title: Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux.
abstract: BACKGROUND
  Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett's esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.
  
  
  METHODS
  We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h(2)g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.
  
  
  RESULTS
  We estimated a statistically significant genetic variance explained for BE (h(2)g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10(-9)) and for EA (h(2)g = 25 %; SE = 5%; one-sided P = 2 × 10(-7)). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10(-6)), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.
  
  
  CONCLUSIONS
  We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
authors.affiliation: Affiliations of authors: Statistical Genetics (WEE, SM) and Cancer Control Group (DCW), QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia (WEE, SM); Department of Biostatistics, University of Washington, Seattle, WA (DML); Department of Biosciences and Nutrition (MD, FB, MZ) Department of Medical Epidemiology and Biostatistics (NLP, PKEM), Unit of Upper Gastrointestinal Research, Department of Molecular Medicine and Surgery (HN) , and Department of Medical Epidemiology and Biostatistics (WY) , Karolinska Institutet, Stockholm, Sweden; Gastrocentrum Medicin, Karolinska University Hospital, Stockholm, Sweden (FB, PTS); Division of Public Health Sciences (LEO, TLV) and Division of Human Biology (BJR), Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (HT); Division of Gastroenterology & Hepatology (YR), Department of Otolaryngology (YR), and GI Outcomes Unit (YR), Mayo Clinic, Rochester, MN; Department of Epidemiology, MD Anderson Cancer Center, Houston, TX (W-HC); Centre for Public Health, Queen's University, Belfast, Ireland (LJM); Department of Epidemiology, School of Public Health (MDG) and Division of Gastroenterology and Hepatology, UNC School of Medicine (NJS) , University of North Carolina, Chapel Hill, NC (MDG); Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, ON, Canada (GL); Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA (LB); Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada (AGC); Yale School of Public Health, New Haven, CT (HAR); Department of Oncology, The Medical School, University of Sheffield, Sheffield, UK (NCB); Division of Research and Oakland Medical Center, Kaiser Permanente, Oakland, CA (DAC); Division of Epidemiology, University of Leeds, Leeds, UK (LJH); Department of Preventive Medicine,
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mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics*; D016022:Case-Control Studies; D025063:Chromosome Disorders / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000235:genetics*; D005260:Female; D005764:Gastroesophageal Reflux / Q000235:genetics*; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D015995:Prevalence; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D012984:Software; D018433:Twin Studies as Topic