Search

Your search keyword '"Kawalia, A"' showing total 222 results
Start Over Author "Kawalia, A"
222 results on '"Kawalia, A"'

1. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen GJ, Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J, Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W, Berr, Claudine, Bis, Joshua C, Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A, Fernández, Maria Victoria, Fox, Nick C, Galimberti, Daniela, Genin, Emmanuelle, Gille, Johan JP, Le Guen, Yann, Guerreiro, Rita, Haines, Jonathan L, Holmes, Clive, Ikram, M Arfan, Ikram, M Kamran, Jansen, Iris E, Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W, Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel MAM, Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O, Morgan, Kevin, Myers, Richard M, Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A, Raybould, Rachel, Redon, Richard, Reinders, Marcel JT, Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S, Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D, Scheltens, Philip, Schott, Jonathan M, Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik A, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccolo’, Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J, Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C, Greicius, Michael D, Yokoyama, Jennifer S, Cruchaga, Carlos, Hardy, John, and Ramirez, Alfredo

Subjects
Biological Sciences, Genetics, Dementia, Alzheimer's Disease, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Human Genome, Prevention, Acquired Cognitive Impairment, Neurodegenerative, Aging, Clinical Research, Biotechnology, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Adenosine Triphosphatases, Alzheimer Disease, ATP Binding Cassette Transporter 1, Genome-Wide Association Study, Risk Factors, Exosomes, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

Published
2022

2. 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

3. 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
DESGESCO (Dementia Genetics Spanish Consortium), EADB, EADB, IFGC (International FTD-Genomics Consortium), IPDGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Alzheimer’s disease, Amyotrophic lateral sclerosis, Dementia with Lewy bodies, Frontotemporal dementia, Longevity, Multiple sclerosis, Neurodegenerative disease, PLCG2, Parkinson’s disease, Phospholipase C Gamma 2, Progressive supranuclear palsy, Alzheimer's disease, Parkinson's disease, Alzheimer's Disease, frontotemporal dementia, dementia with Lewy-bodies, progressive suprauclear palsy, Parkinson's Disease, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disease, longevity, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
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

4. The genomic and clinical landscape of fetal akinesia

Author

Pergande, Matthias, Motameny, Susanne, Özdemir, Özkan, Kreutzer, Mona, Wang, Haicui, Daimagüler, Hülya-Sevcan, Becker, Kerstin, Karakaya, Mert, Ehrhardt, Harald, Elcioglu, Nursel, Ostojic, Slavica, Chao, Cho-Ming, Kawalia, Amit, Duman, Özgür, Koy, Anne, Hahn, Andreas, Reimann, Jens, Schoner, Katharina, Schänzer, Anne, Westhoff, Jens H., Schwaibold, Eva Maria Christina, Cossee, Mireille, Imbert-Bouteille, Marion, von Pein, Harald, Haliloglu, Göknur, Topaloglu, Haluk, Altmüller, Janine, Nürnberg, Peter, Thiele, Holger, Heller, Raoul, and Cirak, Sebahattin

Published
2020
Full Text
View/download PDF

5. Correction: The genomic and clinical landscape of fetal akinesia

Author

Pergande, Matthias, Motameny, Susanne, Özdemir, Özkan, Kreutzer, Mona, Wang, Haicui, Daimagüler, Hülya-Sevcan, Becker, Kerstin, Karakaya, Mert, Ehrhardt, Harald, Elcioglu, Nursel, Ostojic, Slavica, Chao, Cho-Ming, Kawalia, Amit, Duman, Özgür, Koy, Anne, Hahn, Andreas, Reimann, Jens, Schoner, Katharina, Schänzer, Anne, Westhoff, Jens H., Schwaibold, Eva Maria Christina, Cossee, Mireille, Imbert-Bouteille, Marion, von Pein, Harald, Haliloglu, Göknur, Topaloglu, Haluk, Altmüller, Janine, Nürnberg, Peter, Thiele, Holger, Heller, Raoul, and Cirak, Sebahattin

Published
2020
Full Text
View/download PDF

6. Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia.

