Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals

Abstract

Objectives: To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study.

Design: Nested case-control genome-wide association study.

Setting: The Washington Heights-Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.

Participants: Five hundred forty-nine affected and 544 unaffected individuals of Caribbean Hispanic ancestry.

Intervention: The Illumina HumanHap 650Y chip for genotyping.

Main outcome measure: Clinical diagnosis or pathologically confirmed diagnosis of LOAD.

Results: The strongest support for allelic association was for rs9945493 on 18q23 (P=1.7×10(-7)), but 22 additional single-nucleotide polymorphisms (SNPs) had a P value less than 9×10(-6) under 3 different analyses: unadjusted and stratified by the presence or absence of the APOE ε4 allele. Of these SNPs, 5 SNPs (rs4669573 and rs10197851 on 2p25.1; rs11711889 on 3q25.2; rs1117750 on 7p21.1; and rs7908652 on 10q23.1) were associated with LOAD in an independent cohort from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study. We also replicated genetic associations for CLU, PICALM, and BIN1.

Conclusions: Our genome-wide search of Caribbean Hispanic individuals identified several novel genetic variants associated with LOAD and replicated these associations in a white cohort. We also replicated associations in CLU, PICALM, and BIN1 in the Caribbean Hispanic cohort.

Figure 1

Population structure of a Caribbean Hispanic population. The dark gray dots represent Hispanic white individuals, while the black dots represent Hispanic African individuals. The light gray dots represent individuals from other Central American countries. The Figure was generated using STRUCTURE.

Figure 2

Manhattan plot of allelic association analysis in a Caribbean Hispanic population. The results of genome-wide association analysis are presented. One single-nucleotide polymorphism has a P value less than 9 × 10⁻⁶ and multiple single-nucleotide polymorphisms have P values less than 9 × 10⁻⁶.

Figure 3

Association between CUGBP2 and late-onset Alzheimer disease (LOAD) among homozygous APOE ε4 carriers in Caribbean Hispanic subjects vs National Institute on Aging Late-Onset Alzheimer’s Disease study European American subjects. Two models were used to examine the relation between CUGBP2 and LOAD, conditional on APOE ε4 status. Model 1 is homozygous APOE ε4 carriers vs others; model 2 is homozygous APOE ε4 carriers vs homozygous APOE ε3 carriers. The remaining subjects were excluded from the analysis. bp Indicates base pair. The base pair location on the x-axis is not in scale.