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2. Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain

Author

Fujita, Masashi, Gao, Zongmei, Zeng, Lu, McCabe, Cristin, White, Charles C., Ng, Bernard, Green, Gilad Sahar, Rozenblatt-Rosen, Orit, Phillips, Devan, Amir-Zilberstein, Liat, Lee, Hyo, Pearse, II, Richard V., Khan, Atlas, Vardarajan, Badri N., Kiryluk, Krzysztof, Ye, Chun Jimmie, Klein, Hans-Ulrich, Wang, Gao, Regev, Aviv, Habib, Naomi, Schneider, Julie A., Wang, Yanling, Young-Pearse, Tracy, Mostafavi, Sara, Bennett, David A., Menon, Vilas, and De Jager, Philip L.

Published
2024
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5. Sex-Specific Association of the X Chromosome With Cognitive Change and Tau Pathology in Aging and Alzheimer Disease

Author

Davis, Emily J, Solsberg, Caroline W, White, Charles C, Miñones-Moyano, Elena, Sirota, Marina, Chibnik, Lori, Bennett, David A, De Jager, Philip L, Yokoyama, Jennifer S, and Dubal, Dena B

Subjects
Brain Disorders, Human Genome, Alzheimer's Disease, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Acquired Cognitive Impairment, Dementia, Neurodegenerative, Genetics, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Aged, 80 and over, Alzheimer Disease, Chromosomes, Human, X, Cognition, Cognitive Dysfunction, Cohort Studies, Dorsolateral Prefrontal Cortex, Female, Humans, Male, Middle Aged, Neurofibrillary Tangles, Sex Characteristics, Transcriptome, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ImportanceThe X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown.ObjectiveTo determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD.Design, setting, participantsThis study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021.Main outcomes and measuresThe main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored.ResultsSamples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women.Conclusions and relevanceIn this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.

Published
2021

6. A second X chromosome contributes to resilience in a mouse model of Alzheimer’s disease

Author

Davis, Emily J, Broestl, Lauren, Abdulai-Saiku, Samira, Worden, Kurtresha, Bonham, Luke W, Miñones-Moyano, Elena, Moreno, Arturo J, Wang, Dan, Chang, Kevin, Williams, Gina, Garay, Bayardo I, Lobach, Iryna, Devidze, Nino, Kim, Daniel, Anderson-Bergman, Cliff, Yu, Gui-Qiu, White, Charles C, Harris, Julie A, Miller, Bruce L, Bennett, David A, Arnold, Arthur P, De Jager, Phil L, Palop, Jorge J, Panning, Barbara, Yokoyama, Jennifer S, Mucke, Lennart, and Dubal, Dena B

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Behavioral and Social Science, Dementia, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease, Aging, Brain Disorders, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Animals, Female, Male, Mice, Sex Characteristics, Testis, X Chromosome, Y Chromosome, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

A major sex difference in Alzheimer's disease (AD) is that men with the disease die earlier than do women. In aging and preclinical AD, men also show more cognitive deficits. Here, we show that the X chromosome affects AD-related vulnerability in mice expressing the human amyloid precursor protein (hAPP), a model of AD. XY-hAPP mice genetically modified to develop testicles or ovaries showed worse mortality and deficits than did XX-hAPP mice with either gonad, indicating a sex chromosome effect. To dissect whether the absence of a second X chromosome or the presence of a Y chromosome conferred a disadvantage on male mice, we varied sex chromosome dosage. With or without a Y chromosome, hAPP mice with one X chromosome showed worse mortality and deficits than did those with two X chromosomes. Thus, adding a second X chromosome conferred resilience to XY males and XO females. In addition, the Y chromosome, its sex-determining region Y gene (Sry), or testicular development modified mortality in hAPP mice with one X chromosome such that XY males with testicles survived longer than did XY or XO females with ovaries. Furthermore, a second X chromosome conferred resilience potentially through the candidate gene Kdm6a, which does not undergo X-linked inactivation. In humans, genetic variation in KDM6A was linked to higher brain expression and associated with less cognitive decline in aging and preclinical AD, suggesting its relevance to human brain health. Our study suggests a potential role for sex chromosomes in modulating disease vulnerability related to AD.

Published
2020

7. Genetic architecture of subcortical brain structures in 38,851 individuals

Author

Satizabal, Claudia L, Adams, Hieab HH, Hibar, Derrek P, White, Charles C, Knol, Maria J, Stein, Jason L, Scholz, Markus, Sargurupremraj, Muralidharan, Jahanshad, Neda, Roshchupkin, Gennady V, Smith, Albert V, Bis, Joshua C, Jian, Xueqiu, Luciano, Michelle, Hofer, Edith, Teumer, Alexander, van der Lee, Sven J, Yang, Jingyun, Yanek, Lisa R, Lee, Tom V, Li, Shuo, Hu, Yanhui, Koh, Jia Yu, Eicher, John D, Desrivières, Sylvane, Arias-Vasquez, Alejandro, Chauhan, Ganesh, Athanasiu, Lavinia, Rentería, Miguel E, Kim, Sungeun, Hoehn, David, Armstrong, Nicola J, Chen, Qiang, Holmes, Avram J, den Braber, Anouk, Kloszewska, Iwona, Andersson, Micael, Espeseth, Thomas, Grimm, Oliver, Abramovic, Lucija, Alhusaini, Saud, Milaneschi, Yuri, Papmeyer, Martina, Axelsson, Tomas, Ehrlich, Stefan, Roiz-Santiañez, Roberto, Kraemer, Bernd, Håberg, Asta K, Jones, Hannah J, Pike, G Bruce, Stein, Dan J, Stevens, Allison, Bralten, Janita, Vernooij, Meike W, Harris, Tamara B, Filippi, Irina, Witte, A Veronica, Guadalupe, Tulio, Wittfeld, Katharina, Mosley, Thomas H, Becker, James T, Doan, Nhat Trung, Hagenaars, Saskia P, Saba, Yasaman, Cuellar-Partida, Gabriel, Amin, Najaf, Hilal, Saima, Nho, Kwangsik, Mirza-Schreiber, Nazanin, Arfanakis, Konstantinos, Becker, Diane M, Ames, David, Goldman, Aaron L, Lee, Phil H, Boomsma, Dorret I, Lovestone, Simon, Giddaluru, Sudheer, Le Hellard, Stephanie, Mattheisen, Manuel, Bohlken, Marc M, Kasperaviciute, Dalia, Schmaal, Lianne, Lawrie, Stephen M, Agartz, Ingrid, Walton, Esther, Tordesillas-Gutierrez, Diana, Davies, Gareth E, Shin, Jean, Ipser, Jonathan C, Vinke, Louis N, Hoogman, Martine, Jia, Tianye, Burkhardt, Ralph, Klein, Marieke, Crivello, Fabrice, Janowitz, Deborah, Carmichael, Owen, Haukvik, Unn K, Aribisala, Benjamin S, and Schmidt, Helena

Subjects
Biological Sciences, Genetics, Neurosciences, Biotechnology, Mental Health, Human Genome, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Aged, Animals, Brain, Cohort Studies, Drosophila melanogaster, Genetic Variation, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders, Organ Size, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Published
2019

8. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W, Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C, Damotte, Vincent, Naj, Adam C, Boland, Anne, Vronskaya, Maria, van der Lee, Sven J, Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R, Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L, Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B, Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N, Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W, Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L, Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C, Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T, Adams, Hieab H, Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A, Dombroski, Beth A, Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B, Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S, Meslage, Stéphane, Kornhuber, Johannes, White, Charles C, Song, Yuenjoo, Barber, Robert C, Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M, Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L Adrienne, Albert, Marilyn S, De Deyn, Peter P, Gu, Wei, Himali, Jayanadra J, Beekly, Duane, Squassina, Alessio, Hartmann, Annette M, Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E, Doody, Rachelle S, Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J, and Benito, Yolanda A

Subjects
Biochemistry and Cell Biology, Biological Sciences, Alzheimer Disease Genetics Consortium, European Alzheimer’s Disease Initiative, Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology, Genetics
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019