Author

Rong Zhang, Jan Gehlen, Amit Kawalia, Maria-Theodora Melissari, Tikam Chand Dakal, Athira M Menon, Julia Höfele, Korbinian Riedhammer, Lea Waffenschmidt, Julia Fabian, Katinka Breuer, Jeshurun Kalanithy, Alina Christine Hilger, Amit Sharma, Alice Hölscher, Thomas M Boemers, Markus Pauly, Andreas Leutner, Jörg Fuchs, Guido Seitz, Barbara M Ludwikowski, Barbara Gomez, Jochen Hubertus, Andreas Heydweiller, Ralf Kurz, Johannes Leonhardt, Ferdinand Kosch, Stefan Holland-Cunz, Oliver Münsterer, Beno Ure, Eberhard Schmiedeke, Jörg Neser, Petra Degenhardt, Stefanie Märzheuser, Katharina Kleine, Mattias Schäfer, Nicole Spychalski, Oliver J Deffaa, Jan-Hendrik Gosemann, Martin Lacher, Stefanie Heilmann-Heimbach, Nadine Zwink, Ekkehart Jenetzky, Michael Ludwig, Phillip Grote, Johannes Schumacher, Holger Thiele, and Heiko Reutter

Subjects
Medicine, Science
Abstract

INTRODUCTION:Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. METHODS:To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. RESULTS:In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. CONCLUSION:Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.

Published
2020
Full Text
View/download PDF

7. Alzheimer’s disease-associated (hydroxy)methylomic changes in the brain and blood

Author

Lardenoije, Roy, Roubroeks, Janou A. Y., Pishva, Ehsan, Leber, Markus, Wagner, Holger, Iatrou, Artemis, Smith, Adam R., Smith, Rebecca G., Eijssen, Lars M. T., Kleineidam, Luca, Kawalia, Amit, Hoffmann, Per, Luck, Tobias, Riedel-Heller, Steffi, Jessen, Frank, Maier, Wolfgang, Wagner, Michael, Hurlemann, René, Kenis, Gunter, Ali, Muhammad, del Sol, Antonio, Mastroeni, Diego, Delvaux, Elaine, Coleman, Paul D., Mill, Jonathan, Rutten, Bart P. F., Lunnon, Katie, Ramirez, Alfredo, and van den Hove, Daniël L. A.

Published
2019
Full Text
View/download PDF

9. Rare gene deletions in genetic generalized and Rolandic epilepsies.

Author

Kamel Jabbari, Dheeraj R Bobbili, Dennis Lal, Eva M Reinthaler, Julian Schubert, Stefan Wolking, Vishal Sinha, Susanne Motameny, Holger Thiele, Amit Kawalia, Janine Altmüller, Mohammad Reza Toliat, Robert Kraaij, Jeroen van Rooij, André G Uitterlinden, M Arfan Ikram, EuroEPINOMICS CoGIE Consortium, Federico Zara, Anna-Elina Lehesjoki, Roland Krause, Fritz Zimprich, Thomas Sander, Bernd A Neubauer, Patrick May, Holger Lerche, and Peter Nürnberg

Subjects
Medicine, Science
Abstract

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE.

Published
2018
Full Text
View/download PDF

11. 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., Benito, Yolanda A., Holmes, Clive, Karamujić-Čomić, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roshchupkin, Gennady, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernández, Isabel, Kamboh, M. Ilyas, Brundin, RoseMarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluís, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, Jr, W. T., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome I., Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, George-Hyslop, Peter St, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Inés, Carracedo, Ángel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Frölich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Kölsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Hüll, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Jöckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan I., Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Nöthen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O’Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossù, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Alzheimer Disease Genetics Consortium (ADGC), The 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), Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stéphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O’Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.

Published
2019
Full Text
View/download PDF

12. Recurrent and Prolonged Infections in a Child with a Homozygous IFIH1 Nonsense Mutation

Author

Maha Zaki, Michaela Thoenes, Amit Kawalia, Peter Nürnberg, Rolf Kaiser, Raoul Heller, and Hanno J. Bolz

Subjects
IFIH1, immunodeficiency, consanguinity, infection, loss-of-function, whole-exome sequencing, Genetics, QH426-470
Abstract

