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Your search keyword '"Carrasquillo, Minerva M"' showing total 16 results
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16 results on '"Carrasquillo, Minerva M"'

1. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N, Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E, Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tárraga L, Maier W, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YAL, Scheltens P, Gasser T, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TIA, Heutink P, Sánchez-Juan P, Posthuma D, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, and Holstege H

Subjects
Alleles, Alzheimer Disease genetics, Amyotrophic Lateral Sclerosis genetics, Brain immunology, Brain metabolism, Brain pathology, Frontotemporal Dementia genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lewy Body Disease genetics, Microglia metabolism, Multiple Sclerosis genetics, Neuroimaging, Parkinson Disease genetics, Risk, Dementia genetics, Longevity genetics, Mutation, Phospholipase C gamma genetics
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019
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2. Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

Author

Xicota, Laura, Cosentino, Stephanie, Vardarajan, Badri, Mayeux, Richard, Perls, Thomas T, Andersen, Stacy L, Zmuda, Joseph M, Thyagarajan, Bharat, Yashin, Anatoli, Wojczynski, Mary K, Krinsky‐McHale, Sharon, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark E, Schupf, Nicole, Lee, Joseph H, Barral, Sandra, Study, the Long‐Life Family, Abner, Erin, Adams, Perrie M, Aguirre, Alyssa, Albert, Marilyn S, Albin, Roger L, Allen, Mariet, Alvarez, Lisa, Andrews, Howard, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Ayres, Gayle, Barber, Robert C, Barnes, Lisa L, Bartlett, Jackie, Beach, Thomas G, Becker, James T, Beecham, Gary W, Benchek, Penelope, Bennett, David A, Bertelson, John, Biber, Sarah A, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Brewer, James B, Burke, James R, Burns, Jeffrey M, Bush, William S, Buxbaum, Joseph D, Byrd, Goldie, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Chan, Kwun C, Chasse, Scott, Chen, Yen‐Chi, Chesselet, Marie‐Francoise, Chin, Nathaniel A, Chui, Helena C, Chung, Jaeyoon, Craft, Suzanne, Crane, Paul K, Cranney, Marissa, Cruchaga, Carlos, Cuccaro, Michael L, Culhane, Jessica, Cullum, C Munro, Darby, Eveleen, Davis, Barbara, De Jager, Philip L, DeCarli, Charles, DeToledo, John C, Dickson, Dennis W, Dobbins, Nic, Duara, Ranjan, Ertekin‐Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallin, Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Farrell, John, Farrer, Lindsay A, Fernandez‐Hernandez, Victoria, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gamboa, Adriana, Gauthreaux, Kathryn M, Gefen, Tamar, Geschwind, Daniel H, Ghetti, Bernardino, and Gilbert, John R

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Dementia, Alzheimer's Disease, Genetics, Aging, Brain Disorders, Acquired Cognitive Impairment, Human Genome, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, Genetic Predisposition to Disease, Genome-Wide Association Study, Microtubule-Associated Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, genetic risk, late-onset Alzheimer's disease, microtubule protein, MTUS2 gene, whole genome sequence, Long‐Life Family Study, Alzheimer's Disease Genetic Consortium, Alzheimer's Biomarkers Consortium‐Down Syndrome, late‐onset Alzheimer's disease, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Published
2024

3. Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Parkinson's Disease, Genetics, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

4. Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases

Author

Allen, Mariet, Wang, Xue, Burgess, Jeremy D, Watzlawik, Jens, Serie, Daniel J, Younkin, Curtis S, Nguyen, Thuy, Malphrus, Kimberly G, Lincoln, Sarah, Carrasquillo, Minerva M, Ho, Charlotte, Chakrabarty, Paramita, Strickland, Samantha, Murray, Melissa E, Swarup, Vivek, Geschwind, Daniel H, Seyfried, Nicholas T, Dammer, Eric B, Lah, James J, Levey, Allan I, Golde, Todd E, Funk, Cory, Li, Hongdong, Price, Nathan D, Petersen, Ronald C, Graff‐Radford, Neill R, Younkin, Steven G, Dickson, Dennis W, Crook, Julia R, Asmann, Yan W, and Ertekin‐Taner, Nilüfer

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Aging, Acquired Cognitive Impairment, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Neurodegenerative, Alzheimer's Disease, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Alzheimer Disease, Brain, Cohort Studies, Computational Biology, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Male, Myelin Sheath, Neurons, Supranuclear Palsy, Progressive, Transcriptome, Proteinopathies, Alzheimer's disease, Progressive supranuclear palsy, Myelination, Coexpression networks, Temporal cortex, Cerebellum, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionComparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways.MethodsWe analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects.ResultsWe identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in both AD and PSP, when compared with control TCX samples.DiscussionDownregulation of myelination networks may underlie both PSP and AD pathophysiology, but may be more pronounced in PSP. These data also highlight conservation of transcriptional networks across brain regions and the influence of cell type changes on these networks.