9. CpG-related SNPs in the MS4A region have a dose-dependent effect on risk of late-onset Alzheimer disease.

Author

Ma, Yiyi, Jun, Gyungah R, Chung, Jaeyoon, Zhang, Xiaoling, Kunkle, Brian W, Naj, Adam C, White, Charles C, Bennett, David A, De Jager, Philip L, Alzheimer’s Disease Genetics Consortium, Mayeux, Richard, Haines, Jonathan L, Pericak-Vance, Margaret A, Schellenberg, Gerard D, Farrer, Lindsay A, and Lunetta, Kathryn L

Subjects
Alzheimer’s Disease Genetics Consortium, Brain, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Membrane Proteins, Dinucleoside Phosphates, Prognosis, Risk, Cohort Studies, DNA Methylation, CpG Islands, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genome-Wide Association Study, Alzheimer disease, DNA methylation, eQTL, epigenetics, genetics, mQTL, Dementia, Genetics, Neurodegenerative, Brain Disorders, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurosciences, Alzheimer's Disease, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Neurological, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

CpG-related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We conducted a genome-wide association study using a sliding-window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome-wide significant (p

Published
2019

10. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Author

Kunkle, Brian W, Grenier-Boley, Benjamin, Sims, Rebecca, Bis, Joshua C, Damotte, Vincent, Naj, Adam C, Boland, Anne, Vronskaya, Maria, van der Lee, Sven J, Amlie-Wolf, Alexandre, Bellenguez, Céline, Frizatti, Aura, Chouraki, Vincent, Martin, Eden R, Sleegers, Kristel, Badarinarayan, Nandini, Jakobsdottir, Johanna, Hamilton-Nelson, Kara L, Moreno-Grau, Sonia, Olaso, Robert, Raybould, Rachel, Chen, Yuning, Kuzma, Amanda B, Hiltunen, Mikko, Morgan, Taniesha, Ahmad, Shahzad, Vardarajan, Badri N, Epelbaum, Jacques, Hoffmann, Per, Boada, Merce, Beecham, Gary W, Garnier, Jean-Guillaume, Harold, Denise, Fitzpatrick, Annette L, Valladares, Otto, Moutet, Marie-Laure, Gerrish, Amy, Smith, Albert V, Qu, Liming, Bacq, Delphine, Denning, Nicola, Jian, Xueqiu, Zhao, Yi, Del Zompo, Maria, Fox, Nick C, Choi, Seung-Hoan, Mateo, Ignacio, Hughes, Joseph T, Adams, Hieab H, Malamon, John, Sanchez-Garcia, Florentino, Patel, Yogen, Brody, Jennifer A, Dombroski, Beth A, Naranjo, Maria Candida Deniz, Daniilidou, Makrina, Eiriksdottir, Gudny, Mukherjee, Shubhabrata, Wallon, David, Uphill, James, Aspelund, Thor, Cantwell, Laura B, Garzia, Fabienne, Galimberti, Daniela, Hofer, Edith, Butkiewicz, Mariusz, Fin, Bertrand, Scarpini, Elio, Sarnowski, Chloe, Bush, Will S, Meslage, Stéphane, Kornhuber, Johannes, White, Charles C, Song, Yuenjoo, Barber, Robert C, Engelborghs, Sebastiaan, Sordon, Sabrina, Voijnovic, Dina, Adams, Perrie M, Vandenberghe, Rik, Mayhaus, Manuel, Cupples, L Adrienne, Albert, Marilyn S, De Deyn, Peter P, Gu, Wei, Himali, Jayanadra J, Beekly, Duane, Squassina, Alessio, Hartmann, Annette M, Orellana, Adelina, Blacker, Deborah, Rodriguez-Rodriguez, Eloy, Lovestone, Simon, Garcia, Melissa E, Doody, Rachelle S, Munoz-Fernadez, Carmen, Sussams, Rebecca, Lin, Honghuang, Fairchild, Thomas J, and Benito, Yolanda A

Subjects
Biochemistry and Cell Biology, Genetics, Biological Sciences, Neurodegenerative, Dementia, Alzheimer's Disease, Aging, Prevention, Brain Disorders, Neurosciences, Clinical Research, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Neurological, Aged, Alzheimer Disease, Amyloid beta-Peptides, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Testing, Genome-Wide Association Study, Haplotypes, Humans, Immunity, Lipid Metabolism, Lipids, Male, tau Proteins, Alzheimer Disease Genetics Consortium (ADGC), European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES), Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Published
2019

12. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.

Author

Sims, Rebecca, van der Lee, Sven J, Naj, Adam C, Bellenguez, Céline, Badarinarayan, Nandini, Jakobsdottir, Johanna, Kunkle, Brian W, Boland, Anne, Raybould, Rachel, Bis, Joshua C, Martin, Eden R, Grenier-Boley, Benjamin, Heilmann-Heimbach, Stefanie, Chouraki, Vincent, Kuzma, Amanda B, Sleegers, Kristel, Vronskaya, Maria, Ruiz, Agustin, Graham, Robert R, Olaso, Robert, Hoffmann, Per, Grove, Megan L, Vardarajan, Badri N, Hiltunen, Mikko, Nöthen, Markus M, White, Charles C, Hamilton-Nelson, Kara L, Epelbaum, Jacques, Maier, Wolfgang, Choi, Seung-Hoan, Beecham, Gary W, Dulary, Cécile, Herms, Stefan, Smith, Albert V, Funk, Cory C, Derbois, Céline, Forstner, Andreas J, Ahmad, Shahzad, Li, Hongdong, Bacq, Delphine, Harold, Denise, Satizabal, Claudia L, Valladares, Otto, Squassina, Alessio, Thomas, Rhodri, Brody, Jennifer A, Qu, Liming, Sánchez-Juan, Pascual, Morgan, Taniesha, Wolters, Frank J, Zhao, Yi, Garcia, Florentino Sanchez, Denning, Nicola, Fornage, Myriam, Malamon, John, Naranjo, Maria Candida Deniz, Majounie, Elisa, Mosley, Thomas H, Dombroski, Beth, Wallon, David, Lupton, Michelle K, Dupuis, Josée, Whitehead, Patrice, Fratiglioni, Laura, Medway, Christopher, Jian, Xueqiu, Mukherjee, Shubhabrata, Keller, Lina, Brown, Kristelle, Lin, Honghuang, Cantwell, Laura B, Panza, Francesco, McGuinness, Bernadette, Moreno-Grau, Sonia, Burgess, Jeremy D, Solfrizzi, Vincenzo, Proitsi, Petra, Adams, Hieab H, Allen, Mariet, Seripa, Davide, Pastor, Pau, Cupples, L Adrienne, Price, Nathan D, Hannequin, Didier, Frank-García, Ana, Levy, Daniel, Chakrabarty, Paramita, Caffarra, Paolo, Giegling, Ina, Beiser, Alexa S, Giedraitis, Vilmantas, Hampel, Harald, Garcia, Melissa E, Wang, Xue, Lannfelt, Lars, Mecocci, Patrizia, Eiriksdottir, Gudny, Crane, Paul K, Pasquier, Florence, and Boccardi, Virginia

Subjects
ARUK Consortium, GERAD/PERADES, CHARGE, ADGC, EADI, Microglia, Humans, Alzheimer Disease, Genetic Predisposition to Disease, Adaptor Proteins, Signal Transducing, Membrane Glycoproteins, Receptors, Immunologic, Odds Ratio, Case-Control Studies, Gene Expression Profiling, Amino Acid Sequence, Sequence Homology, Amino Acid, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Phospholipase C gamma, Immunity, Innate, Protein Interaction Maps, Exome, Neurodegenerative, Brain Disorders, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Alzheimer's Disease, Aging, Acquired Cognitive Impairment, 2.1 Biological and endogenous factors, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Published
2017

13. Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Author

van Leeuwen, Elisabeth M, Sabo, Aniko, Bis, Joshua C, Huffman, Jennifer E, Manichaikul, Ani, Smith, Albert V, Feitosa, Mary F, Demissie, Serkalem, Joshi, Peter K, Duan, Qing, Marten, Jonathan, van Klinken, Jan B, Surakka, Ida, Nolte, Ilja M, Zhang, Weihua, Mbarek, Hamdi, Li-Gao, Ruifang, Trompet, Stella, Verweij, Niek, Evangelou, Evangelos, Lyytikäinen, Leo-Pekka, Tayo, Bamidele O, Deelen, Joris, van der Most, Peter J, van der Laan, Sander W, Arking, Dan E, Morrison, Alanna, Dehghan, Abbas, Franco, Oscar H, Hofman, Albert, Rivadeneira, Fernando, Sijbrands, Eric J, Uitterlinden, Andre G, Mychaleckyj, Josyf C, Campbell, Archie, Hocking, Lynne J, Padmanabhan, Sandosh, Brody, Jennifer A, Rice, Kenneth M, White, Charles C, Harris, Tamara, Isaacs, Aaron, Campbell, Harry, Lange, Leslie A, Rudan, Igor, Kolcic, Ivana, Navarro, Pau, Zemunik, Tatijana, Salomaa, Veikko, Study, The LifeLines Cohort, Kooner, Angad S, Kooner, Jaspal S, Lehne, Benjamin, Scott, William R, Tan, Sian-Tsung, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Willemsen, Gonneke, de Mutsert, Renée, Ford, Ian, Gansevoort, Ron T, Segura-Lepe, Marcelo P, Raitakari, Olli T, Viikari, Jorma S, Nikus, Kjell, Forrester, Terrence, McKenzie, Colin A, de Craen, Anton JM, de Ruijter, Hester M, Group, CHARGE Lipids Working, Pasterkamp, Gerard, Snieder, Harold, Oldehinkel, Albertine J, Slagboom, P Eline, Cooper, Richard S, Kähönen, Mika, Lehtimäki, Terho, Elliott, Paul, van der Harst, Pim, Jukema, J Wouter, Mook-Kanamori, Dennis O, Boomsma, Dorret I, Chambers, John C, Swertz, Morris, Ripatti, Samuli, van Dijk, Ko Willems, Vitart, Veronique, Polasek, Ozren, Hayward, Caroline, Wilson, James G, Wilson, James F, Gudnason, Vilmundur, Rich, Stephen S, Psaty, Bruce M, Borecki, Ingrid B, Boerwinkle, Eric, Rotter, Jerome I, Cupples, L Adrienne, and van Duijn, Cornelia M

Subjects
Biological Sciences, Genetics, Biotechnology, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Angiopoietin-Like Protein 4, Angiopoietins, Exons, Fasting, Female, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, LifeLines Cohort Study, CHARGE Lipids Working Group, Complex traits, Epidemiology, Genome-wide, circulating lipid levels, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundSo far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.MethodsWe used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.ResultsOur study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.ConclusionsThis study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

Published
2016

14. Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Author

Dehghan, Abbas, Bis, Joshua C, White, Charles C, Smith, Albert Vernon, Morrison, Alanna C, Cupples, L Adrienne, Trompet, Stella, Chasman, Daniel I, Lumley, Thomas, Völker, Uwe, Buckley, Brendan M, Ding, Jingzhong, Jensen, Majken K, Folsom, Aaron R, Kritchevsky, Stephen B, Girman, Cynthia J, Ford, Ian, Dörr, Marcus, Salomaa, Veikko, Uitterlinden, André G, Eiriksdottir, Gudny, Vasan, Ramachandran S, Franceschini, Nora, Carty, Cara L, Virtamo, Jarmo, Demissie, Serkalem, Amouyel, Philippe, Arveiler, Dominique, Heckbert, Susan R, Ferrières, Jean, Ducimetière, Pierre, Smith, Nicholas L, Wang, Ying A, Siscovick, David S, Rice, Kenneth M, Wiklund, Per-Gunnar, Taylor, Kent D, Evans, Alun, Kee, Frank, Rotter, Jerome I, Karvanen, Juha, Kuulasmaa, Kari, Heiss, Gerardo, Kraft, Peter, Launer, Lenore J, Hofman, Albert, Markus, Marcello RP, Rose, Lynda M, Silander, Kaisa, Wagner, Peter, Benjamin, Emelia J, Lohman, Kurt, Stott, David J, Rivadeneira, Fernando, Harris, Tamara B, Levy, Daniel, Liu, Yongmei, Rimm, Eric B, Jukema, J Wouter, Völzke, Henry, Ridker, Paul M, Blankenberg, Stefan, Franco, Oscar H, Gudnason, Vilmundur, Psaty, Bruce M, Boerwinkle, Eric, and O'Donnell, Christopher J

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Heart Disease - Coronary Heart Disease, Prevention, Human Genome, Cardiovascular, Heart Disease, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Aetiology, Good Health and Well Being, Aged, Cohort Studies, Cooperative Behavior, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies, General Science & Technology
Abstract

BackgroundData are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.MethodsWe performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.ResultsIn Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value

Published
2016

16. A genome‐wide association study of LATE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change) reveals a distinct genetic architecture

Author

Yang, Hyun‐Sik, primary, Mukherjee, Shubhabrata, additional, Latimer, Caitlin S, additional, Teng, Ling, additional, White, Charles C, additional, Yu, Lei, additional, Sperling, Reisa A., additional, Larson, Eric B, additional, Crane, Paul K, additional, Keene, C Dirk, additional, Bennett, David A. A, additional, Schneider, Julie A, additional, and De Jager, Philip L, additional

Published
2023
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17. Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue

Author

Ma, Yiyi, Dammer, Eric B., Felsky, Daniel, Duong, Duc M., Klein, Hans-Ulrich, White, Charles C., Zhou, Maotian, Logsdon, Benjamin A., McCabe, Cristin, Xu, Jishu, Wang, Minghui, Wingo, Thomas S., Lah, James J., Zhang, Bin, Schneider, Julie, Allen, Mariet, Wang, Xue, Ertekin-Taner, Nilüfer, Seyfried, Nicholas T., Levey, Allan I., Bennett, David A., and De Jager, Philip L.

Published
2021
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18. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Author

Winkler, Thomas W, Justice, Anne E, Graff, Mariaelisa, Barata, Llilda, Feitosa, Mary F, Chu, Su, Czajkowski, Jacek, Esko, Tõnu, Fall, Tove, Kilpeläinen, Tuomas O, Lu, Yingchang, Mägi, Reedik, Mihailov, Evelin, Pers, Tune H, Rüeger, Sina, Teumer, Alexander, Ehret, Georg B, Ferreira, Teresa, Heard-Costa, Nancy L, Karjalainen, Juha, Lagou, Vasiliki, Mahajan, Anubha, Neinast, Michael D, Prokopenko, Inga, Simino, Jeannette, Teslovich, Tanya M, Jansen, Rick, Westra, Harm-Jan, White, Charles C, Absher, Devin, Ahluwalia, Tarunveer S, Ahmad, Shafqat, Albrecht, Eva, Alves, Alexessander Couto, Bragg-Gresham, Jennifer L, de Craen, Anton JM, Bis, Joshua C, Bonnefond, Amélie, Boucher, Gabrielle, Cadby, Gemma, Cheng, Yu-Ching, Chiang, Charleston WK, Delgado, Graciela, Demirkan, Ayse, Dueker, Nicole, Eklund, Niina, Eiriksdottir, Gudny, Eriksson, Joel, Feenstra, Bjarke, Fischer, Krista, Frau, Francesca, Galesloot, Tessel E, Geller, Frank, Goel, Anuj, Gorski, Mathias, Grammer, Tanja B, Gustafsson, Stefan, Haitjema, Saskia, Hottenga, Jouke-Jan, Huffman, Jennifer E, Jackson, Anne U, Jacobs, Kevin B, Johansson, Åsa, Kaakinen, Marika, Kleber, Marcus E, Lahti, Jari, Mateo Leach, Irene, Lehne, Benjamin, Liu, Youfang, Lo, Ken Sin, Lorentzon, Mattias, Luan, Jian'an, Madden, Pamela AF, Mangino, Massimo, McKnight, Barbara, Medina-Gomez, Carolina, Monda, Keri L, Montasser, May E, Müller, Gabriele, Müller-Nurasyid, Martina, Nolte, Ilja M, Panoutsopoulou, Kalliope, Pascoe, Laura, Paternoster, Lavinia, Rayner, Nigel W, Renström, Frida, Rizzi, Federica, Rose, Lynda M, Ryan, Kathy A, Salo, Perttu, Sanna, Serena, Scharnagl, Hubert, Shi, Jianxin, Smith, Albert Vernon, Southam, Lorraine, Stančáková, Alena, Steinthorsdottir, Valgerdur, Strawbridge, Rona J, Sung, Yun Ju, and Tachmazidou, Ioanna

Subjects
CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Humans, Genetic Predisposition to Disease, Body Mass Index, Body Size, Waist-Hip Ratio, Chromosome Mapping, Age Factors, Sex Characteristics, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Developmental Biology, Genetics
Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR

Published
2015

19. Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.

