Abstract
The 12 genome-wide association studies (GWAS) published to-date for late-onset Alzheimer's disease (LOAD) have identified over 40 candidate LOAD risk modifiers, in addition to apolipoprotein (APOE) e4.A few of these novel LOAD candidate genes, namely BIN1, CLU, CR1, EXOC3L2 and PICALM, have shown consistent replication, and are thus credible LOAD susceptibility genes. To evaluate other promising LOAD candidate genes, we have added data from our large, case-control series (n = 5,043) to meta-analyses of all published follow-up case-control association studies for six LOAD candidate genes that have shown significant association across multiple studies (TNK1, GAB2, LOC651924, GWA-14q32.13, PGBD1 and GALP) and for an additional nine previously suggested candidate genes. Meta-analyses remained significant at three loci after addition of our data: GAB2 (OR = 0.78, p = 0.007), LOC651924 (OR = 0.91, p =0.01) and TNK1 (OR = 0.92, p = 0.02). Breslow-Day tests revealed significant heterogeneity between studies for GAB2 (p<0.0001) and GWA-14q32.13 (p = 0.006). We have also provided suggestive evidence that PGBD1 (p = 0.04) and EBF3 (p = 0.03) are associated with age-at-onset of LOAD. Finally, we tested for interactions between these 15 genes, APOE e4 and the five novel LOAD genes BIN1, CLU, CR1, EXOC3L2 and PICALM but none were significant after correction for multiple testing. Overall, this large, independent follow-up study for 15 of the top LOAD candidate genes provides support for GAB2 and LOC651924 (6q24.1) as risk modifiers of LOAD and novel associations between PGBD1 and EBF3 with age-at-onset.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 273-282 |
| Number of pages | 10 |
| Journal | Human Genetics |
| Volume | 129 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2011 |
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ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
Cite this
Investigation of 15 of the top candidate genes for late-onset Alzheimer's disease. / Belbin, Olivia; Carrasquillo, Minerva M; Crump, Michael; Culley, Oliver J.; Hunter, Talisha A.; Ma, Li; Bisceglio, Gina; Zou, Fanggeng; Allen, Mariet; Dickson, Dennis W; Graff Radford, Neill R; Petersen, Ronald Carl; Morgan, Kevin; Younkin, Steven G.
In: Human Genetics, Vol. 129, No. 3, 03.2011, p. 273-282.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Investigation of 15 of the top candidate genes for late-onset Alzheimer's disease
AU - Belbin, Olivia
AU - Carrasquillo, Minerva M
AU - Crump, Michael
AU - Culley, Oliver J.
AU - Hunter, Talisha A.
AU - Ma, Li
AU - Bisceglio, Gina
AU - Zou, Fanggeng
AU - Allen, Mariet
AU - Dickson, Dennis W
AU - Graff Radford, Neill R
AU - Petersen, Ronald Carl
AU - Morgan, Kevin
AU - Younkin, Steven G
PY - 2011/3
Y1 - 2011/3
N2 - The 12 genome-wide association studies (GWAS) published to-date for late-onset Alzheimer's disease (LOAD) have identified over 40 candidate LOAD risk modifiers, in addition to apolipoprotein (APOE) e4.A few of these novel LOAD candidate genes, namely BIN1, CLU, CR1, EXOC3L2 and PICALM, have shown consistent replication, and are thus credible LOAD susceptibility genes. To evaluate other promising LOAD candidate genes, we have added data from our large, case-control series (n = 5,043) to meta-analyses of all published follow-up case-control association studies for six LOAD candidate genes that have shown significant association across multiple studies (TNK1, GAB2, LOC651924, GWA-14q32.13, PGBD1 and GALP) and for an additional nine previously suggested candidate genes. Meta-analyses remained significant at three loci after addition of our data: GAB2 (OR = 0.78, p = 0.007), LOC651924 (OR = 0.91, p =0.01) and TNK1 (OR = 0.92, p = 0.02). Breslow-Day tests revealed significant heterogeneity between studies for GAB2 (p<0.0001) and GWA-14q32.13 (p = 0.006). We have also provided suggestive evidence that PGBD1 (p = 0.04) and EBF3 (p = 0.03) are associated with age-at-onset of LOAD. Finally, we tested for interactions between these 15 genes, APOE e4 and the five novel LOAD genes BIN1, CLU, CR1, EXOC3L2 and PICALM but none were significant after correction for multiple testing. Overall, this large, independent follow-up study for 15 of the top LOAD candidate genes provides support for GAB2 and LOC651924 (6q24.1) as risk modifiers of LOAD and novel associations between PGBD1 and EBF3 with age-at-onset.
AB - The 12 genome-wide association studies (GWAS) published to-date for late-onset Alzheimer's disease (LOAD) have identified over 40 candidate LOAD risk modifiers, in addition to apolipoprotein (APOE) e4.A few of these novel LOAD candidate genes, namely BIN1, CLU, CR1, EXOC3L2 and PICALM, have shown consistent replication, and are thus credible LOAD susceptibility genes. To evaluate other promising LOAD candidate genes, we have added data from our large, case-control series (n = 5,043) to meta-analyses of all published follow-up case-control association studies for six LOAD candidate genes that have shown significant association across multiple studies (TNK1, GAB2, LOC651924, GWA-14q32.13, PGBD1 and GALP) and for an additional nine previously suggested candidate genes. Meta-analyses remained significant at three loci after addition of our data: GAB2 (OR = 0.78, p = 0.007), LOC651924 (OR = 0.91, p =0.01) and TNK1 (OR = 0.92, p = 0.02). Breslow-Day tests revealed significant heterogeneity between studies for GAB2 (p<0.0001) and GWA-14q32.13 (p = 0.006). We have also provided suggestive evidence that PGBD1 (p = 0.04) and EBF3 (p = 0.03) are associated with age-at-onset of LOAD. Finally, we tested for interactions between these 15 genes, APOE e4 and the five novel LOAD genes BIN1, CLU, CR1, EXOC3L2 and PICALM but none were significant after correction for multiple testing. Overall, this large, independent follow-up study for 15 of the top LOAD candidate genes provides support for GAB2 and LOC651924 (6q24.1) as risk modifiers of LOAD and novel associations between PGBD1 and EBF3 with age-at-onset.
UR - http://www.scopus.com/inward/record.url?scp=79953752763&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953752763&partnerID=8YFLogxK
U2 - 10.1007/s00439-010-0924-2
DO - 10.1007/s00439-010-0924-2
M3 - Article
C2 - 21132329
AN - SCOPUS:79953752763
VL - 129
SP - 273
EP - 282
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 3
ER -