Published
2018

5. Transethnic genome‐wide scan identifies novel Alzheimer's disease loci

Author

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 SK, 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, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Barmada, Michjael M, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Green, Robert C, and Growdon, John H

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Genetics, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aging, Human Genome, Prevention, Dementia, Alzheimer's Disease, Biotechnology, Brain Disorders, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Apolipoprotein E4, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Heparin-binding EGF-like Growth Factor, Humans, Membrane Glycoproteins, Molecular Chaperones, NFI Transcription Factors, Peroxisomal Bifunctional Enzyme, Polymorphism, Single Nucleotide, Receptors, GABA, Alzheimer's Disease Genetics Consortium, APOE interaction, Alzheimer's disease, Genome-wide association, Transethnic, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionGenetic 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.MethodsWe 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.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P

Published
2017

6. ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Author

Cukier, Holly N, Kunkle, Brian W, Vardarajan, Badri N, Rolati, Sophie, Hamilton-Nelson, Kara L, Kohli, Martin A, Whitehead, Patrice L, Dombroski, Beth A, Van Booven, Derek, Lang, Rosalyn, Dykxhoorn, Derek M, Farrer, Lindsay A, Cuccaro, Michael L, Vance, Jeffery M, Gilbert, John R, Beecham, Gary W, Martin, Eden R, Carney, Regina M, Mayeux, Richard, Schellenberg, Gerard D, Byrd, Goldie S, Haines, Jonathan L, Pericak-Vance, Margaret A, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barmada, M Michael, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cai, Guiqing, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fallin, M Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Go, Rodney CP, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Griffith, Patrick, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Haroutunian, Vahram, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, and Jin, Lee-Way

Subjects
Biological Sciences, Genetics, Human Genome, Neurodegenerative, Neurosciences, Dementia, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Alzheimer's Disease, Clinical Research, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Genetics Consortium, Clinical sciences
Abstract

ObjectiveTo identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.MethodsCustom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.ResultsA 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.ConclusionsThis common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Published
2016

7. Assessment of the genetic variance of late-onset Alzheimer's disease

Author

Ridge, Perry G, Hoyt, Kaitlyn B, Boehme, Kevin, Mukherjee, Shubhabrata, Crane, Paul K, Haines, Jonathan L, Mayeux, Richard, Farrer, Lindsay A, Pericak-Vance, Margaret A, Schellenberg, Gerard D, Kauwe, John SK, Consortium, Alzheimer's Disease Genetics, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barber, Robert C, Barmada, Michael M, Barnes, Lisa L, Barral, Sandra, Beach, Thomas G, Becker, James T, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Ertekin-Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Hardy, John, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M Ilyas, Karydas, Anna, Katz, Mindy J, Kaye, Jeffrey A, Kim, Ronald, and Kowall, Neil W

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Neurodegenerative, Dementia, Alzheimer's Disease, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Human Genome, Brain Disorders, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Datasets as Topic, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Membrane Glycoproteins, Netrin Receptors, Polymorphism, Single Nucleotide, Receptors, Cell Surface, Receptors, Immunologic, Risk, Alzheimer's Disease Genetics Consortium, Alzheimer's disease, Genetic variance, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Published
2016

8. Novel late-onset Alzheimer disease loci variants associate with brain gene expression.

Author

Allen, Mariet, Zou, Fanggeng, Chai, High Seng, Younkin, Curtis S, Crook, Julia, Pankratz, V Shane, Carrasquillo, Minerva M, Rowley, Christopher N, Nair, Asha A, Middha, Sumit, Maharjan, Sooraj, Nguyen, Thuy, Ma, Li, Malphrus, Kimberly G, Palusak, Ryan, Lincoln, Sarah, Bisceglio, Gina, Georgescu, Constantin, Schultz, Debra, Rakhshan, Fariborz, Kolbert, Christopher P, Jen, Jin, Haines, Jonathan L, Mayeux, Richard, Pericak-Vance, Margaret A, Farrer, Lindsay A, Schellenberg, Gerard D, Petersen, Ronald C, Graff-Radford, Neill R, Dickson, Dennis W, Younkin, Steven G, Ertekin-Taner, Nilüfer, Alzheimer's Disease Genetics Consortium (ADGC), Apostolova, Liana G, Arnold, Steven E, Baldwin, Clinton T, Barber, Robert, Barmada, Michael M, Beach, Thomas, Beecham, Gary W, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Buros, Jacqueline, Buxbaum, Joseph D, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlson, Chris S, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cotman, Carl W, Crane, Paul K, Cruchaga, Carlos, Cummings, Jeffrey L, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Diaz-Arrastia, Ramon, Dick, Malcolm, Dombroski, Beth A, Duara, Ranjan, Ellis, William D, Evans, Denis, Faber, Kelley M, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew, Galasko, Douglas R, Gallins, Paul J, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Gilman, Sid, Giordani, Bruno, Glass, Jonathan D, Goate, Alison M, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hardy, John, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, and Huentelman, Matthew J

