title: A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of erectile dysfunction following radiation therapy for prostate cancer.
abstract: OBJECTIVE
  To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy.
  
  
  METHODS
  A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays.
  
  
  RESULTS
  Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1×10(-5) to 6.2×10(-4)). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value=1.7×10(-29)). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value=2.1×10(-19)). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage.
  
  
  CONCLUSIONS
  This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.
authors.affiliation: Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kerns
authors.forename: Richard
authors.initials: R
authors.lastname: Stock
authors.forename: Nelson
authors.initials: N
authors.lastname: Stone
authors.forename: Michael
authors.initials: M
authors.lastname: Buckstein
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Shao
authors.forename: Christopher
authors.initials: C
authors.lastname: Campbell
authors.forename: Lynda
authors.initials: L
authors.lastname: Rath
authors.forename: Dirk
authors.initials: D
authors.lastname: De Ruysscher
authors.forename: Guido
authors.initials: G
authors.lastname: Lammering
authors.forename: Rosetta
authors.initials: R
authors.lastname: Hixson
authors.forename: Jamie
authors.initials: J
authors.lastname: Cesaretti
authors.forename: Mitchell
authors.initials: M
authors.lastname: Terk
authors.forename: Harry
authors.initials: H
authors.lastname: Ostrer
authors.forename: Barry S
authors.initials: BS
authors.lastname: Rosenstein
mesh_terms: D000367:Age Factors; D000368:Aged; D001918:Brachytherapy / Q000379:methods; D007172:Erectile Dysfunction / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010165:Palladium / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000208:ethnology / Q000235:genetics / Q000532:radiotherapy*; D011868:Radioisotopes / Q000627:therapeutic use; D020266:Radiotherapy, Conformal / Q000379:methods
chemical_list: D007457:Iodine Radioisotopes; D011868:Radioisotopes; D010165:Palladium