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

Quantile difference plot of tests of allele frequency differences in APOE ε4-carrier versus non-carrier cases.SNPs in the APOE region are not included.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3040659&req=5

pgen-1001308-g007: Quantile difference plot of tests of allele frequency differences in APOE ε4-carrier versus non-carrier cases.SNPs in the APOE region are not included.

Mentions: Two sources of evidence suggested that an important source of potential confounding was APOE genotype. The first was the effect of adjustment for APOE genotype, which had a notable effect on the distribution of resulting genome-wide p-values. Simple adjustment of APOE through binary ε4-status yielded a distribution of p-values that was closer to a uniform distribution than was obtained from unadjusted analysis. However, deviation from the expected distribution was still evident (Figure 6A, 6B, cyan points), and there was still evidence for association with SNP rs2075650 near APOE (Figure 6C) in both the unrelated and related samples (p = 1.5×10−9 for CCun, and p = 1.2×10−7 for CCall). The full APOE adjustment achieved the best control of the distribution of p-values (Figure 6A, 6B, black points), and produced close to the expected uniform distribution of p-values under the distribution (Figure S3). Addition of the PCs as covariates alone did not produce the desired distribution of p-values (Figure S4, Table S7) and in addition to the full APOE adjustment in the CCun sample did not provide further improvement to the distribution of p-values over the APOE adjustment (Table S8 versus Table S3). This analysis also eliminated all statistically significant association with SNPs in the APOE region (Figure 6C), and evidence for adequate genomic control within each APOE stratum was reasonable (λ = 0.997, 1.02, 1.009, 1.003 for the ε4/ε4, ε4/ε3, ε3/ε3 and ε3/ε2+ε2/ε2 strata, respectively). A second source of evidence for confounding or population stratification was obtained from the results from the case-only analysis: the genome-wide distribution of p-values from the allele frequency comparison in ε4 carriers vs. non-carriers in the case-only sample also showed an overall deviation from the expected distribution in the direction of an excess of small p-values (Figure 7). This indicates that there are many markers that are correlation with APOE in the highly-ascertained case sample.


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)

Quantile difference plot of tests of allele frequency differences in APOE ε4-carrier versus non-carrier cases.SNPs in the APOE region are not included.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1001308-g007: Quantile difference plot of tests of allele frequency differences in APOE ε4-carrier versus non-carrier cases.SNPs in the APOE region are not included.
Mentions: Two sources of evidence suggested that an important source of potential confounding was APOE genotype. The first was the effect of adjustment for APOE genotype, which had a notable effect on the distribution of resulting genome-wide p-values. Simple adjustment of APOE through binary ε4-status yielded a distribution of p-values that was closer to a uniform distribution than was obtained from unadjusted analysis. However, deviation from the expected distribution was still evident (Figure 6A, 6B, cyan points), and there was still evidence for association with SNP rs2075650 near APOE (Figure 6C) in both the unrelated and related samples (p = 1.5×10−9 for CCun, and p = 1.2×10−7 for CCall). The full APOE adjustment achieved the best control of the distribution of p-values (Figure 6A, 6B, black points), and produced close to the expected uniform distribution of p-values under the distribution (Figure S3). Addition of the PCs as covariates alone did not produce the desired distribution of p-values (Figure S4, Table S7) and in addition to the full APOE adjustment in the CCun sample did not provide further improvement to the distribution of p-values over the APOE adjustment (Table S8 versus Table S3). This analysis also eliminated all statistically significant association with SNPs in the APOE region (Figure 6C), and evidence for adequate genomic control within each APOE stratum was reasonable (λ = 0.997, 1.02, 1.009, 1.003 for the ε4/ε4, ε4/ε3, ε3/ε3 and ε3/ε2+ε2/ε2 strata, respectively). A second source of evidence for confounding or population stratification was obtained from the results from the case-only analysis: the genome-wide distribution of p-values from the allele frequency comparison in ε4 carriers vs. non-carriers in the case-only sample also showed an overall deviation from the expected distribution in the direction of an excess of small p-values (Figure 7). This indicates that there are many markers that are correlation with APOE in the highly-ascertained case sample.

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