D059467:Transcriptome / Q000235:genetics*