Subjects
Alzheimer's Disease Genetics Consortium, Temporal Lobe, Humans, Alzheimer Disease, Genetic Predisposition to Disease, RNA, Autopsy, Linear Models, Risk Factors, Gene Expression, Brain Chemistry, Genotype, Gene Dosage, Polymorphism, Single Nucleotide, Alleles, Aged, Female, Male, Apolipoprotein E4, Clinical Research, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, Human Genome, Neurosciences, Dementia, Neurodegenerative, Genetics, Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aetiology, 2.1 Biological and endogenous factors, Neurological, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveRecent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression.MethodsWe measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies (∼400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes ±100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs ±100 kb of their location and tested for cis-associations.ResultsCLU rs11136000 (p = 7.81 × 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 × 10(-4)-1.86 × 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 × 10(-5)-9.09 × 10(-9)), some of which also associate with AD risk (p = 2.64 × 10(-2)-6.25 × 10(-5)).ConclusionsCLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.

Published
2012

9. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Author

Naj, Adam C, Jun, Gyungah, Beecham, Gary W, Wang, Li-San, Vardarajan, Badri Narayan, Buros, Jacqueline, Gallins, Paul J, Buxbaum, Joseph D, Jarvik, Gail P, Crane, Paul K, Larson, Eric B, Bird, Thomas D, Boeve, Bradley F, Graff-Radford, Neill R, De Jager, Philip L, Evans, Denis, Schneider, Julie A, Carrasquillo, Minerva M, Ertekin-Taner, Nilufer, Younkin, Steven G, Cruchaga, Carlos, Kauwe, John SK, Nowotny, Petra, Kramer, Patricia, Hardy, John, Huentelman, Matthew J, Myers, Amanda J, Barmada, Michael M, Demirci, F Yesim, Baldwin, Clinton T, Green, Robert C, Rogaeva, Ekaterina, George-Hyslop, Peter St, Arnold, Steven E, Barber, Robert, Beach, Thomas, Bigio, Eileen H, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Carlson, Chris S, Carney, Regina M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cotman, Carl W, Cummings, Jeffrey L, DeCarli, Charles, DeKosky, Steven T, Diaz-Arrastia, Ramon, Dick, Malcolm, Dickson, Dennis W, Ellis, William G, Faber, Kelley M, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Ganguli, Mary, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Gilman, Sid, Giordani, Bruno, Glass, Jonathan D, Growdon, John H, Hamilton, Ronald L, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, Jin, Lee-Way, Johnson, Nancy, Karlawish, Jason, Karydas, Anna, Kaye, Jeffrey A, Kim, Ronald, Koo, Edward H, Kowall, Neil W, Lah, James J, Levey, Allan I, Lieberman, Andrew P, Lopez, Oscar L, Mack, Wendy J, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, and Miller, Bruce L

Subjects
Biological Sciences, Genetics, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Alzheimer's Disease, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Aging, 2.1 Biological and endogenous factors, Neurological, Adaptor Proteins, Signal Transducing, Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Cohort Studies, Cytoskeletal Proteins, Databases, Genetic, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Membrane Proteins, Multigene Family, Polymorphism, Single Nucleotide, Receptor, EphA1, Sialic Acid Binding Ig-like Lectin 3, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Published
2011

10. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank), EADB (Alzheimer Disease European DNA biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
Aging, amyotrophic lateral sclerosis, Parkinson's disease, Dementia with Lewy bodies, progressive suprauclear palsy, Neurodegenerative, Neurodegenerative disease, Alzheimer's Disease, multiple sclerosis, frontotemporal dementia, DESGESCO (Dementia Genetics Spanish Consortium), EADB, RiMod-FTD, 2.1 Biological and endogenous factors, Aetiology, Alzheimer's Disease Related Dementias (ADRD), IPDGC, Brain, Parkinson Disease, Phospholipase C Gamma 2, dementia with Lewy-bodies, Neurological, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Microglia, Alzheimer’s disease, Lewy Body Disease, Risk, Longevity, Clinical Sciences, Neuroimaging, PLCG2, Rare Diseases, IFGC (International FTD-Genomics Consortium), Alzheimer Disease, Clinical Research, Acquired Cognitive Impairment, Genetics, Humans, Genetic Predisposition to Disease, Alleles, Neurology & Neurosurgery, Phospholipase C gamma, Progressive supranuclear palsy, Prevention, Netherlands Brain Bank, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Mutation, Parkinson’s disease, Dementia, Genome-Wide Association Study
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