In an Egyptian girl born to consanguineous parents, whole-exome sequencing (WES) identified a homozygous mutation in PHGDH, c.1273G>A (p.Val425Met), indicating 3-phosphoglycerate dehydrogenase deficiency. This diagnosis was compatible with the patient’s microcephaly, severe psychomotor retardation, seizures and cataracts. However, she additionally suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization, suggesting a secondary, predisposing and potentially Mendelian, condition. A local reactivation of an EBV infection in the respiratory tract was detected after a recent chest infection, likely representing an opportunistic infection based on a compromised immune system. Further inspection of WES data revealed a homozygous nonsense mutation, c.2665A>T (p.Lys889∗), in IFIH1, encoding MDA5. MDA5 detects long viral double-stranded RNA that is generated during replication of picorna viruses, and thereby activates the type I interferon signaling pathway. The results of Western blot analysis of protein from cultured fibroblasts of the patient indicates absence of wild type MDA5/IFIH1, compatible with NMD. We propose that, analogous to the severe course of primary influenza infection due to biallelic deficiency of a downstream effector, IRF7, homozygous loss of IFIH1 defines a novel Mendelian immunodeficiency disorder that increases susceptibility to severe viral infections. This is contrasted to heterozygous gain-of-function IFIH1 mutations in autoimmune diseases. Our findings highlight the potential of comprehensive genomic investigations in patients from consanguineous families to identify monogenic predispositions to severe infections.

Published
2017
Full Text
View/download PDF

13. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

Author

Schramm, Catherine, Charbonnier, Camille, Zaréa, Aline, Lacour, Morgane, Wallon, David, Boland, Anne, Deleuze, Jean-François, Olaso, Robert, Alarcon, Flora, Campion, Dominique, Nuel, Grégory, Nicolas, Gaël, Collaborators Daniela Andriuta, Pierre, Anthony, Sophie, Auriacombe, Anna-Chloé, Balageas, Guillaume, Ballan, Mélanie, Barbay, Emilie, Beaufils, Yannick, Béjot, Serge, Belliard, Marie, Benaiteau, Karim, Bennys, Frédéric, Blanc, Stéphanie, Bombois, Claire Boutoleau Bretonnière, Pierre, Branger, Jasmine, Carlier, Leslie, Cartz-Piver, Pascaline, Cassagnaud, Giovanni, Castelnovo, Christine, Champion, Annabelle, Chaussenot, Mathieu, Ceccaldi, Valérie, Chauviré, Yaohua, Chen, Julien, Cogez, Emmanuel, Cognat, Fabienne, Contegal-Callier, Lea, Corneille, Philippe, Couratier, Hélène, Courtemanche, Benjamin, Cretin, Charlotte, Crinquette, Bernard, Croisille, Benjamin, Dauriat, Sophie, Dautricourt, Vincent de la Sayette, Astrid De Liège, Marie De Verdal, Didier, Deffond, Benoit, Delpont, Florence, Demurger, Vincent, Deramecourt, Céline, Derollez, Mira, Didic, Giulia, Diemert, Elsa, Dionet, Philippe, Diraison, Aude, Doan, Martine Doco Fenzy, Boris, Dufournet, Julien, Dumurgier, Hélène, Durand, Anas, Dutray, Frédérique, Etcharry-Bouyx, Maté, Formaglio, Audrey, Gabelle, Anne, Gainche-Salmon, Jean-Claude, Getenet, Emmanuelle, Ginglinger, Olivier, Godefroy, Mathilde, Graber, Chloé, Gregoire, Stephan, Grimaldi, Julien, Gueniat, Claude, Gueriot, Sophie, Haffen, Lorraine, Hamelin, Didier, Hannequin, Cezara, Hanta, Clémence, Hardy, Geoffroy, Hautecloque, Camille, Heitz, Claire, Hourregue, Thérèse, Jonveaux, Snejana, Jurici, Catia, Khoumri, Lejla, Koric, Pierre, Krolak-Salmon, Pierre, Labauge, Morgane, Lacour, Julien, Lagarde, Hélène-Marie, Lanoiselée, Brice, Laurens, Isabelle Le Ber, Gwenaël Le Guyader, Amélie, Leblanc, Thibaud, Lebouvier, Anas, Lippi, Marie-Anne, Mackowiak, Eloi, Magnin, Cecilia, Marelli, Olivier, Martinaud, Aurélien, Maureille, Emilie, Milongo-Rigal, Sophie, Mohr, Hélène, Mollion, Olivier, Moreaud, Alexandre, Morin, Gaël, Nicolas, Julia, Nivelle, Camille, Noiray, Elisabeth, Ollagnon-Roman, Claire, Paquet, Jérémie, Pariente, Florence, Pasquier, Alexandre, Perron, Nathalie, Philippi, Virginie, Pichon, Vincent, Planche, Céline, Poirsier, Marie, Rafiq, Pauline, Rod-Olivieri, Adeline, Rollin-Sillaire, Carole, Roué-Jagot, Dario, Saracino, Marie, Sarazin, Mathilde, Sauvée, François, Sellal, Lila Sirven Villaros, Christel, Thauvin, Camille, Tisserand, Christophe, Tomasino, Cédric, Turpinat, Laurène Van Damme, Olivier, Vercruysse, Alice, Voilly, Nathalie, Wagemann, David, Wallon, Aline, Zarea, Shahzad, Ahmad, Philippe, Amouyel, Claudine, Berr, Anne, Boland, Paola, Bossu, Femke, Bouwman, Jose, Bras, Dominique, Campion, Camille, Charbonnier, Jordi, Clarimon, Antonio, Daniele, Jean-François, Dartigues, Stéphanie, Debette, Jean-François, Deleuze, Nicola, Denning, Oriol, Dols-Icardo, Nick, C Fox, Daniela, Galimberti, Emmanuelle, Génin, Hans, Gille, Benjamin, Grenier-Boley, Detelina, Grozeva, Rita, Guerreiro, John, J Hardy, Clive, Holmes, Henne, Holstege, Marc, Hulsman, Holger, Hummerich, M Arfan Ikram, M Kamran Ikram, Iris, Jansen, Amit, Kawalia, Robert, Kraaij, Jean-Charles, Lambert, Marc, Lathrop, Afina, W Lemstra, Alberto, Lleo, Lauren, Luckcuck, Marcel M A, M Mannens, Rachel, Marshall, Carlo, Masullo, Simon, Mead, Mecocci, Patrizia, Alun, Meggy, Merel, O Mol, Kevin, Morgan, Benedetta, Nacmias, Penny, J Norsworthy, Pau, Pastor, Olivier, Quenez, Alfredo, Ramirez, Rachel, Raybould, Richard, Redon, Marcel J, T Reinders, Anne-Claire, Richard, Steffi, G Riedel-Heller, Fernando, Rivadeneira, Stéphane, Rousseau, Natalie, S Ryan, Salha, Saad, Pascual, Sanchez-Juan, Philip, Scheltens, Jonathan, M Schott, Davide, Seripa, Daoud, Sie, Rebecca, Sims, Erik, Sistermans, Sandro, Sorbi, Resie van Spaendonk, Gianfranco, Spalleta, Nicćolo, Tesi, Betty, Tijms, André, G Uitterlinden, Wiesje, M van der Flier, Sven, J van der Lee, Cornelia, M van Duijn, Jeroen G, J van Rooij, John, C van Swieten, Pieter, J de Visser, Michael, Wagner, and Julie, Williams

