Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.
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 mult...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-02-01
|
| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001308&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850126449574412288 |
|---|---|
| author | Ellen M Wijsman Nathan D Pankratz Yoonha Choi Joseph H Rothstein Kelley M Faber Rong Cheng Joseph H Lee Thomas D Bird David A Bennett Ramon Diaz-Arrastia Alison M Goate Martin Farlow Bernardino Ghetti Robert A Sweet Tatiana M Foroud Richard Mayeux NIA-LOAD/NCRAD Family Study Group |
| author_facet | Ellen M Wijsman Nathan D Pankratz Yoonha Choi Joseph H Rothstein Kelley M Faber Rong Cheng Joseph H Lee Thomas D Bird David A Bennett Ramon Diaz-Arrastia Alison M Goate Martin Farlow Bernardino Ghetti Robert A Sweet Tatiana M Foroud Richard Mayeux NIA-LOAD/NCRAD Family Study Group |
| author_sort | Ellen M Wijsman |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bcc36e189ec444929a0949cdbbbdb429 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2011-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-bcc36e189ec444929a0949cdbbbdb4292025-08-20T02:33:55ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-02-0172e100130810.1371/journal.pgen.1001308Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.Ellen M WijsmanNathan D PankratzYoonha ChoiJoseph H RothsteinKelley M FaberRong ChengJoseph H LeeThomas D BirdDavid A BennettRamon Diaz-ArrastiaAlison M GoateMartin FarlowBernardino GhettiRobert A SweetTatiana M ForoudRichard MayeuxNIA-LOAD/NCRAD Family Study GroupLate-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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001308&type=printable |
| spellingShingle | Ellen M Wijsman Nathan D Pankratz Yoonha Choi Joseph H Rothstein Kelley M Faber Rong Cheng Joseph H Lee Thomas D Bird David A Bennett Ramon Diaz-Arrastia Alison M Goate Martin Farlow Bernardino Ghetti Robert A Sweet Tatiana M Foroud Richard Mayeux NIA-LOAD/NCRAD Family Study Group Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genetics |
| title | Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. |
| title_full | Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. |
| title_fullStr | Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. |
| title_full_unstemmed | Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. |
| title_short | Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. |
| title_sort | genome wide association of familial late onset alzheimer s disease replicates bin1 and clu and nominates cugbp2 in interaction with apoe |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1001308&type=printable |
| work_keys_str_mv | AT ellenmwijsman genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT nathandpankratz genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT yoonhachoi genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT josephhrothstein genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT kelleymfaber genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT rongcheng genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT josephhlee genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT thomasdbird genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT davidabennett genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT ramondiazarrastia genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT alisonmgoate genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT martinfarlow genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT bernardinoghetti genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT robertasweet genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT tatianamforoud genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT richardmayeux genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe AT nialoadncradfamilystudygroup genomewideassociationoffamiliallateonsetalzheimersdiseasereplicatesbin1andcluandnominatescugbp2ininteractionwithapoe |