title: Strategy for mapping quantitative trait loci (QTL) by using human metapopulations.
abstract: OBJECTIVE
  To present a novel strategy for mapping quantitative trait loci (QTL), using human metapopulations. The strategy is based on the expectation that in geographic clusters of small and distinct human isolates, a combination of founder effect and genetic drift can dramatically increase population frequency of rare QTL variants with large effect. In such cases, the distribution of QT measurements in an (affected) isolate is expected to deviate from that observed in neighboring isolates.
  
  
  METHODS
  We tested this hypothesis in 9 villages from a larger Croatian isolate resource, where 7 Mendelian disorders have been previously reported. The values of 10 physiological and biochemical QTs were measured in a random sample of 1001 individuals (100 inhabitants of each of 9 villages and 101 immigrant controls).
  
  
  RESULTS
  Significant over- or under- representation of individuals from specific villages in extreme ends of standardized QT measurement distribution was found 10 times more frequently than expected by chance. The large majority of such clusters of individuals with extreme QT values (34/36, 94.4%) originated from the 6 villages with the most pronounced geographic isolation and endogamy.
  
  
  CONCLUSIONS
  Early epidemiological assessment supports the feasibility of the proposed strategy. Clusters of individuals with extreme QT values responsible for over-representation of single villages can usually be linked to a larger pedigree and may be useful for further QTL mapping, using linkage analysis.
authors.affiliation: Department of Public Health Sciences, Faculty of Medicine, University of Edinburgh, Edinburgh, Scotland, UK. irudan@mef.hr
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Biloglav
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Carothers
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
mesh_terms: D001827:Body Height; D002874:Chromosome Mapping; D017523:Croatia; D004392:Dwarfism / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D005843:Geography; D006801:Humans; D008297:Male; D008957:Models, Genetic; D040641:Quantitative Trait Loci