Author

van Leeuwen, Elisabeth M, Karssen, Lennart C, Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, van Enckevort, David J, Huffman, Jennifer E, White, Charles C, Feitosa, Mary F, Bartz, Traci M, Manichaikul, Ani, Joshi, Peter K, Peloso, Gina M, Deelen, Patrick, van Dijk, Freerk, Willemsen, Gonneke, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Francioli, Laurent C, Menelaou, Androniki, Pulit, Sara L, Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A, Franco, Oscar H, Mateo Leach, Irene, Beekman, Marian, de Craen, Anton JM, Uh, Hae-Won, Trochet, Holly, Hocking, Lynne J, Porteous, David J, Sattar, Naveed, Packard, Chris J, Buckley, Brendan M, Brody, Jennifer A, Bis, Joshua C, Rotter, Jerome I, Mychaleckyj, Josyf C, Campbell, Harry, Duan, Qing, Lange, Leslie A, Wilson, James F, Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F, Rich, Stephen S, Psaty, Bruce M, Borecki, Ingrid B, Kearney, Patricia M, Stott, David J, Adrienne Cupples, L, Genome of The Netherlands Consortium, Jukema, J Wouter, van der Harst, Pim, Sijbrands, Eric J, Hottenga, Jouke-Jan, Uitterlinden, Andre G, Swertz, Morris A, van Ommen, Gert-Jan B, de Bakker, Paul IW, Eline Slagboom, P, Boomsma, Dorret I, Wijmenga, Cisca, and van Duijn, Cornelia M

Subjects
Genome of The Netherlands Consortium, Humans, Cholesterol, ATP-Binding Cassette Transporters, Gene Frequency, Mutation, Missense, Netherlands, Genetic Association Studies, Mutation, Missense
Abstract

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value

Published
2015

20. Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

Author

van Leeuwen, Elisabeth M, Huffman, Jennifer E, Bis, Joshua C, Isaacs, Aaron, Mulder, Monique, Sabo, Aniko, Smith, Albert V, Demissie, Serkalem, Manichaikul, Ani, Brody, Jennifer A, Feitosa, Mary F, Duan, Qing, Schraut, Katharina E, Navarro, Pau, van Vliet-Ostaptchouk, Jana V, Zhu, Gu, Mbarek, Hamdi, Trompet, Stella, Verweij, Niek, Lyytikäinen, Leo-Pekka, Deelen, Joris, Nolte, Ilja M, van der Laan, Sander W, Davies, Gail, Vermeij-Verdoold, Andrea JM, van Oosterhout, Andy ALJ, Vergeer-Drop, Jeannette M, Arking, Dan E, Trochet, Holly, Medina-Gomez, Carolina, Rivadeneira, Fernando, Uitterlinden, Andre G, Dehghan, Abbas, Franco, Oscar H, Sijbrands, Eric J, Hofman, Albert, White, Charles C, Mychaleckyj, Josyf C, Peloso, Gina M, Swertz, Morris A, Willemsen, Gonneke, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Ford, Ian, Buckley, Brendan M, de Craen, Anton JM, Starr, John M, Deary, Ian J, Pasterkamp, Gerard, Oldehinkel, Albertine J, Snieder, Harold, Slagboom, P Eline, Nikus, Kjell, Kähönen, Mika, Lehtimäki, Terho, Viikari, Jorma S, Raitakari, Olli T, van der Harst, Pim, Jukema, J Wouter, Hottenga, Jouke-Jan, Boomsma, Dorret I, Whitfield, John B, Montgomery, Grant, Martin, Nicholas G, Polasek, Ozren, Vitart, Veronique, Hayward, Caroline, Kolcic, Ivana, Wright, Alan F, Rudan, Igor, Joshi, Peter K, Wilson, James F, Lange, Leslie A, Wilson, James G, Gudnason, Vilmundur, Harris, Tamar B, Morrison, Alanna C, Borecki, Ingrid B, Rich, Stephen S, Padmanabhan, Sandosh, Psaty, Bruce M, Rotter, Jerome I, Smith, Blair H, Boerwinkle, Eric, Cupples, L Adrienne, and van Duijn, Cornelia

Subjects
Biological Sciences, Genetics, Aetiology, 2.1 Biological and endogenous factors, Generation Scotland, LifeLines Cohort Study, CHARGE Lipids Working Group, Biochemistry and Cell Biology, Medical Biotechnology, Clinical Sciences, Biochemistry and cell biology
Abstract

BackgroundIndividuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.MethodsWe performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.ResultsThe meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10-509), βadjusted=0.859 mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.ConclusionsThe causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

Published
2015

23. Association of Levels of Fasting Glucose and Insulin With Rare Variants at the Chromosome 11p11.2-MADD Locus

Author

Cornes, Belinda K, Brody, Jennifer A, Nikpoor, Naghmeh, Morrison, Alanna C, Chu, Huan, Ahn, Byung Soo, Wang, Shuai, Dauriz, Marco, Barzilay, Joshua I, Dupuis, Josée, Florez, Jose C, Coresh, Josef, Gibbs, Richard A, Kao, WH Linda, Liu, Ching-Ti, McKnight, Barbara, Muzny, Donna, Pankow, James S, Reid, Jeffrey G, White, Charles C, Johnson, Andrew D, Wong, Tien Y, Psaty, Bruce M, Boerwinkle, Eric, Rotter, Jerome I, Siscovick, David S, Sladek, Robert, and Meigs, James B

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Human Genome, Diabetes, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Metabolic and endocrine, Aged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, genetic epidemiology, glucose, human genetics, insulin, molecular genetics, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BackgroundCommon variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.Methods and resultsSequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency 2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.ConclusionsSequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

Published
2014

25. Genetics of coronary artery calcification among African Americans, a meta-analysis

Author

Wojczynski, Mary K, Li, Mingyao, Bielak, Lawrence F, Kerr, Kathleen F, Reiner, Alex P, Wong, Nathan D, Yanek, Lisa R, Qu, Liming, White, Charles C, Lange, Leslie A, Ferguson, Jane F, He, Jing, Young, Taylor, Mosley, Thomas H, Smith, Jennifer A, Kral, Brian G, Guo, Xiuqing, Wong, Quenna, Ganesh, Santhi K, Heckbert, Susan R, Griswold, Michael E, O’Leary, Daniel H, Budoff, Matthew, Carr, J, Taylor,, Herman A, Bluemke, David A, Demissie, Serkalem, Hwang, Shih-Jen, Paltoo, Dina N, Polak, Joseph F, Psaty, Bruce M, Becker, Diane M, Province, Michael A, Post, Wendy S, O’Donnell, Christopher J, Wilson, James G, Harris, Tamara B, Kavousi, Maryam, Cupples, L, Rotter, Jerome I, Fornage, Myriam, Becker, Lewis C, Peyser, Patricia A, Borecki, Ingrid B, and Reilly, Muredach P

Abstract

Abstract Background Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. Methods We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Results Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p

