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Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.

Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R, NIA-LOAD/NCRAD Family Study Gro - PLoS Genet. (2011)

Bottom Line: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly.Association in this gene was replicated in an independent sample consisting of three cohorts.We suggest that similar adjustments may also be needed for many other large multi-site studies.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Genetics, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.

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First four principal components (PCs) in the European-American sample alone.Colors represent inferred ancestry. Black: northwest (NW) Europe; green: southeast (SE) Europe; cyan: Ashkenazi Jewish (AJ); magenta: indeterminate (omitted from subpopulation analyses).
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pgen-1001308-g002: First four principal components (PCs) in the European-American sample alone.Colors represent inferred ancestry. Black: northwest (NW) Europe; green: southeast (SE) Europe; cyan: Ashkenazi Jewish (AJ); magenta: indeterminate (omitted from subpopulation analyses).

Mentions: The European-American-specific principal components (PCs) revealed substructure within the sample. Although apparent with the first two principal components (PC1 and PC2), three subgroups were most clearly defined by the first and fourth principal components (Figure 2). Estimated fractions of each subpopulation varied across sites (Table 2), with the NW group the largest (90.2%) sample (Table 2). A few subjects fell between the main clusters, and were excluded in subsequent subgroup analyses (Figure 2). Subgroup assignments were strongly supported by likelihood computations based on European subgroup-specific AIMs, and by comparison of allele frequencies in the three groups with those of the AIMs. Large between-group allele frequency differences between the NW and other groups near lactase on chromosome 2 and HLA on chromosome 6 [81] further supported these subgroup assignments: e.g., allele frequency differences >0.55 for SNPs near lactase, as do overall comparison of allele frequency differences between pairs of populations. Although the median allele frequency difference was relatively low (<0.04) for all three pairs of populations (Figure 3A), 7%, 9% and 12% of the markers had a substantial allele frequency difference of >0.1 in the NW-SE, AJ-SE, and NW-AJ comparison, respectively. These larger allele frequency differences coupled with varying fractions of cases from the different contributing sites (Table 2) predispose to confounding.


Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.

Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R, NIA-LOAD/NCRAD Family Study Gro - PLoS Genet. (2011)

First four principal components (PCs) in the European-American sample alone.Colors represent inferred ancestry. Black: northwest (NW) Europe; green: southeast (SE) Europe; cyan: Ashkenazi Jewish (AJ); magenta: indeterminate (omitted from subpopulation analyses).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3040659&req=5

pgen-1001308-g002: First four principal components (PCs) in the European-American sample alone.Colors represent inferred ancestry. Black: northwest (NW) Europe; green: southeast (SE) Europe; cyan: Ashkenazi Jewish (AJ); magenta: indeterminate (omitted from subpopulation analyses).
Mentions: The European-American-specific principal components (PCs) revealed substructure within the sample. Although apparent with the first two principal components (PC1 and PC2), three subgroups were most clearly defined by the first and fourth principal components (Figure 2). Estimated fractions of each subpopulation varied across sites (Table 2), with the NW group the largest (90.2%) sample (Table 2). A few subjects fell between the main clusters, and were excluded in subsequent subgroup analyses (Figure 2). Subgroup assignments were strongly supported by likelihood computations based on European subgroup-specific AIMs, and by comparison of allele frequencies in the three groups with those of the AIMs. Large between-group allele frequency differences between the NW and other groups near lactase on chromosome 2 and HLA on chromosome 6 [81] further supported these subgroup assignments: e.g., allele frequency differences >0.55 for SNPs near lactase, as do overall comparison of allele frequency differences between pairs of populations. Although the median allele frequency difference was relatively low (<0.04) for all three pairs of populations (Figure 3A), 7%, 9% and 12% of the markers had a substantial allele frequency difference of >0.1 in the NW-SE, AJ-SE, and NW-AJ comparison, respectively. These larger allele frequency differences coupled with varying fractions of cases from the different contributing sites (Table 2) predispose to confounding.

Bottom Line: Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly.Association in this gene was replicated in an independent sample consisting of three cohorts.We suggest that similar adjustments may also be needed for many other large multi-site studies.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Genetics, University of Washington, Seattle, Washington, United States of America.

ABSTRACT
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10(-81)), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10(-8)). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.

Show MeSH
Related in: MedlinePlus