Subjects
Genotype, Membrane Transport Proteins, Penetrance, Lifetime risk, Pedigree, Expectation-maximization algorithm, Settore MED/26 - NEUROLOGIA, Apolipoproteins E, Missing genotypes, Alzheimer Disease, Case-Control Studies, SORL1, Alzheimer, Genetics, Humans, Molecular Medicine, Molecular Biology, LDL-Receptor Related Proteins, APOE, Genetics (clinical)
Abstract

Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. Conclusions We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.

Published
2022

14. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Author

Moawia, Abubakar, Shaheen, Ranad, Rasool, Sajida, Waseem, Syeda Seema, Ewida, Nour, Budde, Birgit, Kawalia, Amit, Motameny, Susanne, Khan, Kamal, Fatima, Ambrin, Jameel, Muhammad, Ullah, Farid, Akram, Talia, Ali, Zafar, Abdullah, Uzma, Irshad, Saba, Höhne, Wolfgang, Noegel, Angelika Anna, Al‐Owain, Mohammed, Hörtnagel, Konstanze, Stöbe, Petra, Baig, Shahid Mahmood, Nürnberg, Peter, Alkuraya, Fowzan Sami, Hahn, Andreas, and Hussain, Muhammad Sajid

Published
2017
Full Text
View/download PDF

15. Comprehensive molecular analysis of 61 Egyptian families with hereditary nonsyndromic hearing loss

Author

Janine Altmüller, Birgit Budde, Holger Thiele, Susanne Motameny, Peter Nürnberg, Kathryn Konrad, Eman Abdel Fattah Sayed, Christian Becker, Mostafa R. Mohamed, Andreas Breß, Mohammad R. Toliat, Enass S. Mohamed, Amit Kawalia, Markus Pfister, Gudrun Nürnberg, and Maha Abdelgaber Aly