Published
2019

11. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Author

Escott-Price, Valentina, Bellenguez, Céline, DeStefano, Anita L, Galimberti, Daniela, Scarpini, Elio, Bonuccelli, Ubaldo, Mancuso, Michelangelo, Siciliano, Gabriele, Moebus, Susanne, Mecocci, Patrizia, Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald, Lambert, Jean-Charles, Pilotto, Alberto, Frank-García, Ana, Panza, Francesco, Solfrizzi, Vincenzo, Caffarra, Paolo, Nacmias, Benedetta, Perry, William, Mayhaus, Manuel, Lannfelt, Lars, Hakonarson, Hakon, Ibrahim-Verbaas, Carla A, Pichler, Sabrina, Carrasquillo, Minerva M, Ingelsson, Martin, Beekly, Duane, Alvarez, Victoria, Zou, Fanggeng, Valladares, Otto, Younkin, Steven G, Coto, Eliecer, Hamilton-Nelson, Kara L, Naj, Adam C, Gu, Wei, Razquin, Cristina, Pastor, Pau, Mateo, Ignacio, Owen, Michael J, Faber, Kelley M, Jonsson, Palmi V, Combarros, Onofre, O'Donovan, Michael C, Cantwell, Laura B, Sims, Rebecca, Soininen, Hilkka, Blacker, Deborah, Mead, Simon, Mosley, Thomas H, Bennett, David A, Harris, Tamara B, Fratiglioni, Laura, Holmes, Clive, de Bruijn, Renee F A G, Passmore, Peter, Jun, Gyungah, Montine, Thomas J, Bettens, Karolien, Rotter, Jerome I, Brice, Alexis, Morgan, Kevin, Foroud, Tatiana M, Kukull, Walter A, Hannequin, Didier, Powell, John F, Nalls, Michael A, Bis, Joshua C, Ritchie, Karen, Lunetta, Kathryn L, Kauwe, John S K, Boerwinkle, Eric, Riemenschneider, Matthias, Boada, Mercè, Hiltunen, Mikko, Martin, Eden R, Schmidt, Reinhold, Rujescu, Dan, Beecham, Gary W, Dartigues, Jean-François, Mayeux, Richard, Tzourio, Christophe, Hofman, Albert, Nöthen, Markus M, Graff, Caroline, Psaty, Bruce M, Haines, Jonathan L, Lathrop, Mark, Pericak-Vance, Margaret A, Grenier-Boley, Benjamin, Launer, Lenore J, Van Broeckhoven, Christine, Farrer, Lindsay A, van Duijn, Cornelia M, Ramirez, Alfredo, Seshadri, Sudha, Schellenberg, Gerard D, Amouyel, Philippe, Williams, Julie, Study, Cardiovascular Health, Russo, Giancarlo, Olson, Jean, Kronmal, Richard, Arnold, Alice M, Robbins, John, Carlson, Michelle, Burke, Gregory, Kuller, Lewis H, Tracy, Russell, Gottdiener, John, Prineas, Ronald, Wang, Li-San, Thornton-Wells, Tricia A, Becker, James T, Enright, Paul, Klein, Ronald, O'Leary, Daniel H, Denning, Nicola, Smith, Albert V, Chouraki, Vincent, Thomas, Charlene, Ikram, M Arfan, Zelenika, Diana, Vardarajan, Badri N, Kamatani, Yoichiro, Lin, Chiao-Feng, Choi, Seung-Hoan, Schmidt, Helena, Kunkle, Brian, Dunstan, Melanie L, Vronskaya, Maria, Consortium, United Kingdom Brain Expression, Johnson, Andrew D, Ruiz, Agustin, Bihoreau, Marie-Thérèse, Reitz, Christiane, Pasquier, Florence, Harold, Denise, Hollingworth, Paul, Hanon, Olivier, Fitzpatrick, Annette L, Buxbaum, Joseph D, Campion, Dominique, Crane, Paul K, Baldwin, Clinton, Becker, Tim, Gudnason, Vilmundur, Cruchaga, Carlos, Jones, Lesley, Craig, David, Amin, Najaf, Berr, Claudine, Lopez, Oscar L, De Jager, Philip L, Deramecourt, Vincent, Johnston, Janet A, Evans, Denis, Lovestone, Simon, Letenneur, Luc, Holmans, Peter, Hernández, Isabel, Rubinsztein, David C, Eiriksdottir, Gudny, Sleegers, Kristel, Goate, Alison M, Fiévet, Nathalie, Huentelman, Matthew J, Gill, Michael, Brown, Kristelle, Kamboh, M Ilyas, Gerrish, Amy, Keller, Lina, Barberger-Gateau, Pascale, McGuinness, Bernadette, Larson, Eric B, Myers, Amanda J, Dufouil, Carole, Todd, Stephen, Wallon, David, Love, Seth, Rogaeva, Ekaterina, Vedernikov, Alexey, Gallacher, John, George-Hyslop, Peter St, Clarimon, Jordi, Lleo, Alberto, Bayer, Anthony, Tsuang, Debby W, Yu, Lei, Tsolaki, Magda, Bossù, Paola, Spalletta, Gianfranco, Richards, Alexander, Proitsi, Petra, Collinge, John, Sorbi, Sandro, Garcia, Florentino Sanchez, Fox, Nick C, Hardy, John, Naranjo, Maria Candida Deniz, Bosco, Paolo, Clarke, Robert, Brayne, Carol, Neurology, Radiology & Nuclear Medicine, Epidemiology, UAM. Departamento de Medicina, Universidad de Cantabria, and United Kingdom Brain Expression

