Genome-Wide Survey of Large Rare Copy Number Variants in Alzheimer’s Disease Among Caribbean Hispanics

G3: Genes, Genomes, Genetics

Joseph H. Lee⁴  Peter St. George-Hyslop¹  Mahdi Ghani⁵  Dalila Pinto²  Danielle Moreno⁵  Yakov Grinberg⁵  Christine Sato⁵  Ekaterina Rogaeva⁶  Richard Mayeux³  Stephen W. Scherer² 

[1] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CCambridge Institute for Medical ResearchDepartment of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United KingdomTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CCambridge Institute for Medical ResearchDepartment of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United KingdomDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CCambridge Institute for Medical ResearchDepartment of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United KingdomCambridge Institute for Medical ResearchTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CCambridge Institute for Medical ResearchDepartment of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United KingdomDepartment of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United KingdomTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CCambridge Institute for Medical ResearchDepartment of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, United Kingdom;Genetics and Genomic Biology, Hospital for Sick Children, Toronto, Ontario M5G 1L7, CGenetics and Genomic Biology, Hospital for Sick Children, Toronto, Ontario M5G 1L7, CGenetics and Genomic Biology, Hospital for Sick Children, Toronto, Ontario M5G 1L7, C;Taub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsTaub Institute for Research on Alzheimer’s Disease and the Aging BraiTaub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Taub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsDepartments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsTaub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and Surgeons;Taub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsDepartment of Epidemiology, School of Public Health, Columbia University, New York, New York 10032Taub Institute for Research on Alzheimer’s Disease and the Aging BraiTaub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsDepartment of Epidemiology, School of Public Health, Columbia University, New York, New York 10032Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Taub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsDepartment of Epidemiology, School of Public Health, Columbia University, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsTaub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsDepartment of Epidemiology, School of Public Health, Columbia University, New York, New York 10032Department of Epidemiology, School of Public Health, Columbia University, New York, New York 10032Taub Institute for Research on Alzheimer’s Disease and the Aging BraiGertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York 10032Departments of Neurology, Psychiatry, and Medicine, College of Physicians and SurgeonsDepartment of Epidemiology, School of Public Health, Columbia University, New York, New York 10032;Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, C;Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, CTanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, CDepartment of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, C

关键词: gene;    deletion;    duplication;    Alzheimer’s Disease;    copy number variants;   

DOI  :  10.1534/g3.111.000869

学科分类：生物科学（综合）

来源: Genetics Society of America

【 摘 要 】

Recently genome-wide association studies have identified significant association between Alzheimer’s disease (AD) and variations in CLU, PICALM, BIN1, CR1, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7. However, the pathogenic variants in these loci have not yet been found. We conducted a genome-wide scan for large copy number variation (CNV) in a dataset of Caribbean Hispanic origin (554 controls and 559 AD cases that were previously investigated in a SNP-based genome-wide association study using Illumina HumanHap 650Y platform). We ran four CNV calling algorithms to obtain high-confidence calls for large CNVs (>100 kb) that were detected by at least two algorithms. Global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications, total or average CNV size; or number of genes affected by CNVs. However, we observed a nominal association between AD and a ∼470 kb duplication on chromosome 15q11.2 (P = 0.037). This duplication, encompassing up to five genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1) was present in 10 cases (2.6%) and 3 controls (0.8%). The dosage increase of CYFIP1 and NIPA1 genes was further confirmed by quantitative PCR. The current study did not detect CNVs that affect novel AD loci identified by recent genome-wide association studies. However, because the array technology used in our study has limitations in detecting small CNVs, future studies must carefully assess novel AD genes for the presence of disease-related CNVs.

【 授权许可】

Unknown