Subjects
Male, 0301 basic medicine, MYO15A, Candidate gene, MYO7A, Hearing loss, Hearing Loss, Sensorineural, Deafness, 030105 genetics & heredity, Biology, 03 medical and health sciences, Genetic linkage, otorhinolaryngologic diseases, Genetics, medicine, Humans, Family, Genetics (clinical), Massive parallel sequencing, Genetic heterogeneity, High-Throughput Nucleotide Sequencing, Pedigree, 030104 developmental biology, Etiology, Egypt, Female, medicine.symptom
Abstract

Nonsyndromic hearing loss is an extremely heterogeneous disorder. Thus, clinical diagnostics is challenging, in particular due to differences in the etiology of hearing loss between populations. With this study, we wanted to elucidate the genetic basis of hearing loss in 61 consanguineous Egyptian families. In 25 families, linkage analysis was used as a prescreening to identify regions for targeted sequencing of candidate genes. Initially, the coding regions of 12 and later of 94 genes associated with hearing loss were enriched and subjected to massively parallel sequencing (MPS) with diagnostic yields of 36% and 75%, respectively. Causative variants were identified in 48 families (79%). They were found in 23 different genes with the majority being located in MYO15A (15.3%), SLC26A4 (9.7%), GJB2 (8.3%), and MYO7A (6.4%). As many as 32 variants were novel ones at the time of detection. Five variants were shared by two, three, or even four families. Our study provides a first survey of the mutational spectrum of deaf patients in Egypt revealing less GJB2 variants than in many European populations. It underlines the value of targeted enrichment of well-selected deafness genes in combination with MPS in the diagnostics of this frequent and genetically heterogeneous disorder.

Published
2020

16. Leveraging the power of high performance computing for next generation sequencing data analysis: tricks and twists from a high throughput exome workflow.

Author

Amit Kawalia, Susanne Motameny, Stephan Wonczak, Holger Thiele, Lech Nieroda, Kamel Jabbari, Stefan Borowski, Vishal Sinha, Wilfried Gunia, Ulrich Lang, Viktor Achter, and Peter Nürnberg

Subjects
Medicine, Science
Abstract

Next generation sequencing (NGS) has been a great success and is now a standard method of research in the life sciences. With this technology, dozens of whole genomes or hundreds of exomes can be sequenced in rather short time, producing huge amounts of data. Complex bioinformatics analyses are required to turn these data into scientific findings. In order to run these analyses fast, automated workflows implemented on high performance computers are state of the art. While providing sufficient compute power and storage to meet the NGS data challenge, high performance computing (HPC) systems require special care when utilized for high throughput processing. This is especially true if the HPC system is shared by different users. Here, stability, robustness and maintainability are as important for automated workflows as speed and throughput. To achieve all of these aims, dedicated solutions have to be developed. In this paper, we present the tricks and twists that we utilized in the implementation of our exome data processing workflow. It may serve as a guideline for other high throughput data analysis projects using a similar infrastructure. The code implementing our solutions is provided in the supporting information files.