Published
2013

26. Genome-Wide Association of Pericardial Fat Identifies a Unique Locus for Ectopic Fat

Author

Fox, Caroline S, White, Charles C, Lohman, Kurt, Heard-Costa, Nancy, Cohen, Paul, Zhang, Yingying, Johnson, Andrew D, Emilsson, Valur, Liu, Ching-Ti, Chen, Y-D Ida, Taylor, Kent D, Allison, Matthew, Budoff, Matthew, Rotter, Jerome I, Carr, J Jeffrey, Hoffmann, Udo, Ding, Jingzhong, Cupples, L Adrienne, and Liu, Yongmei

Subjects
Biological Sciences, Genetics, Atherosclerosis, Prevention, Heart Disease, Aging, Nutrition, Obesity, Cardiovascular, Metabolic and endocrine, Adipose Tissue, Adult, Animals, Asian People, Black People, Body Fat Distribution, Body Mass Index, Calcium-Calmodulin-Dependent Protein Kinases, Coronary Disease, Female, Gene Expression Regulation, Genome-Wide Association Study, Hispanic or Latino, Humans, Intra-Abdominal Fat, Intracellular Signaling Peptides and Proteins, Male, Mice, Middle Aged, Pericardium, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Tomography, X-Ray Computed, White People, CARDIoGRAM Consortium, Developmental Biology
Abstract

Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7 × 10(-08)). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.

Published
2012

27. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Author

Speliotes, Elizabeth K, Willer, Cristen J, Berndt, Sonja I, Monda, Keri L, Thorleifsson, Gudmar, Jackson, Anne U, Allen, Hana Lango, Lindgren, Cecilia M, Luan, Jian'an, Mägi, Reedik, Randall, Joshua C, Vedantam, Sailaja, Winkler, Thomas W, Qi, Lu, Workalemahu, Tsegaselassie, Heid, Iris M, Steinthorsdottir, Valgerdur, Stringham, Heather M, Weedon, Michael N, Wheeler, Eleanor, Wood, Andrew R, Ferreira, Teresa, Weyant, Robert J, Segrè, Ayellet V, Estrada, Karol, Liang, Liming, Nemesh, James, Park, Ju-Hyun, Gustafsson, Stefan, Kilpeläinen, Tuomas O, Yang, Jian, Bouatia-Naji, Nabila, Esko, Tõnu, Feitosa, Mary F, Kutalik, Zoltán, Mangino, Massimo, Raychaudhuri, Soumya, Scherag, Andre, Smith, Albert Vernon, Welch, Ryan, Zhao, Jing Hua, Aben, Katja K, Absher, Devin M, Amin, Najaf, Dixon, Anna L, Fisher, Eva, Glazer, Nicole L, Goddard, Michael E, Heard-Costa, Nancy L, Hoesel, Volker, Hottenga, Jouke-Jan, Johansson, Åsa, Johnson, Toby, Ketkar, Shamika, Lamina, Claudia, Li, Shengxu, Moffatt, Miriam F, Myers, Richard H, Narisu, Narisu, Perry, John RB, Peters, Marjolein J, Preuss, Michael, Ripatti, Samuli, Rivadeneira, Fernando, Sandholt, Camilla, Scott, Laura J, Timpson, Nicholas J, Tyrer, Jonathan P, van Wingerden, Sophie, Watanabe, Richard M, White, Charles C, Wiklund, Fredrik, Barlassina, Christina, Chasman, Daniel I, Cooper, Matthew N, Jansson, John-Olov, Lawrence, Robert W, Pellikka, Niina, Prokopenko, Inga, Shi, Jianxin, Thiering, Elisabeth, Alavere, Helene, Alibrandi, Maria TS, Almgren, Peter, Arnold, Alice M, Aspelund, Thor, Atwood, Larry D, Balkau, Beverley, Balmforth, Anthony J, Bennett, Amanda J, Ben-Shlomo, Yoav, Bergman, Richard N, Bergmann, Sven, Biebermann, Heike, Blakemore, Alexandra IF, Boes, Tanja, Bonnycastle, Lori L, Bornstein, Stefan R, Brown, Morris J, and Buchanan, Thomas A

Subjects
Biological Sciences, Genetics, Prevention, Human Genome, Body Height, Body Mass Index, Body Size, Body Weight, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Obesity, Polymorphism, Single Nucleotide, White People, MAGIC, Procardis Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Published
2010

28. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression

Author

Carrasquillo, Minerva M., Allen, Mariet, Burgess, Jeremy D., Wang, Xue, Strickland, Samantha L., Aryal, Shivani, Siuda, Joanna, Kachadoorian, Michaela L., Medway, Christopher, Younkin, Curtis S., Nair, Asha, Wang, Chen, Chanana, Pritha, Serie, Daniel, Nguyen, Thuy, Lincoln, Sarah, Malphrus, Kimberly G., Morgan, Kevin, Golde, Todd E., Price, Nathan D., White, Charles C., De Jager, Philip L., Bennett, David A., Asmann, Yan W., Crook, Julia E., Petersen, Ronald C., Graff-Radford, Neill R., Dickson, Dennis W., Younkin, Steven G., and Ertekin-Taner, Nilüfer

