Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals | Genetics and Genomics | JAMA Neurology | JAMA Network
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Original Contribution
March 2011

Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals

Author Affiliations

Author Affiliations: Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Lee, Cheng, Barral, Reitz, Lantigua, and Mayeux), Gertrude H. Sergievsky Center (Drs Lee and Mayeux), and Departments of Neurology (Drs Barral, Reitz, and Mayeux), Psychiatry (Dr Mayeux), and Medicine (Dr Lantigua), College of Physicians and Surgeons, and Department of Epidemiology, School of Public Health (Drs Lee and Mayeux), Columbia University, New York, New York; Universidad Tecnológica de Santiago, Santiago, Dominican Republic (Dr Medrano); Department of Internal Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico (Dr Jiménez-Velazquez); Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, and Toronto Western Hospital Research Institute, Toronto, Ontario, Canada (Drs Rogaeva and St. George-Hyslop); and Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, England (Dr St. George-Hyslop).

Arch Neurol. 2011;68(3):320-328. doi:10.1001/archneurol.2010.292

Numerous genome-wide association studies (GWAS) have been published for late-onset Alzheimer disease (LOAD).1-13 Aside from APOE, additional candidate susceptibility genes identified using GWAS methods for LOAD have included GAB2, GALP, 14q32.13, LOC651924, PGBD1, TNK1, CR1, CLU, PICALM, and BIN1.14,15 In addition, variants in SORL1 identified by Rogaeva et al16 have been replicated in several independent cohorts and were significantly associated with LOAD in a meta-analysis.17 Difficulties inherent to the genetics of complex diseases (eg, etiologic heterogeneity, gene × environment and gene × gene interactions, and methylation) remain with these studies, and much work needs to be done. For example, the strength of association, or effect size, as measured by odds ratios (ORs) varies widely across studies and is generally small. Yet, these GWAS have identified a number of candidate genes that need to be replicated and their functional roles determined. Despite the increasing number of identified susceptibility genetic variants, a relatively large proportion of genetic variance remains unexplained.18 This has much to do with both the complexity of the genetics and inadequacy of heritability as a measure of genetic contribution. Similar phenomena have been observed in other common, complex genetic diseases and invoked a term, genetic dark matter, in GWAS.19,20

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