Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci

Abstract

Objective: To identify putative genetic loci related to the risk of late-onset Alzheimer disease (LOAD).

Design: Linkage analysis and family-based and case-control association analyses from a genomewide scan using approximately 6000 single-nucleotide polymorphic markers at an average intermarker distance of 0.65 cM.

Setting: The National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD) was created to expand the resources for studies to identify additional genes contributing to the risk for LOAD.

Participants: We investigated 1902 individuals from 328 families with LOAD and 236 unrelated control subjects.

Main outcome measures: Clinical diagnosis of LOAD.

Results: The strongest overall finding was at chromosome 19q13.32, confirming the effect of the apolipoprotein E gene on LOAD risk in the family-based and case-control analyses. However, single-nucleotide polymorphisms at the following loci were also statistically significant in 1 or more of the analyses performed: 7p22.2, 7p21.3, and 16q21 in the linkage analyses; 17q21.31 and 22q11.21 in the family-based association analysis; and 7q31.1 and 22q12.3 in the case-control analysis. Positive associations at 7q31.1 and 20q13.33 were also significant in the meta-analysis results in a publicly available database.

Conclusions: Several additional loci may harbor genetic variants associated with LOAD. This data set provides a wealth of phenotypic and genotypic information for use as a resource in discovery and confirmatory research.

Figure 1

Multipoint logarithm of odds (LOD) scores for late-onset Alzheimer disease (LOAD). A, Multipoint LOD scores for a broad definition of LOAD (ie, definite, probable, and possible). Results for all 22 chromosomes are shown on a single graph. Single-nucleotide polymorphisms (SNPs) near the gene for apolipoprotein E (APOE) at 19q13.31−2 had the highest LOD scores. Additional SNP clusters at 7p22.1, 8p21.3, 6q21, and 18q12.2 also had LOD scores of 2.0 or greater in 1 of the analyses. B, Multipoint LOD scores for a narrow definition of LOAD (ie, definite and probable). Results for all 22 chromosomes are shown on a single graph.

Figure 2

Family-based association test (FBAT) analysis using broad (ie, definite, probable, and possible) and narrow (ie, definite and probable) definitions of late-onset Alzheimer disease (LOAD). The –log₁₀(P) represents logarithm-transformed P values for the Z scores from the FBAT analysis. The single-nucleotide polymorphisms (SNPs) at 22q11.21 showed the strongest association (P=.000063). An SNP proximal to 17q21.31 was also strongly associated with LOAD, a marker near the gene encoding tau at 17q21.1. Under the narrow definition, 9 SNPs had P values less than .001. At 8p21.3, SNP rs4427168 showed the most significant association with LOAD (P=.000174). This SNP and rs174345 at 22q11.21 were associated with LOAD under both disease definitions.