caa a22 4500 445861606 CHVBK 20180317145445.0 cr unu---uuuuu 170323e20110301xx s 000 0 eng 10.1007/s00439-010-0924-2 doi (NATIONALLICENCE)springer-10.1007/s00439-010-0924-2 Investigation of 15 of the top candidate genes for late-onset Alzheimer's disease [Elektronische Daten] [Olivia Belbin, Minerva Carrasquillo, Michael Crump, Oliver Culley, Talisha Hunter, Li Ma, Gina Bisceglio, Fanggeng Zou, Mariet Allen, Dennis Dickson, Neill Graff-Radford, Ronald Petersen, Kevin Morgan, Steven Younkin] 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) ε4. 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 ε4 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. The Author(s), 2010 Belbin Olivia Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Carrasquillo Minerva Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Crump Michael Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Culley Oliver Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Hunter Talisha Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Ma Li Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Bisceglio Gina Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Zou Fanggeng Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Allen Mariet Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Dickson Dennis Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Graff-Radford Neill Department of Neurology, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Petersen Ronald Department of Neurology and the Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, 55905, Rochester, MN, USA aut Morgan Kevin Human Genetics, School of Molecular Medical Sciences, University Hospital, Queen's Medical Centre, NG7 2UH, Nottingham, UK aut Younkin Steven Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut Human Genetics Springer-Verlag 129/3(2011-03-01), 273-282 0340-6717 129:3<273 2011 129 439 https://doi.org/10.1007/s00439-010-0924-2 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-010-0924-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Belbin Olivia Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Carrasquillo Minerva Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Crump Michael Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Culley Oliver Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Hunter Talisha Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Ma Li Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Bisceglio Gina Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Zou Fanggeng Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Allen Mariet Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Dickson Dennis Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Graff-Radford Neill Department of Neurology, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 700 1- Petersen Ronald Department of Neurology and the Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, 55905, Rochester, MN, USA aut NATIONALLICENCE 700 1- Morgan Kevin Human Genetics, School of Molecular Medical Sciences, University Hospital, Queen's Medical Centre, NG7 2UH, Nottingham, UK aut NATIONALLICENCE 700 1- Younkin Steven Department of Neuroscience, Mayo Clinic College of Medicine, 32224, Jacksonville, FL, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/3(2011-03-01), 273-282 0340-6717 129:3<273 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer