title: Interrogating local population structure for fine mapping in genome-wide association studies.
abstract: BACKGROUND
  Adjustment for population structure is necessary to avoid bias in genetic association studies of susceptibility variants for complex diseases. Population structure may differ from one genomic region to another due to the variability of individual ancestry associated with migration, random genetic drift or natural selection. Current association methods for correcting population stratification usually involve adjustment of global ancestry between study subjects.
  
  
  RESULTS
  We suggest interrogating local population structure for fine mapping to more accurately locate true casual genes by better adjusting the confounding effect due to local ancestry. By extensive simulations on genome-wide datasets, we show that adjusting global ancestry may lead to false positives when local population structure is an important confounding factor. In contrast, adjusting local ancestry can effectively prevent false positives due to local population structure and thus can improve fine mapping for disease gene localization. We applied the local and global adjustments to the analysis of datasets from three genome-wide association studies, including European Americans, African Americans and Nigerians. Both European Americans and African Americans demonstrate greater variability in local ancestry than Nigerians. Adjusting local ancestry successfully eliminated the known spurious association between SNPs in the LCT gene and height due to the population structure existed in European Americans.
  
  
  BACKGROUND
  xiaofeng.zhu@case.edu
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Huaizhen
authors.initials: H
authors.lastname: Qin
authors.forename: Nathan
authors.initials: N
authors.lastname: Morris
authors.forename: Sun J
authors.initials: SJ
authors.lastname: Kang
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Bamidele
authors.initials: B
authors.lastname: Tayo
authors.forename: Helen
authors.initials: H
authors.lastname: Lyon
authors.forename: Joel
authors.initials: J
authors.lastname: Hirschhorn
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhu
mesh_terms: D002874:Chromosome Mapping / Q000379:methods*; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics; D025341:Principal Component Analysis; D012641:Selection, Genetic