Subjects
Genetics and Molecular Biology (all), Alzheimer Disease, Carrier Proteins, Case-Control Studies, Genome-Wide Association Study, Heat-Shock Proteins, Humans, Polymorphism, Single Nucleotide, Receptors, Antigen, B-Cell, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), Medicine (all), genotype, Medizin, lcsh:Medicine, genetics [Alzheimer Disease], Genome-wide association study, Genomics--Data processing, Disease, genetics [Carrier Proteins], Biochemistry, Alzheimer's disease, 0302 clinical medicine, genetics [Heat-Shock Proteins], genetics [Receptors, Antigen, B-Cell], Disease susceptibility--Genetic aspects, Receptors, Pathology, Medicine and Health Sciences, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, pathogenesis, Genomics, Single Nucleotide, Neurology, Antigen, Physical Sciences, protein degradation, Alzheimer disease, Engineering sciences. Technology, Statistics (Mathematics), Research Article, medicine.medical_specialty, Medicina, Geriatrik, Late onset, Biostatistics, Biology, Medical sciences, 03 medical and health sciences, Molecular genetics, Mental Health and Psychiatry, Genome-Wide Association Studies, medicine, chromosome 8, Dementia, ddc:610, Polymorphism, QH426, Genetic Association Studies, 030304 developmental biology, TP53INP1 protein, human, lcsh:R, Case-control study, B-Cell, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, medicine.disease, R1, Human genetics, immune system, Geriatrics, FOS: Biological sciences, Alzheimer's disease--Genetic aspects, RC0321, lcsh:Q, Mathematics, 030217 neurology & neurosurgery
Abstract