Published
2017
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29. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, Ganesh, Adams, Hieab H.H., Satizabal, Claudia L., Bis, Joshua C., Teumer, Alexander, Sargurupremraj, Muralidharan, Hofer, Edith, Trompet, Stella, Hilal, Saima, Smith, Albert Vernon, Jian, Xueqiu, Malik, Rainer, Traylor, Matthew, Pulit, Sara L., Amouyel, Philippe, Mazoyer, Bernard, Zhu, Yi-Cheng, Kaffashian, Sara, Schilling, Sabrina, Beecham, Gary W., Montine, Thomas J., Schellenberg, Gerard D., Kjartansson, Olafur, Guðnason, Vilmundur, Knopman, David S., Griswold, Michael E., Windham, B. Gwen, Gottesman, Rebecca F., Mosley, Thomas H., Schmidt, Reinhold, Saba, Yasaman, Schmidt, Helena, Takeuchi, Fumihiko, Yamaguchi, Shuhei, Nabika, Toru, Kato, Norihiro, Rajan, Kumar B., Aggarwal, Neelum T., De Jager, Philip L., Evans, Denis A., Psaty, Bruce M., Rotter, Jerome I., Rice, Kenneth, Lopez, Oscar L., Liao, Jiemin, Chen, Christopher, Cheng, Ching-Yu, Wong, Tien Y., Ikram, Mohammad K., van der Lee, Sven J., Amin, Najaf, Chouraki, Vincent, DeStefano, Anita L., Aparicio, Hugo J., Romero, Jose R., Maillard, Pauline, DeCarli, Charles, Wardlaw, Joanna M., Hernández, Maria del C. Valdés, Luciano, Michelle, Liewald, David, Deary, Ian J., Starr, John M., Bastin, Mark E., Muñoz Maniega, Susana, Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, Uh, Hae-Won, Lemmens, Robin, Brodaty, Henry, Wright, Margaret J., Ames, David, Boncoraglio, Giorgio B., Hopewell, Jemma C., Beecham, Ashley H., Blanton, Susan H., Wright, Clinton B., Sacco, Ralph L., Wen, Wei, Thalamuthu, Anbupalam, Armstrong, Nicola J., Chong, Elizabeth, Schofield, Peter R., Kwok, John B., van der Grond, Jeroen, Stott, David J., Ford, Ian, Jukema, J. 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Dichgans, Martin, Kittner, Steven J., Markus, Hugh S., Ikram, Mohammad A., Fornage, Myriam, Launer, Lenore J., Seshadri, Sudha, Longstreth, W.T., Jr, Debette, Stéphanie, Almgren, Peter, Anderson, Christopher D., Arnett, Donna K., Attia, John, Ay, Hakan, Benavente, Oscar R., Bevan, Steve, Brown, Robert D., Bustamante, Mariana, Cheng, Yu-Ching, Cole, John W., Cotlarciuc, Ioana, Cruchaga, Carlos, de Bakker, Paul IW., Delavaran, Hossein, Dichgans, Martin, Engström, Gunnar, Fornage, Myriam, Grewal, Raji P., Heitsch, Laura, Holliday, Elizabeth, Ibanez, Laure, Ilinca, Andreea, Irvin, Marguerite R., Jackson, Rebecca D., Jern, Christina, Jimenez-Conde, Jordi, Johnson, Julie A., Jood, Katarina, Kissela, Brett M., Kittner, Steven J., Kleindorfer, Dawn O., Labovitz, Daniel, Laurie, Cathy C., Lee, Jin-Moo, Lemmens, Robin, Levi, Christopher, Li, Linxin, Lindgren, Arne G., Maguire, Jane, Markus, Hugh S., McArdle, Patrick F., Melander, Olle, Meschia, James F., Mitchell, Braxton D., Müller-Nurasyid, Martina, Norrving, Bo, Peddareddygari, Leema Reddy, Pera, Joanna, Pulit, Sara L., Rexrode, Kathryn, Ribasés, Marta, Roquer, Jaume, Rost, Natalia S., Rothwell, Peter M., Rundek, Tatjana, Sacco, Ralph L., Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Soriano-Tárraga, Carolina, Stanne, Tara, Stauch, Konstantin, Stine, O C., Sudlow, Cathie LM., Thijs, Vincent N.S., Wasssertheil-Smoller, Sylvia, Weir, David, Williams, Stephen R., Wong, Quenna, Woo, Daniel, Worrall, Bradford B., Xu, Huichun, Seshadri, Sudha, Hyacinth, Hyacinth I, Marini, Sandro, Nyquist, Paul, Lewis, Cathryn, Hansen, Bjorn, Norrving, Bo, Rosand, Jonathan, Biffi, Alessandro, Kourkoulis, Christina, Anderson, Chris, Giese, Anne-Katrin, Sacco, Ralph, Sharma, Pankaj, Chung, Jong-Won, Kim, Gyeong-Moon, Lubitz, Steven, Bourcier, Romain, Howson, Joanna, Granata, Alessandra, Drazyk, Anna, Markus, Hugh, Wardlaw, Joanna, Mitchell, Braxton, Cole, John, Hopewell, Jemma, Walters, Robin, Turnbull, Iain, Worrall, Bradford, Bis, 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Tan, Rhea, Danesh, John, Rutten-Jacobs, Loes, Donatti, Amanda, Avelar, Wagner, Broderick, Joseph, Woo, Daniel, Sudlow, Cathie, Rannikmae, Kristiina, McDonough, Caitrin Wheeler, van Agtmael, Tom, Walters, Matthew, Söderholm, Martin, Lorentzen, Erik, Olsson, Sandra, Stanne, Tara, Olsson, Martina, Akinyemi, Rufus, Cotlatciuc, Ioana, McArdle, Patrick, Dave, Tushar, Kittner, Steven, Attia, John, Faber, James E, Millwood, Iona, Márquez, Elsa Valdés, Mancuso, Michelangelo, Vibo, Riina, Korv, Janika, Maguire, Jane, Fornage, Myriam, Majersik, Jennifer, DeHavenon, Adam, Alexander, Matthew, Sale, Michele, Southerland, Andrew, Owens, Debra, Psaty, Bruce, Longstreth, W. T., Jr, Wolfe, Stacey Quintero, Langefeld, Carl, Cruchaga, Carlos, Konrad, Jan, Sheth, Kevin, Falcone, Guido, Donahue, Kathleen, Simpkins, Alexis N, Liang Byorn, Tan Wei, Chan, Bernard, Clatworthy, Phil, Florez, Jose, Harshfield, Eric, Hozawa, Atsushi, Hsu, Chung, Hu, Chaur-Jong, Ibanez, Laure, Ihara, Masafumi, Lange, Marcos, Lee, Soo Ji, Lee, I-Hui, Musolino, Patricia, Nakatomi, Hirofumi, Park, Kwang-Yeol, Rich, Stephen S, Riley, Chris, Sung, Joohon, Suzuki, Hideaki, Vo, Katie, Washida, Kazuo, Ibenez, Laura Garcia, Slowik, Agnieszka, Hofman, Albert, Algra, Ale, Reiner, Alex P, Doney, Alexander S F, Gschwendtner, Andreas, Ilinca, Andreea, Giese, Anne-Katrin, Lindgren, Arne, Vicente, Astrid M, Norrving, Bo, Nordestgaard, Børge G, Mitchell, Braxton D, Worrall, Bradford B, Psaty, Bruce M, Carty, Cara L, Sudlow, Cathie, Anderson, Christopher D, Levi, Christopher, Satizabal, Claudia L, Palmer, Colin N A, Gamble, Dale M, Woo, Daniel, Saleheen, Danish, Ringelstein, E Bernd, Valdimarsson, Einar, Holliday, Elizabeth, Davies, Gail, Chauhan, Ganesh, Pasterkamp, Gerard, Boncoraglio, Giorgio, Kuhlenbäumer, Gregor, Thorleifsson, Gudmar, Falcone, Guido J, Pare, Guillame, Schmidt, Helena, Delavaran, Hossein, Markus, Hugh S, Aparicio, Hugo J, Deary, Ian, Cotlarciuc, Ioana, Fernandez-Cadenas, Israel, Meschia, James, Hopewell, Jemma C, Liu, Jingmin, Montaner, Joan, Pera, Joanna, Cole, John, Attia, John R, Rosand, Jonathan, Ferro, Jose M, Bis, Joshua, Furie, Karen, Stefansson, Kari, Berger, Klaus, Kostulas, Konstantinos, Rannikmae, Kristina, Ikram, M Arfan, Benn, Marianne, Dichgans, Martin, Farrall, Martin, Pandolfo, Massimo, Traylor, Matthew, Walters, Matthew, Sale, Michele, Nalls, Mike, Fornage, Myriam, van Zuydam, Natalie R, Sharma, Pankaj, Abrantes, Patricia, de Bakker, Paul IW, Higgins, Peter, Lichtner, Peter, Rothwell, Peter M, Amouyel, Philippe, Yang, Qiong, Malik, Rainer, Schmidt, Reinhold, Clarke, Robert, Lemmens, Robin, van der Laan, Sander W, Pulit, Sara L, Abboud, Sherine, Oliveira, Sofia A, Gretarsdottir, Solveig, Debette, Stephanie, Williams, Stephen R, Bevan, Steve, Kittner, Steven J, Seshadri, Sudha, Mosley, Thomas, Battey, Thomas WK, Tatlisumak, Turgut, Thorsteinsdottir, Unnur, Thijs, Vincent NS, Longstreth, W T, Zhao, Wei, Chen, Wei-Min, Cheng, Yu-Ching, 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., Beecham, Gary W., 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., Byrd, Goldie S., Cai, Guiqing, Cairns, Nigel J., Cantwell, Laura B., Cao, Chuanhai, Carlsson, Cynthia M., Carney, Regina 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., Farrer, Lindsay A., Ferris, Steven, Foroud, Tatiana M., Frosch, Matthew P., Galasko, Douglas R., Gearing, Marla, Geschwind, Daniel H., Ghetti, Bernardino, Gilbert, John