Mahdi Ghani1, Christiane Reitz2, Rong Cheng3, Badri Narayan Vardarajan4, Gyungah Jun5, Christine Sato1, Adam Naj6, Ruchita Rajbhandary6, Li-San Wang7, Otto Valladares7, Chiao-Feng Lin7, Eric B Larson8, Neill R Graff-Radford9, Denis Evans10, Philip L De Jager11, Paul K Crane12, Joseph D Buxbaum13, Jill R Murrell14, Towfique Raj15, Nilufer Ertekin-Taner9, Mark Logue16, Clinton T Baldwin16, Robert C Green17, Lisa L Barnes18, Laura B Cantwell7, M Daniele Fallin19, Rodney C P Go20, Patrick A Griffith21, Thomas O Obisesan22, Jennifer J Manly23, Kathryn L Lunetta24, M Ilyas Kamboh25, Oscar L Lopez26, David A Bennett27, Hugh Hendrie28, Kathleen S Hall29, Alison M Goate30, Goldie S Byrd31, Walter A Kukull32, Tatiana M Foroud33, Jonathan L Haines34, Lindsay A Farrer35, Margaret A Pericak-Vance6, Joseph H Lee2, Gerard D Schellenberg7, Peter St George-Hyslop1, Richard Mayeux2, Ekaterina Rogaeva1. 1. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada. 2. 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. 3. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York. 4. Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York. 5. Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts6Department of Biostatistics, Boston University, Boston, Massachusetts7Department of Ophthalmology, Boston University, Boston, Massachusetts. 6. The John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida. 7. Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia. 8. Department of Medicine, University of Washington, Seattle11Group Health Research Institute, Group Health, Seattle, Washington. 9. Department of Neuroscience, Mayo Clinic, Jacksonville, Florida13Department of Neurology, Mayo Clinic, Jacksonville, Florida. 10. Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois. 11. 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. 12. Department of Medicine, University of Washington, Seattle. 13. 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. 14. Department of Medical and Molecular Genetics, Indiana University, Indianapolis. 15. Harvard Medical School, Boston, Massachusetts. 16. Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts. 17. 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. 18. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois26Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois. 19. Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland. 20. School of Public Health, University of Alabama at Birmingham. 21. SABA University School of Medicine, SABA, Dutch Caribbean. 22. Division of Geriatrics, Howard University Hospital, Washington, DC. 23. 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. 24. Department of Biostatistics, Boston University, Boston, Massachusetts. 25. Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania32Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania. 26. Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania. 27. Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois33Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois. 28. Indiana University Center for Aging Research, Indianapolis35Department of Psychiatry, Indiana University School of Medicine, Indianapolis36Regenstrief Institute Inc, Indianapolis, Indiana. 29. Department of Psychiatry, Indiana University School of Medicine, Indianapolis. 30. Hope Center Program on Protein Aggregation and Neurodegeneration, Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri. 31. Department of Biology, North Carolina A & T University, Greensboro. 32. National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle. 33. Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois. 34. Vanderbilt Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee. 35. Department of Medicine (Biomedical Genetics), Boston University, Boston, Massachusetts6Department of Biostatistics, Boston University, Boston, Massachusetts7Department of Ophthalmology, Boston University, Boston, Massachusetts41Department of Neurology, Bo.
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.
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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