title: Cumulative risk impact of five genetic variants associated with papillary thyroid carcinoma.
abstract: BACKGROUND
  Two recent genome-wide association studies (GWASs) identified five single nucleotide polymorphisms (SNPs; rs965513, rs944289, rs966423, rs2439302, and rs116909374) associated with papillary thyroid carcinoma (PTC). Each variant showed highly significant but moderate to low disease risk. Here we assessed the cumulative risk and predictive value of the five SNPs.
  
  
  METHODS
  We genotyped two cohorts of individuals, 747 PTC cases and 1047 controls from Ohio and 1795 PTC cases and 2090 controls from Poland. Cumulative genetic risk scores were calculated using unweighted and weighted approaches.
  
  
  RESULTS
  All five SNPs showed significant association with PTC. The average cumulative risk score in cases was significantly higher than in controls (p<2.2×10(-16)). Each additional risk allele increased the risk of having PTC by 1.51 [95% confidence interval (CI) 1.4, 1.64] in Ohio and by 1.35 [95% CI 1.27, 1.44] in Poland. An analysis was performed weighing risk alleles by effect size and assigning individuals to three weighted risk score groups, low (≤2), medium (2-5), and high (>5). Individuals in the high group were significantly more susceptible to PTC compared with individuals in the low group with an odds ratio of 8.7 [95% CI 5.8, 13.3] in Ohio and 4.24 [95% CI 3.10, 5.84] in Poland. Almost identical results were obtained when follicular variant PTCs and microPTCs were omitted. These five SNPs explained 11% of the familial risk of thyroid cancer in the Ohio cohort and 6% in the Polish cohort.
  
  
  CONCLUSIONS
  As the genetic risk score increases, the risk of having PTC increases. However, the predictive power of the cumulative effect of these five variants is only moderately high and clinical use may not be feasible until more variants are detected.
authors: 1 Human Cancer Genetics Program and Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors: Sandya
authors: S
authors: Liyanarachchi
authors: Anna
authors: A
authors: Wojcicka
authors: Wei
authors: W
authors: Li
authors: Malgorzata
authors: M
authors: Czetwertynska
authors: Elzbieta
authors: E
authors: Stachlewska
authors: Rebecca
authors: R
authors: Nagy
authors: Kevin
authors: K
authors: Hoag
authors: Bernard
authors: B
authors: Wen
authors: Rafal
authors: R
authors: Ploski
authors: Matthew D
authors: MD
authors: Ringel
authors: Izabella
authors: I
authors: Kozłowicz-Gudzinska
authors: Wojciech
authors: W
authors: Gierlikowski
authors: Krystian
authors: K
authors: Jazdzewski
authors: Huiling
authors: H
authors: He
authors: Albert
authors: A
authors: de la Chapelle
mesh_terms: D000328:Adult; D000483:Alleles; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
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