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 C.
AU - Morgan, Kevin
AU - Younkin, Steven G.
N1 - Funding Information:
Acknowledgments Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD) were used in this study. We thank contributors, including the Alzheimer’s Disease Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. This work was supported by grants from the US National Institutes of Health, NIA R01 AG18023 (N.R.G.-R., Steven G. Younkin); Mayo Alzheimer’s Disease Research Center, P50 AG16574 (R.C.P., D.W.D., N.R.G.-R., Steven G. Younkin); Mayo Alzheimer’s Disease Patient Registry, U01 AG06576 (R.C.P.); and US National Institute on Aging, AG25711, AG17216, AG03949 (D.W.D.). Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24AG21886) awarded by the National Institute on Aging (NIA), were used in this study. This project was also generously supported by the Robert and Clarice Smith Postdoctoral Fellowship (M.M.C.); Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program (R.C.P., D.W.D., N.R.G.-R.; Steven G. Younkin) and by the Palumbo Professorship in Alzheimer’s Disease Research (Steven G. Younkin). K.M. is funded by the Alzheimer’s Research Trust and the Big Lottery Fund
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.
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U2 - 10.1007/s00439-010-0924-2
DO - 10.1007/s00439-010-0924-2
M3 - Article
C2 - 21132329
AN - SCOPUS:79953752763
SN - 0340-6717
VL - 129
SP - 273
EP - 282
JO - Human Genetics
JF - Human Genetics
IS - 3
ER -