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Lee JH, Cheng R, Barral S, et al. Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals. 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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