title: Runs of homozygosity and inbreeding in thyroid cancer.
abstract: BACKGROUND
  Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of thyroid cancer (TC). Most cancer predisposition genes identified through GWASs function in a co-dominant manner, and studies have not found evidence for recessively functioning disease loci in TC. Our study examines whether homozygosity is associated with an increased risk of TC and searches for novel recessively acting disease loci.
  
  
  METHODS
  Data from a previously conducted GWAS were used for the estimation of the proportion of phenotypic variance explained by all common SNPs, the detection of runs of homozygosity (ROH) and the determination of inbreeding to unravel their influence on TC.
  
  
  RESULTS
  Inbreeding coefficients were significantly higher among cases than controls. Association on a SNP-by-SNP basis was controlled by using the false discovery rate at a level of q* < 0.05, with 34 SNPs representing true differences in homozygosity between cases and controls. The average size, the number and total length of ROHs per person were significantly higher in cases than in controls. A total of 16 recurrent ROHs of rather short length were identified although their association with TC risk was not significant at a genome-wide level. Several recurrent ROHs harbor genes associated with risk of TC. All of the ROHs showed significant evidence for natural selection (iHS, Fst, Fay and Wu's H).
  
  
  CONCLUSIONS
  Our results support the existence of recessive alleles in TC susceptibility. Although regions of homozygosity were rather small, it might be possible that variants within these ROHs affect TC risk and may function in a recessive manner.
authors.affiliation: Molecular Genetic Epidemiology, C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. h.thomsen@dkfz-heidelberg.de.
authors.forename: Hauke
authors.initials: H
authors.lastname: Thomsen
authors.affiliation: Molecular Genetic Epidemiology, C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.affiliation: Molecular Genetic Epidemiology, C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.|Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Gisella
authors.initials: G
authors.lastname: Figlioli
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Cipollini
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Cristaudo
authors.affiliation: Blood Centre, Azienda Ospedaliero Universitaria A. Meyer, Firenze, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bambi
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel, Basel, Switzerland.|Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel, Basel, Switzerland.|Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.affiliation: Molecular Genetic Epidemiology, C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.|Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.affiliation: Molecular Genetic Epidemiology, C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.|Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D003241:Consanguinity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012641:Selection, Genetic; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
keywords: GWAS; Inbreeding; Runs of homozygosity; Thyroid cancer