R., Go, Rodney C.P., Goate, Alison M., Graff-Radford, Neill R., Green, Robert C., Griffith, Patrick, Growdon, John H., Haines, Jonathan L., Hakonarson, Hakon, Hamilton, Ronald L., Hamilton-Nelson, Kara L., Haroutunian, Vahram, Harrell, Lindy E., Honig, Lawrence S., Huebinger, Ryan M., Hulette, Christine M., Hyman, Bradley T., Jicha, Gregory A., Jin, Lee-Way, Jun, Gyungah, Kamboh, M. Ilyas, Karydas, Anna, Kauwe, John S.K., Kaye, Jeffrey A., Kim, Ronald, Kowall, Neil W., Kramer, Joel H., Kukull, Walter A., Kunkle, Brian W., LaFerla, Frank M., Lah, James J., Lang-Walker, Rosalyn, Larson, Eric B., Leverenz, James B., Levey, Allan I., Li, Ge, Lieberman, Andrew P., Logue, Mark W., Lopez, Oscar L., Lunetta, Kathryn L., Lyketsos, Constantine G., Mack, Wendy J., Manly, Jennifer J., Marson, Daniel C., Martin, Eden R., Martiniuk, Frank, Mash, Deborah C., Masliah, Eliezer, Mayeux, Richard, McKee, Ann C., Mesulam, Marsel, Miller, Bruce L., Miller, Carol A., Miller, Joshua W., Montine, Thomas J., Morris, John C., Murrell, Jill R., Naj, Adam C., Obisesan, Thomas O., Olichney, John M., Pankratz, Vernon S., Parisi, Joseph E., Partch, Amanda, Paulson, Henry L., Pericak-Vance, Margaret A., Perry, William, Peskind, Elaine, Petersen, Ronald C., Pierce, Aimee, Poon, Wayne W., Potter, Huntington, Quinn, Joseph F., Raj, Ashok, Raj, Towfique, Raskind, Murray, Reiman, Eric M., Reisberg, Barry, Reitz, Christiane, Ringman, John M., Roberson, Erik D., Rosen, Howard J., Rosenberg, Roger N., Sager, Mark A., Sano, Mary, Saykin, Andrew J., Schellenberg, Gerard D., Schneider, Julie A., Schneider, Lon S., Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tanzi, Rudolph E., Thornton-Wells, Tricia A., Trojanowski, John Q., Troncoso, Juan C., Tsuang, Debby W., Valladares, Otto, Van Deerlin, Vivianna M., Van Eldik, Linda J., Vardarajan, Badri N., Vinters, Harry V., Vonsattel, Jean Paul, Wang, Li-San, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Williamson, Jennifer, Wingo, Thomas S., Wishnek, Sarah, Woltjer, Randall L., Wright, Clinton B., Younkin, Steven G., Yu, Chang-En, Yu, Lei, Chauhan, Ganesh, Chu, Audrey Y., Fornage, Myriam, Bis, Joshua C., Havulinna, Aki S., Sargurupremraj, Muralidharan, Smith, Albert Vernon, Adams, Hieab H.H., Choi, Seung Hoan, Trompet, Stella, Garcia, Melissa E., Manichaikul, Ani, Teumer, Alexander, Gustafsson, Stefan, Bartz, Traci M., Bellenguez, Céline, Vidal, Jean Sebastien, Jian, Xueqiu, Kjartansson, Olafur, Wiggins, Kerri L., Satizabal, Claudia L., Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Deelen, Joris, Hoed, Marcel den, Heckbert, Susan R., Rice, Kenneth, Smith, Nicholas L., Wong, Quenna, Aparicio, Hugo J., Buring, Julie E., Ridker, Paul M, Berr, Claudine, Dartigues, Jean-François, Hamsten, Anders, Magnusson, Patrik K., Pedersen, Nancy L., Lannfelt, Lars, Lind, Lars, Lindgren, Cecilia M., Morris, Andrew P., Hofman, Albert, Koudstaal, Peter J., Portegies, Marileen LP., Uitterlinden, André G., de Craen, Anton JM, Ford, Ian, Jukema, J. Wouter, Stott, David J, Allen, Norrina B., Sale, Michele M., Johnson, Andrew D, Bennett, David A., De Jager, Philip L., White, Charles C., Grabe, Hans Jörgen, Paulista Markus, Marcello Ricardo, Lopez, Oscar L, Rotter, Jerome I., Nalls, Michael A., Gottesman, Rebecca F., Griswold, Michael E., Knopman, David S., Windham, B. Gwen, Beiser, Alexa, Vartiainen, Erkki, French, Curtis R., Kurth, Tobias, Psaty, Bruce M., Harris, Tamara B., Rich, Stephen S, deStefano, Anita L., Schmidt, Carsten Oliver, Salomaa, Veikko, Mosley, Thomas H., Ingelsson, Erik, van Duijn, Cornelia M., Tzourio, Christophe, Launer, Lenore J, Ikram, M. Arfan, Chasman, Daniel I., Longstreth, W. T., Jr, Seshadri, Sudha, Debette, Stéphanie, Verhaaren, Benjamin F.J., Debette, Stéphanie, Bis, Joshua C., Smith, Jennifer A., Ikram, M. Kamran, Adams, Hieab H., Beecham, Ashley H., Rajan, Kumar B., Lopez, Lorna M., Barral, Sandra, van Buchem, Mark A., van der Grond, Jeroen, Smith, Albert V., Hegenscheid, Katrin, Aggarwal, Neelum T., de Andrade, Mariza, Atkinson, Elizabeth J., Beekman, Marian, Beiser, Alexa S., Blanton, Susan H., Boerwinkle, Eric, Brickman, Adam M., Bryan, R. Nick, Chauhan, Ganesh, Chen, Christopher P.L.H., Chouraki, Vincent, de Craen, Anton J.M., Crivello, Fabrice, Deary, Ian J., Deelen, Joris, De Jager, Philip L., Dufouil, Carole, Elkind, Mitchell S.V., Evans, Denis A., Freudenberger, Paul, Gottesman, Rebecca F., Guðnason, Vilmundur, Habes, Mohamad, Heckbert, Susan R., Heiss, Gerardo, Hilal, Saima, Hofer, Edith, Hofman, Albert, Ibrahim-Verbaas, Carla A., Knopman, David S., Lewis, Cora E., Liao, Jiemin, Liewald, David C.M., Luciano, Michelle, van der Lugt, Aad, Martinez, Oliver O., Mayeux, Richard, Mazoyer, Bernard, Nalls, Mike, Nauck, Matthias, Niessen, Wiro J., Oostra, Ben A., Psaty, Bruce M., Rice, Kenneth M., Rotter, Jerome I., von Sarnowski, Bettina, Schmidt, Helena, Schreiner, Pamela J., Schuur, Maaike, Sidney, Stephen S., Sigurdsson, Sigurdur, Slagboom, P. Eline, Stott, David J.M., van Swieten, John C., Teumer, Alexander, Töglhofer, Anna Maria, Traylor, Matthew, Trompet, Stella, Turner, Stephen T., Tzourio, Christophe, Uh, Hae-Won, Uitterlinden, André G., Vernooij, Meike W., Wang, Jing J., Wong, Tien Y., Wardlaw, Joanna M., Windham, B. Gwen, Wittfeld, Katharina, Wolf, Christiane, Wright, Clinton B., Yang, Qiong, Zhao, Wei, Zijdenbos, Alex, Jukema, J. Wouter, Sacco, Ralph L., Kardia, Sharon L.R., Amouyel, Philippe, Mosley, Thomas H., Longstreth, W. T., Jr, DeCarli, Charles C., van Duijn, Cornelia M., Schmidt, Reinhold, Launer, Lenore J., Grabe, Hans J., Seshadri, Sudha S., Ikram, M. Arfan, Fornage, Myriam, Bis, Joshua C., Kavousi, Maryam, Franceschini, Nora, Isaacs, Aaron, Abecasis, Gonçalo R, Schminke, Ulf, Post, Wendy, Smith, Albert V., Cupples, L. Adrienne, Markus, Hugh S, Schmidt, Reinhold, Huffman, Jennifer E., Lehtimäki, Terho, Baumert, Jens, Münzel, Thomas, Heckbert, Susan R., Dehghan, Abbas, North, Kari, Oostra, Ben, Bevan, Steve, Stoegerer, Eva-Maria, Hayward, Caroline, Raitakari, Olli, Meisinger, Christa, Schillert, Arne, Sanna, Serena, Völzke, Henry, Cheng, Yu-Ching, Thorsson, Bolli, Fox, Caroline S., Rice, Kenneth, Rivadeneira, Fernando, Nambi, Vijay, Halperin, Eran, Petrovic, Katja E., Peltonen, Leena, Wichmann, H. Erich, Schnabel, Renate B., Dörr, Marcus, Parsa, Afshin, Aspelund, Thor, Demissie, Serkalem, Kathiresan, Sekar, Reilly, Muredach P., Taylor, Kent, Uitterlinden, Andre, Couper, David J., Sitzer, Matthias, Kähönen, Mika, Illig, Thomas, Wild, Philipp S., Orru, Marco, Lüdemann, Jan, Shuldiner, Alan R., Eiriksdottir, Gudny, White, Charles C., Rotter, Jerome I., Hofman, Albert, Seissler, Jochen, Zeller, Tanja, Usala, Gianluca, Ernst, Florian, Launer, Lenore J., DʼAgostino, Ralph B., Sr, OʼLeary, Daniel H., Ballantyne, Christie, Thiery, Joachim, Ziegler, Andreas, Lakatta, Edward G., Chilukoti, Ravi Kumar, Harris, Tamara B., Wolf, Philip A., Psaty, Bruce M., Polak, Joseph F, Li, Xia, Rathmann, Wolfgang, Uda, Manuela, Boerwinkle, Eric, Klopp, Norman, Schmidt, Helena, Wilson, James F, Viikari, Jorma, Koenig, Wolfgang, Blankenberg, Stefan, Newman, Anne B., Witteman, Jacqueline, Heiss, Gerardo, van Duijn, Cornelia, Scuteri, Angelo, Homuth, Georg, Mitchell, Braxton D., Gudnason, Vilmundur, and O’Donnell, Christopher J.