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease, The i-Select chips was funded by the French National Foundation on Alzheimer's disease and related disorders. The French National Fondation on Alzheimer's disease and related disorders supported several I-GAP meetings and communications. Data management involved the Centre National de Génotypage,and was supported by the Institut Pasteur de Lille, Inserm, FRC (fondation pour la recherche sur le cerveau) and Rotary. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) and by the LABEX GENMED grant (Medical Genomics). The French National Foundation on Alzheimer's disease and related disorders and the Alzheimer's Association (Chicago, Illinois) grant supported IGAP in-person meetings, communication and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses. EADI The authors thank Dr. Anne Boland (CNG) for her technical help in preparing the DNA samples for analyses. This work was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Génotypage. The Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM «Cohortes et collections de données biologiques» programme. Lille Génopôle received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille. Belgium sample collection: The patients were clinically and pathological characterized by the neurologists Sebastiaan Engelborghs, Rik Vandenberghe and Peter P. De Deyn, and in part genetically by Caroline Van Cauwenberghe, Karolien Bettens and Kristel Sleegers. Research at the Antwerp site is funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Foundation Alzheimer Research (SAO-FRA), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund, Belgium. Karolien Bettens is a postdoctoral fellow of the FWO. The Antwerp site authors thank the personnel of the VIB Genetic Service Facility, the Biobank of the Institute Born-Bunge and the Departments of Neurology and Memory Clinics at the Hospital Network Antwerp and the University Hospitals Leuven. Finish sample collection: Financial support for this project was provided by the Health Research Council of the Academy of Finland, EVO grant 5772708 of Kuopio University Hospital, and the Nordic Centre of Excellence in Neurodegeneration. Italian sample collections: the Bologna site (FL) obtained funds from the Italian Ministry of research and University as well as Carimonte Foundation. The Florence site was supported by grant RF-2010-2319722, grant from the the Cassa di Risparmio di Pistoia e Pescia (Grant 2012) and the Cassa di Risparmio di Firenze (Grant 2012). The Milan site was supported by a grant from the «fondazione Monzino». The authors thank the expert contribution of Mr. Carmelo Romano. The Roma site received financial support from Italian Ministry of Health, Grant RF07-08 and RC08-09-10-11-12. The Pisa site is grateful to Dr. Annalisa LoGerfo for her technical assistance in the DNA purification studies. Spanish sample collection: the Madrid site (MB) was supported by grants of the Ministerio de Educación y Ciencia and the Ministerio de Sanidad y Consumo (Instituto de Salud Carlos III), and an institutional grant of the Fundación Ramón Areces to the CBMSO. The authors thank I. Sastre and Dr. A. Martínez-García for the preparation and control of the DNA collection, and Drs. P. Gil and P. Coria for their cooperation in the cases/controls recruitment. The authors are grateful to the Asociación de Familiares de Alzheimer de Madrid (AFAL) for continuous encouragement and help. Swedish sample collection: Financially supported in part by the Swedish Brain Power network, the Marianne and Marcus Wallenberg Foundation, the Swedish Research Council (521-2010-3134), the King Gustaf V and Queen Victoria's Foundation of Freemasons, the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institutet, the Swedish Brain Foundation and the Swedish Alzheimer Foundation. CHARGE AGES: The AGES-Reykjavik Study is funded by National Institutes of Health (NIH) contract N01-AG-12100 (National Institute on Aging (NIA) with contributions from the National Eye Institute, National Institute on Deafness and Other Communication Disorders and National Heart, Lung, and Blood Institute (NHLBI)), the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). ASPS/PRODEM: The Austrian Stroke Prevention Study and The Prospective Dementia Register of the Austrian Alzheimer Society was supported by The Austrian Science Fond (FWF) grant number P20545-P05 (H. Schmidt) and P13180; The Austrian Alzheimer Society; The Medical University of Graz. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and HHSN268200960009C; and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG023629, AG15928, AG20098, AG027058 and AG033193 (Seshadri) from the NIA. A full list of CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS): This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with A_ymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study as also supported by grants from the National Institute on Aging: AG08122 and AG033193 (Seshadri). Drs. Seshadri and DeStefano were also supported by additional grants from the National Institute on Aging: (R01 AG16495; AG031287, AG033040), the National Institute of Neurological Disorders and Stroke (R01 NS17950), and the National Heart, Lung and Blood Institute (U01 HL096917, HL093029 and K24HL038444, RC2-HL102419 and UC2 HL103010. Fundació ACE would like to thank patients and controls who participated in this project. This work has been funded by the Fundación Alzheimur (Murcia), the Ministerio de Educación y Ciencia (PCT-010000-2007-18), (DEX-580000-2008-4), (Gobierno de España), Corporación Tecnológica de Andalucía (08/211) and Agencia IDEA (841318) (Consejería de Innovación, Junta de Andalucía). The authors thank to Ms. Trinitat Port-Carbó and her family for their generous support of Fundació ACE research programs. The Rotterdam Study: The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission;and the Municipality of Rotterdam; by grants from the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), Internationale Stichting Alzheimer Onderzoek, Hersenstichting Nederland, the Netherlands Genomics Initiative–Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging), the Seventh Framework Program (FP7/2007-2013), the ENGAGE project (grant agreement HEALTH-F4-2007-201413), MRACE-grant from the Erasmus Medical Center, the Netherlands Organization for Health Research and Development (ZonMW Veni-grant no. 916.13.054). ARIC: The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01- HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grants R01-HL087641, RC2-HL102419 (Boerwinkle, CHARGE-S), UC2 HL103010, U01-HL096917 (Mosley) and R01-HL093029; NHGRI contract U01- HG004402; and NIH contract HHSN268200625226C and NIA: R01 AG033193 (Seshadri). Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. GERAD Cardiff University was supported by the Wellcome Trust, Medical Research Council (MRC), Alzheimer's Research United Kingdom (ARUK) and the Welsh Government. ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester and Belfast. The Belfast group acknowledges support from the Alzheimer's Society, Ulster Garden Villages, N. Ireland R & D Office and the Royal College of Physicians/Dunhill Medical Trust. The MRC and Mercer's Institute for Research on Ageing supported the Trinity College group. DCR is a Wellcome Trust Principal Research fellow. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer's and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer's Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Centre and their work was supported by the NIHR Queen Square Dementia BRU. LASER-AD was funded by Lundbeck SA. The Bonn group would like to thank Dr. Heike Koelsch for her scientific support. The Bonn group was funded by the German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant number 01GI0102, 01GI0711, 01GI0420. The AgeCoDe study group was supported by the German Federal Ministry for Education and Research grants 01 GI 0710, 01 GI 0712, 01 GI 0713, 01 GI 0714, 01 GI 0715, 01 GI 0716, 01 GI 0717. The Homburg group was funded by the German Federal Ministry of Education and Research (BMBF): German National Genome Research Network (NGFN); Alzheimer's disease Integrated Genome Research Network; AD-IG: 01GS0465. Genotyping of the Bonn case-control sample was funded by the German centre for Neurodegenerative Diseases (DZNE), Germany. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. Harald Hampel was supported by a grant of the Katharina-Hardt-Foundation, Bad Homburg vor der Höhe, Germany. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. Jur. G.Schmidt, Chairman) and BMBF. Coriell Cell Repositories is supported by NINDS and the Intramural Research Program of the National Institute on Aging. The authors acknowledge use of genotype data from the 1958 Birth Cohort collection, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The Nottingham Group (KM) are supported by the Big Lottery. MRC CFAS is part of the consortium and data will be included in future analyses. ADGC The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, R01 AG041797; MIRAGE R01 AG025259; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, and UL1 RR029893; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG034504 to AJM, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. Marcelle Morrison-Bogorad, PhD., Tony Phelps, PhD and Walter Kukull PhD are thanked for helping to co-ordinate this collection. ADNI Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, Glaxo-SmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and by the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, K01 AG030514. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. The authors thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-o_cio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the United States Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. Peter St George-Hyslop is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health

