title: Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND).
abstract: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample.
  
  
  
  A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy.
  
  
  
  The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, 85014, USA. williamsr@mail.nih.gov.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Williams
authors.affiliation: Genetic Analysis and Data Coordinating Center, Case Western Reserve University, Cleveland, OH, 44104, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Elston
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, 85014, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, 85014, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: Division of Nephrology, The University of Texas Health Science Center, San Antonio, TX, 78229, USA.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.affiliation: Department of Nephrology, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Adler
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Divers
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Genetic Analysis and Data Coordinating Center, Case Western Reserve University, Cleveland, OH, 44104, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Igo
authors.affiliation: Department of Nephrology, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Ipp
authors.affiliation: Genetic Analysis and Data Coordinating Center, Case Western Reserve University, Cleveland, OH, 44104, USA.
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Kimmel
authors.affiliation: Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD, 21205, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Klag
authors.affiliation: The University of Chicago Medical Center, Chicago, IL, 60637, USA.
authors.forename: Orly
authors.initials: O
authors.lastname: Kohn
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.affiliation: Loyola University Medical Center, Chicago, IL, 60153, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Leehey
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, 85014, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.affiliation: Divisions of Nephrology and Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
authors.forename: Susanne B
authors.initials: SB
authors.lastname: Nicholas
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, UC Irvine School of Medicine, University of California, Orange, 92868, CA, USA.
authors.forename: Madeleine V
authors.initials: MV
authors.lastname: Pahl
authors.affiliation: Hospital for Sick Children, University Health Network and the University of Toronto, Ontario, M5G1X8, Canada.
authors.forename: Rulan S
authors.initials: RS
authors.lastname: Parekh
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Departments of Medicine and Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, 44104, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Schelling
authors.affiliation: Departments of Medicine and Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, 44104, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Sedor
authors.affiliation: The University of New Mexico, Albuquerque, NM, 87131, USA.
authors.forename: Vallabh O
authors.initials: VO
authors.lastname: Shah
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD, 20892, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Smith
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Division of Nephrology, The University of Texas Health Science Center, San Antonio, TX, 78229, USA.|Department of Biochemistry, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
authors.forename: Farook
authors.initials: F
authors.lastname: Thameem
authors.affiliation: The University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
authors.forename: Denyse
authors.initials: D
authors.lastname: Thornley-Brown
authors.affiliation: Center for Cancer Research, National Cancer Institute, NIH, Leidos Biomedical, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.affiliation: The University of New Mexico, Albuquerque, NM, 87131, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Zager
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, 85014, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000465:Algorithms; D002874:Chromosome Mapping; D003928:Diabetic Nephropathies / Q000208:ethnology / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D016013:Likelihood Functions; D017058:Mexican Americans / Q000235:genetics*; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D014481:United States / Q000208:ethnology; D044465:White People / Q000235:genetics*
chemical_list: D005819:Genetic Markers
keywords: Diabetic nephropathy; Individual genetic ancestry; Population structure; SNP