Published
2019
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30. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease

Author

Mostafavi, Sara, Gaiteri, Chris, Sullivan, Sarah E., White, Charles C., Tasaki, Shinya, Xu, Jishu, Taga, Mariko, Klein, Hans-Ulrich, Patrick, Ellis, Komashko, Vitalina, McCabe, Cristin, Smith, Robert, Bradshaw, Elizabeth M., Root, David E., Regev, Aviv, Yu, Lei, Chibnik, Lori B., Schneider, Julie A., Young-Pearse, Tracy L., Bennett, David A., and De Jager, Philip L.

Published
2018
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33. Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer’s disease

Author

Green, Gilad Sahar, primary, Fujita, Masashi, additional, Yang, Hyun-Sik, additional, Taga, Mariko, additional, McCabe, Cristin, additional, Cain, Anael, additional, White, Charles C., additional, Schmidtner, Anna K., additional, Zeng, Lu, additional, Wang, Yangling, additional, Regev, Aviv, additional, Menon, Vilas, additional, Bennett, David A., additional, Habib, Naomi, additional, and De Jager, Philip L., additional

Published
2023
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36. Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

Author

Fujita, Masashi, primary, Gao, Zongmei, additional, Zeng, Lu, additional, McCabe, Cristin, additional, White, Charles C., additional, Ng, Bernard, additional, Green, Gilad Sahar, additional, Rozenblatt-Rosen, Orit, additional, Phillips, Devan, additional, Amir-Zilberstein, Liat, additional, Lee, Hyo, additional, Pearse, Richard V., additional, Khan, Atlas, additional, Vardarajan, Badri N., additional, Kiryluk, Krzysztof, additional, Ye, Chun Jimmie, additional, Klein, Hans-Ulrich, additional, Wang, Gao, additional, Regev, Aviv, additional, Habib, Naomi, additional, Schneider, Julie A., additional, Wang, Yanling, additional, Young-Pearse, Tracy, additional, Mostafavi, Sara, additional, Bennett, David A., additional, Menon, Vilas, additional, and De Jager, Philip L., additional

Published
2022
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43. Genetic Evidence for a Normal-Weight “Metabolically Obese” Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes

Author

Yaghootkar, Hanieh, Scott, Robert A., White, Charles C., Zhang, Weihua, Speliotes, Elizabeth, Munroe, Patricia B., Ehret, Georg B., Bis, Joshua C., Fox, Caroline S., Walker, Mark, Borecki, Ingrid B., Knowles, Joshua W., Yerges-Armstrong, Laura, Ohlsson, Claes, Perry, John R.B., Chambers, John C., Kooner, Jaspal S., Franceschini, Nora, Langenberg, Claudia, Hivert, Marie-France, Dastani, Zari, Richards, J. Brent, Semple, Robert K., and Frayling, Timothy M.

Published
2014
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45. Identification of genes associated with dissociation of cognitive performance and neuropathological burden: Multistep analysis of genetic, epigenetic, and transcriptional data

Author

White, Charles C., Yang, Hyun-Sik, Yu, Lei, Chibnik, Lori B., Dawe, Robert J., Yang, Jingyun, Klein, Hans-Ulrich, Felsky, Daniel, Ramos-Miguel, Alfredo, Arfanakis, Konstantinos, Honer, William G., Sperling, Reisa A., Schneider, Julie A., Bennett, David A., and De Jager, Philip L.

Subjects
Cognitive disorders -- Risk factors -- Genetic aspects -- Research, Epigenetic inheritance -- Analysis -- Research -- Genetic aspects, Transcription (Genetics) -- Analysis, RNA sequencing -- Analysis, Biological sciences
Abstract

Introduction The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. Methods and findings 'Residual cognition' was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10.sup.-5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = -0.40, 95% CI -0.69 to -0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 x 10.sup.-5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622.sup.A (r.sup.2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies. Conclusions Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy., Author(s): Charles C. White 1,2, Hyun-Sik Yang 1,2,3,4, Lei Yu 5,6, Lori B. Chibnik 2,7, Robert J. Dawe 5,8, Jingyun Yang 5,6, Hans-Ulrich Klein 1,2,4, Daniel Felsky 1,2,4, Alfredo Ramos-Miguel [...]

Published
2017
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46. Multi-cellular communities are perturbed in the aging human brain and Alzheimer’s disease

Author

Cain, Anael, primary, Taga, Mariko, additional, McCabe, Cristin, additional, Green, Gilad, additional, Hekselman, Idan, additional, White, Charles C., additional, Lee, Dylan I., additional, Gaur, Pallavi, additional, Rozenblatt-Rosen, Orit, additional, Zhang, Feng, additional, Yeger-Lotem, Esti, additional, Bennett, David A., additional, Yang, Hyun-Sik, additional, Regev, Aviv, additional, Menon, Vilas, additional, Habib, Naomi, additional, and De Jager, Philip L., additional

Published
2020
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47. Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer’s Dementia

Author

Ouellette, Andrew R., primary, Neuner, Sarah M., additional, Dumitrescu, Logan, additional, Anderson, Laura C., additional, Gatti, Daniel M., additional, Mahoney, Emily R., additional, Bubier, Jason A., additional, Churchill, Gary, additional, Peters, Luanne, additional, Huentelman, Matthew J., additional, Herskowitz, Jeremy H., additional, Yang, Hyun-Sik, additional, Smith, Alexandra N., additional, Reitz, Christiane, additional, Kunkle, Brian W., additional, White, Charles C., additional, De Jager, Philip L., additional, Schneider, Julie A., additional, Bennett, David A., additional, Seyfried, Nicholas T., additional, Chesler, Elissa J., additional, Hadad, Niran, additional, Hohman, Timothy J., additional, and Kaczorowski, Catherine C., additional

Published
2020
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49. Association of social network structure and physical function in patients with multiple sclerosis

Author

Levin, Seth N., primary, Riley, Claire S., additional, Dhand, Amar, additional, White, Charles C., additional, Venkatesh, Shruthi, additional, Boehm, Blake, additional, Nassif, Caren, additional, Socia, Lauren, additional, Onomichi, Kaho, additional, Leavitt, Victoria M., additional, Levine, Libby, additional, Heyman, Rock, additional, Farber, Rebecca S., additional, Vargas, Wendy S., additional, Xia, Zongqi, additional, and De Jager, Philip L., additional

Published
2020
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50. Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology

Author

Yang, Hyun-Sik, primary, White, Charles C., additional, Klein, Hans-Ulrich, additional, Yu, Lei, additional, Gaiteri, Christopher, additional, Ma, Yiyi, additional, Felsky, Daniel, additional, Mostafavi, Sara, additional, Petyuk, Vladislav A., additional, Sperling, Reisa A., additional, Ertekin-Taner, Nilüfer, additional, Schneider, Julie A., additional, Bennett, David A., additional, and De Jager, Philip L., additional

Published
2020
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