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Original Investigation
November 2015

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

Author Affiliations
  • 1Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
  • 2Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York
  • 3Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York
  • 4Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York
  • 5Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts
  • 6Department of Biostatistics, Boston University, Boston, Massachusetts
  • 7Department of Ophthalmology, Boston University, Boston, Massachusetts
  • 8The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida
  • 9Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
  • 10Department of Medicine, University of Washington, Seattle
  • 11Group Health Research Institute, Group Health, Seattle, Washington
  • 12Department of Neuroscience, Mayo Clinic, Jacksonville, Florida
  • 13Department of Neurology, Mayo Clinic, Jacksonville, Florida
  • 14Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
  • 15Program in Translational Neuropsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 16Harvard Medical School, Boston, Massachusetts
  • 17Program in Medical and Population Genetics, The Broad Institute, Cambridge, Massachusetts
  • 18Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
  • 19Department of Genetics and Genomics Sciences, Mount Sinai School of Medicine, New York, New York
  • 20Department of Neuroscience, Mount Sinai School of Medicine, New York, New York
  • 21Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York
  • 22Department of Medical and Molecular Genetics, Indiana University, Indianapolis
  • 23Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 24Partners Center for Personalized Genetic Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
  • 25Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
  • 26Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois
  • 27Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland
  • 28School of Public Health, University of Alabama at Birmingham
  • 29SABA University School of Medicine, SABA, Dutch Caribbean
  • 30Division of Geriatrics, Howard University Hospital, Washington, DC
  • 31Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 32Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 33Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
  • 34Indiana University Center for Aging Research, Indianapolis
  • 35Department of Psychiatry, Indiana University School of Medicine, Indianapolis
  • 36Regenstrief Institute Inc, Indianapolis, Indiana
  • 37Hope Center Program on Protein Aggregation and Neurodegeneration, Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
  • 38Department of Biology, North Carolina A & T University, Greensboro
  • 39National Alzheimer’s Coordinating Center, Department of Epidemiology, University of Washington, Seattle
  • 40Vanderbilt Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
  • 41Department of Neurology, Boston University, Boston, Massachusetts
  • 42Department of Epidemiology, Boston University, Boston, Massachusetts
  • 43Department of Epidemiology, College of Physicians and Surgeons, Columbia University, New York, New York
  • 44Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
JAMA Neurol. 2015;72(11):1313-1323. doi:10.1001/jamaneurol.2015.1700
Abstract

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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