Limits...
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.

Show MeSH

Related in: MedlinePlus

Genome scan of European-American subjects.Panel A: CCall sample analyzed as a single population; panel B: stratified analysis of CCall sample that accounts for three subpopulations (NW, SE, AJ); panel C: stratified analysis of CCall sample across four APOE genotypes; panel D: CCun sample, with covariate adjustment for the number of ε2 and ε4 alleles. Plots have been truncated at −log10p = 10 on the vertical axis to more easily visualize results for most of the genome. Multiple SNPs near APOE on chromosome 19 yielded −log10p≫10 in the analyses that did not control for APOE (Panels A and B, see text for details), and are represented by a single triangle at the top of each such panel. Horizontal line shows genome-wide significance level.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3040659&req=5

pgen-1001308-g004: Genome scan of European-American subjects.Panel A: CCall sample analyzed as a single population; panel B: stratified analysis of CCall sample that accounts for three subpopulations (NW, SE, AJ); panel C: stratified analysis of CCall sample across four APOE genotypes; panel D: CCun sample, with covariate adjustment for the number of ε2 and ε4 alleles. Plots have been truncated at −log10p = 10 on the vertical axis to more easily visualize results for most of the genome. Multiple SNPs near APOE on chromosome 19 yielded −log10p≫10 in the analyses that did not control for APOE (Panels A and B, see text for details), and are represented by a single triangle at the top of each such panel. Horizontal line shows genome-wide significance level.

Mentions: As expected, SNPs near APOE provided the strongest genome-wide evidence for association in the unadjusted analyses (Figure 4A, Table 4). In the primary analyses, SNP rs2075650 in TOMM40, which is in strong linkage disequilibrium with rs429358 in our sample (D′ = 0.70; r2 = 0.45; using the 884 unrelated controls), and which tags the APOE ε4 allele, gave highly significant results in analysis of both the CCall and CCun sample (p = 3.2×10−81 and p = 6.3×10−77, respectively). The secondary analyses gave similar results with rs2075650 in the analysis of the ethnic-stratified analysis for the unweighted combined results, the NW sample, and the AJ sample (p = 1.2×10−15, p = 3.2×10−73, and p = 3.7×10−8, respectively). In each of these analyses, six additional SNPs near APOE also provided very strong support for this association (e.g., in the CCall sample, p-values ranged from p = 4.9×10−10 to p = 2.9×10−24). Only in the small SE sample was the evidence for association with rs2075650 merely suggestive (p = 0.03), consistent with the reduced inflation, in this sample, of the ε4 frequency in cases relative to that observed in the other subgroups (Table 3). For this SE sample, rs7007878 on chromosome 8 at ∼29 MB provided the strongest evidence of association (p = 6.5×10−6).


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)

Genome scan of European-American subjects.Panel A: CCall sample analyzed as a single population; panel B: stratified analysis of CCall sample that accounts for three subpopulations (NW, SE, AJ); panel C: stratified analysis of CCall sample across four APOE genotypes; panel D: CCun sample, with covariate adjustment for the number of ε2 and ε4 alleles. Plots have been truncated at −log10p = 10 on the vertical axis to more easily visualize results for most of the genome. Multiple SNPs near APOE on chromosome 19 yielded −log10p≫10 in the analyses that did not control for APOE (Panels A and B, see text for details), and are represented by a single triangle at the top of each such panel. Horizontal line shows genome-wide significance level.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1001308-g004: Genome scan of European-American subjects.Panel A: CCall sample analyzed as a single population; panel B: stratified analysis of CCall sample that accounts for three subpopulations (NW, SE, AJ); panel C: stratified analysis of CCall sample across four APOE genotypes; panel D: CCun sample, with covariate adjustment for the number of ε2 and ε4 alleles. Plots have been truncated at −log10p = 10 on the vertical axis to more easily visualize results for most of the genome. Multiple SNPs near APOE on chromosome 19 yielded −log10p≫10 in the analyses that did not control for APOE (Panels A and B, see text for details), and are represented by a single triangle at the top of each such panel. Horizontal line shows genome-wide significance level.
Mentions: As expected, SNPs near APOE provided the strongest genome-wide evidence for association in the unadjusted analyses (Figure 4A, Table 4). In the primary analyses, SNP rs2075650 in TOMM40, which is in strong linkage disequilibrium with rs429358 in our sample (D′ = 0.70; r2 = 0.45; using the 884 unrelated controls), and which tags the APOE ε4 allele, gave highly significant results in analysis of both the CCall and CCun sample (p = 3.2×10−81 and p = 6.3×10−77, respectively). The secondary analyses gave similar results with rs2075650 in the analysis of the ethnic-stratified analysis for the unweighted combined results, the NW sample, and the AJ sample (p = 1.2×10−15, p = 3.2×10−73, and p = 3.7×10−8, respectively). In each of these analyses, six additional SNPs near APOE also provided very strong support for this association (e.g., in the CCall sample, p-values ranged from p = 4.9×10−10 to p = 2.9×10−24). Only in the small SE sample was the evidence for association with rs2075650 merely suggestive (p = 0.03), consistent with the reduced inflation, in this sample, of the ε4 frequency in cases relative to that observed in the other subgroups (Table 3). For this SE sample, rs7007878 on chromosome 8 at ∼29 MB provided the strongest evidence of association (p = 6.5×10−6).

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