title: Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.
abstract: OBJECTIVE
  Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays.
  
  
  OBJECTIVE
  To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals.
  
  
  METHODS
  Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals.
  
  
  METHODS
  The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses.
  
  
  RESULTS
  The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers.
  
  
  CONCLUSIONS
  To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Ghani
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York3Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York4.
authors.forename: Christiane
authors.initials: C
authors.lastname: Reitz
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Badri Narayan
authors.initials: BN
authors.lastname: Vardarajan
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts6Department of Biostatistics, Boston University, Boston, Massachusetts7Department of Ophthalmology, Boston University, Boston, Massachusetts.
authors.forename: Gyungah
authors.initials: G
authors.lastname: Jun
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Sato
authors.affiliation: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
authors.forename: Adam
authors.initials: A
authors.lastname: Naj
authors.affiliation: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
authors.forename: Ruchita
authors.initials: R
authors.lastname: Rajbhandary
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Li-San
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Otto
authors.initials: O
authors.lastname: Valladares
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Chiao-Feng
authors.initials: CF
authors.lastname: Lin
authors.affiliation: Department of Medicine, University of Washington, Seattle11Group Health Research Institute, Group Health, Seattle, Washington.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida13Department of Neurology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.
authors.forename: Denis
authors.initials: D
authors.lastname: Evans
authors.affiliation: Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts16Harvard Medical School, Boston, Massachusetts17Program in Medical and Population Genetics, The Broad Institute, Cambridge, Ma.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: Department of Medicine, University of Washington, Seattle.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York19Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, New York20Department of Neuroscience, Mount Sinai School of Medicine, New York, New York2.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University, Indianapolis.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Murrell
authors.affiliation: Harvard Medical School, Boston, Massachusetts.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida13Department of Neurology, Mayo Clinic, Jacksonville, Florida.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts.
authors.forename: Mark
authors.initials: M
authors.lastname: Logue
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts.
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.affiliation: Harvard Medical School, Boston, Massachusetts23Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts24Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois26Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Barnes
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Cantwell
authors.affiliation: Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland.
authors.forename: M Daniele
authors.initials: MD
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authors.affiliation: School of Public Health, University of Alabama at Birmingham.
authors.forename: Rodney C P
authors.initials: RC
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authors.affiliation: SABA University School of Medicine, SABA, Dutch Caribbean.
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authors.initials: PA
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authors.affiliation: Division of Geriatrics, Howard University Hospital, Washington, DC.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Obisesan
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York4Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Manly
authors.affiliation: Department of Biostatistics, Boston University, Boston, Massachusetts.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania32Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
authors.affiliation: Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Lopez
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois33Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Indiana University Center for Aging Research, Indianapolis35Department of Psychiatry, Indiana University School of Medicine, Indianapolis36Regenstrief Institute Inc, Indianapolis, Indiana.
authors.forename: Hugh
authors.initials: H
authors.lastname: Hendrie
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Hall
authors.affiliation: Hope Center Program on Protein Aggregation and Neurodegeneration, Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Biology, North Carolina A & T University, Greensboro.
authors.forename: Goldie S
authors.initials: GS
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authors.affiliation: National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
authors.affiliation: Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.affiliation: Vanderbilt Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts6Department of Biostatistics, Boston University, Boston, Massachusetts7Department of Ophthalmology, Boston University, Boston, Massachusetts41Department of Neurology, Bo.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York3Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York4.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York3Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York4.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ekaterina
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mesh_terms: D001741:Black or African American / Q000208:ethnology*; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D002641:Chicago / Q000208:ethnology; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D007196:Indiana / Q000208:ethnology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*