Transethnic genome-wide scan identifies novel Alzheimer's disease loci
ALZHEIMERS & DEMENTIA
Authors: Jun, Gyungah R.; Chung, Jaeyoon; Mez, Jesse; Barber, Robert; Beecham, Gary W.; Bennett, David A.; Buxbaum, Joseph D.; Byrd, Goldie S.; Carrasquillo, Minerva M.; Crane, Paul K.; Cruchaga, Carlos; De Jager, Philip; Ertekin-Taner, Nilufer; Evans, Denis; Fallin, M. Danielle; Foroud, Tatiana M.; Friedland, Robert P.; Goate, Alison M.; Graff-Radford, Neill R.; Hendrie, Hugh; Hall, Kathleen S.; Hamilton-Nelson, Kara L.; Inzelberg, Rivka; Kamboh, M. Ilyas; Kauwe, John S. K.; Kukull, Walter A.; Kunkle, Brian W.; Kuwano, Ryozo; Larson, Eric B.; Logue, Mark W.; Manly, Jennifer J.; Martin, Eden R.; Montine, Thomas J.; Mukherjee, Shubhabrata; Naj, Adam; Reiman, Eric M.; Reitz, Christiane; Sherva, Richard; St George-Hyslop, Peter H.; Thornton, Timothy; Younkin, Steven G.; Vardarajan, Badri N.; Wang, Li-San; Wendlund, Jens R.; Winslow, Ashley R.; Haines, Jonathan; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard; Lunetta, Kathryn L.; Farrer, Lindsay A.
Abstract
Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)based tests (P < 5 x 10(-8)) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE epsilon 4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 x 10(-6)) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 x 10(-6)). Discussion: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci. (C) 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
Expression, cellular distribution and protein binding of the glioma amplified sequence (GAS41), a highly conserved putative transcription factor
ONCOGENE
Authors: Munnia, A; Schutz, N; Romeike, BFM; Maldener, E; Glass, B; Maas, R; Nastainczyk, W; Feiden, W; Fischer, U; Meese, E
Abstract
The glioma amplified sequence 41 (GAS41) was previously isolated by microdissection mediated cDNA capture from the glioblastoma multiforme cell line TX3868 and shown to be frequently amplified in human gliomas. We determined the complete cDNA sequence of the GAS41 gene, demonstrated that the GAS41 protein is evolutionarily conserved, specifically at the N-terminus, and identified the yeast transcription factor tf2f domain within the GAS41 sequence. A human multiple-tissue Northern blot revealed ubiquitous expression of GAS41 with the highest expression in human brain. After generating polyclonal antibodies we found GAS41 protein expression in the nucleus of the TX3868 cell line by Western blot analysis and immunofluorescence microscopy. The nuclear localization was confirmed for several human tumors including gliomas of different grades of malignancy. In neuroblastoma however, GAS41 was found in the nucleoli but not in the nucleoplasm. Yeast two-hybrid screening of the TX3868 cell line identified the nuclear mitotic apparatus protein (NuMA), the KIAA1009 protein, and prefoldin subunit 1 (PFDN1) as potential interacting partners of GAS41. We generated a polyclonal antibody against the KIAA1009 protein and we demonstrated that the KIAA1009 protein is a nuclear protein, which appears to be co-localized with the GAS41 protein and NuMA.