Published
2014
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12. Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology

Author

Zou, Fanggeng, Belbin, Olivia, Petersen, Ronald C, disease, Genetic and Environmental Risk for Alzheimer’s, Morgan, Kevin, Younkin, Steven G, Harold, Denise, Sims, Rebecca, Gerrish, Amy, Chapman, Jade, Moskvina, Valentina, Abraham, Richard, Carrasquillo, Minerva M, Hollingworth, Paul, Hamshere, Marian, Pahwa, Jaspreet Singh, Dowzell, Kimberley, Williams, Amy, Jones, Nicola, Thomas, Charlene, Stretton, Alexandra, Morgan, Angharad, Williams, Kate, Culley, Oliver J, Lovestone, Simon, Powell, John, Proitsi, Petroula, Lupton, Michelle K, Brayne, Carol, Rubinsztein, David C, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Hunter, Talisha A, Brown, Kristelle, Passmore, Peter, Craig, David, McGuinness, Bernadette, Johnston, Janet A, Todd, Stephen, Holmes, Clive, Mann, David, Smith, A David, Love, Seth, Ma, Li, Kehoe, Patrick G, Hardy, John, Guerreiro, Rita, Singleton, Andrew, Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Bisceglio, Gina D, Heun, Reiner, Schürmann, Britta, Ramirez, Alfredo, Herold, Christine, Lacour, André, Drichel, Dmitriy, van den Bussche, Hendrik, Heuser, Isabella, Kornhuber, Johannes, Wiltfang, Jens, Allen, Mariet, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison, Kauwe, John S K, Cruchaga, Carlos, Nowotny, Petra, Morris, John C, Dickson, Dennis W, Mayo, Kevin, Livingston, Gill, Bass, Nicholas J, Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Nöthen, Markus M, Holmans, Peter, O'Donovan, Michael, Graff-Radford, Neill R, Owen, Michael J, Williams, Julie, and Wiltfang, Jens (Beitragende*r)

Subjects
Male, Pathology, Heredity, Medizin, lcsh:Medicine, Gene Expression, genetics [Alzheimer Disease], pathology [Alzheimer Disease], 0302 clinical medicine, Polymorphism (computer science), Risk Factors, genetics [Adaptor Proteins, Signal Transducing], Senile plaques, lcsh:Science, 0303 health sciences, Multidisciplinary, Temporal Lobe, Neurology, genetics [Polymorphism, Single Nucleotide], Medicine, Female, Alzheimer's disease, Research Article, medicine.medical_specialty, Genotypes, genetics [Genetic Loci], Biology, metabolism [RNA, Messenger], Polymorphism, Single Nucleotide, metabolism [Temporal Lobe], Cell Line, Molecular Genetics, 03 medical and health sciences, metabolism [Adaptor Proteins, Signal Transducing], genetics [RNA, Messenger], Genetic Heterogeneity, Apolipoproteins E, Meta-Analysis as Topic, Alzheimer Disease, genetics [Haplotypes], medicine, GAB2 protein, human, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, RNA, Messenger, Allele, Genetic Association Studies, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, Evolutionary Biology, Population Biology, Genetic heterogeneity, lcsh:R, Case-control study, Computational Biology, Neurofibrillary tangle, pathology [Temporal Lobe], Human Genetics, Epistasis, Genetic, Odds ratio, medicine.disease, R1, Haplotypes, Genetic Loci, Case-Control Studies, Postmortem Changes, Genetics of Disease, North America, Genetic Polymorphism, Epistasis, genetics [Apolipoproteins E], lcsh:Q, Dementia, 030217 neurology & neurosurgery, Population Genetics
Abstract

GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p

Published
2013
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13. Evaluating pathogenic dementia variants in posterior cortical atrophy.

Author

Carrasquillo, Minerva M., Barber, Imelda, Lincoln, Sarah J., Murray, Melissa E., Camsari, Gamze Balci, ul Ain. Khan, Qurat, Thuy Nguyen, Li Ma, Bisceglio, Gina D., Crook, Julia E., Younkin, Steven G., Dickson, Dennis W., Boeve, Bradley F., Graff-Radford, Neill R., Morgan, Kevin, and Ertekin-Taner, Nilüfer

Subjects
*DEMENTIA, *BIOLOGICAL variation, *CEREBRAL atrophy, *VISION disorders, *GENETIC mutation, *GENETICS of Alzheimer's disease, *PRESENILINS, *EXOMES
Abstract

Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX. [ABSTRACT FROM AUTHOR]

Published
2016
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14. Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer’s Disease Pathology

Author

Zou, Fanggeng, Belbin, Olivia, Carrasquillo, Minerva M., Culley, Oliver J., Hunter, Talisha A., Ma, Li, Bisceglio, Gina D., Allen, Mariet, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Morgan, Kevin, and Younkin, Steven G.

Subjects
SIGNAL recognition particle receptor, GENE expression, ALZHEIMER'S disease, CARRIER proteins, HETEROGENEITY, META-analysis
Abstract

GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer’s disease (LOAD) with reported odds ratios (ORs) ranging from 0.75–0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61–1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61–0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82–0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10−7−9.3×10−6). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = −0.34, p = 0.0006) and senile plaque counts (r = −0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = −0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level. [ABSTRACT FROM AUTHOR]

Published
2013
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15. Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, Aß, and Alzheimer's Disease.

Author

Carrasquillo, Minerva M., Belbin, Olivia, Fanggeng Zou, Allen, Mariet, Ertekin-Taner, Nilufer, Ansari, Morad, Wilcox, Samantha L., Kashino, Mariah R., Li Ma, Younkin, Linda H., Younkin, Samuel G., Younkin, Curtis S., Dincman, Toros A., Howard, Melissa E., Howell, Chanley C., Stanton, Chloe M., Watson, Christopher M., Crump, Michael, Vitart, Veronique, and Hayward, Caroline

Subjects
*INSULIN, *MESSENGER RNA, *ALZHEIMER'S disease, *DEMENTIA, *PRESENILE dementia, *NEUROSCIENCES, *GENE expression, *GENETIC regulation, *GENETIC polymorphisms
Abstract

Background: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD). Methodology/Principal Findings: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5x10-8, fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Aβ40 levels (β =20.124, p = 0.011) and total measured plasma Aβ levels (β =20.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association. Conclusions: Thus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Aβ40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect. [ABSTRACT FROM AUTHOR]

Published
2010
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16. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author

Van Der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, Van Den Akker, Erik, Hernández, Isabel, Van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, De Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, Van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA Biobank), EADB (Alzheimer Disease European DNA Biobank), IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium), RiMod-FTD (Risk And Modifying Factors In Fronto-Temporal Dementia), Netherlands Brain Bank (NBB), Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, Van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, Van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, De Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation In Frontotemporal Dementia And Alzheimer’s Disease) Study Group, Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, Van Der Flier, Wiesje M, and Holstege, Henne

Subjects
Lewy Body Disease, Risk, Multiple Sclerosis, Dementia with Lewy bodies, Longevity, Neuroimaging, Neurodegenerative disease, PLCG2, Alzheimer Disease, Humans, Genetic Predisposition to Disease, Alleles, Phospholipase C gamma, Progressive supranuclear palsy, Amyotrophic Lateral Sclerosis, Brain, Parkinson Disease, Phospholipase C Gamma 2, 3. Good health, Frontotemporal Dementia, Mutation, Parkinson’s disease, Dementia, Microglia, Alzheimer’s disease, Genome-Wide Association Study
Abstract

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

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