Published
2015
Full Text
View/download PDF

17. The genomic and clinical landscape of fetal akinesia

Author

Eva Maria Christina Schwaibold, Katharina Schoner, Harald von Pein, Haluk Topaloglu, Harald Ehrhardt, Goknur Haliloglu, Raoul Heller, Haicui Wang, Mona Kreutzer, Mireille Cossée, Andreas Hahn, Slavica Ostojic, Anne Schänzer, Cho-Ming Chao, Mert Karakaya, Özgür Duman, Janine Altmüller, Nursel Elcioglu, Susanne Motameny, Hülya-Sevcan Daimagüler, Holger Thiele, Anne Koy, Özkan Özdemir, Sebahattin Cirak, Marion Imbert-Bouteille, Kerstin Becker, Amit Kawalia, Jens Reimann, Peter Nürnberg, Matthias Pergande, Jens H. Westhoff, Center for Molecular Medicine [Cologne] (CMMC), University of Cologne, Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine, University of Cologne, Cologne Center for Genomics [Cologne] (CCG), University Hospital of Cologne [Cologne], Institute of Human Genetics [Cologne], Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne, Justus-Liebig-Universität Gießen (JLU), Marmara University [Kadıköy - İstanbul], Eastern Mediterranean University (EMU), Mother and Child Health Care Institute of Serbia [Belgrade, Serbia] (MCHCI), Akdeniz University, Rheinische Friedrich-Wilhelms-Universität Bonn, Philipps University of Marburg, Department of Neurology, Justus-Liebig-University, University Children's Hospital of Heidelberg [Heidelberg, Germany], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, University Medical Center of the Johannes Gutenberg-University Mainz, Hacettepe University Children's Hospital, Genetic Health Service New Zealand, Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, Pergande, Matthias, Motameny, Susanne, Oezdemir, Oezkan, Kreutzer, Mona, Wang, Haicui, Daimagueler, Huelya-Sevcan, Becker, Kerstin, Karakaya, Mert, Ehrhardt, Harald, Elcioglu, Nursel, Ostojic, Slavica, Chao, Cho-Ming, Kawalia, Amit, Duman, Ozgur, Koy, Anne, Hahn, Andreas, Reimann, Jens, Schoner, Katharina, Schaenzer, Anne, Westhoff, Jens H., Schwaibold, Eva Maria Christina, Cossee, Mireille, Imbert-Bouteille, Marion, von Pein, Harald, Haliloglu, Goknur, Topaloglu, Haluk, Altmueller, Janine, Nuernberg, Peter, Thiele, Holger, Heller, Raoul, and Cirak, Sebahattin

Subjects
Male, Candidate gene, Myopathy, VARIANTS, Fetal akinesia, MESH: Ryanodine Receptor Calcium Release Channel, 0302 clinical medicine, MESH: Child, Guanine Nucleotide Exchange Factors, MESH: Guanine Nucleotide Exchange Factors, Exome, Copy-number variation, Child, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), Genetics, Arthrogryposis, 0303 health sciences, MESH: Infant, Newborn, MESH: Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, RNA-Binding Proteins, MESH: Infant, 3. Good health, Fetal Diseases, MESH: Fetal Diseases, MESH: Young Adult, Child, Preschool, ASAH1, Female, MESH: DNA Copy Number Variations, medicine.symptom, Adult, GENETICS, Adolescent, DNA Copy Number Variations, MESH: Trans-Activators, MESH: Arthrogryposis, Biology, ASPM, Young Adult, 03 medical and health sciences, Muscular Diseases, medicine, Humans, Genetic Predisposition to Disease, Gene, 030304 developmental biology, MESH: Adolescent, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, MUTATIONS, MESH: Child, Preschool, Infant, Newborn, MESH: Muscular Diseases, Infant, NEMALINE MYOPATHY, Ryanodine Receptor Calcium Release Channel, MESH: Adult, medicine.disease, Congenital myopathy, MESH: Male, MESH: RNA-Binding Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DISTAL ARTHROGRYPOSIS, Trans-Activators, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood.Methods: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA).Results: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis.Conclusion: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.

Published
2020

18. Correction: The genomic and clinical landscape of fetal akinesia

Author

Peter Nürnberg, Katharina Schoner, Haluk Topaloglu, Goknur Haliloglu, Janine Altmüller, Mert Karakaya, Harald Ehrhardt, Hülya-Sevcan Daimagüler, Susanne Motameny, Sebahattin Cirak, Anne Koy, Eva Maria Christina Schwaibold, Mona Kreutzer, Kerstin Becker, Cho-Ming Chao, Marion Imbert-Bouteille, Haicui Wang, Matthias Pergande, Amit Kawalia, Jens H. Westhoff, Jens Reimann, Slavica Ostojic, Harald von Pein, Nursel Elcioglu, Özkan Özdemir, Mireille Cossée, Andreas Hahn, Özgür Duman, Holger Thiele, Raoul Heller, and Anne Schänzer

Subjects
Fetal akinesia, business.industry, Published Erratum, Hardware_INTEGRATEDCIRCUITS, MEDLINE, Medicine, ComputingMilieux_LEGALASPECTSOFCOMPUTING, ComputerApplications_COMPUTERSINOTHERSYSTEMS, Hardware_PERFORMANCEANDRELIABILITY, Bioinformatics, business, GeneralLiterature_MISCELLANEOUS, Genetics (clinical)
Abstract

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

Published
2020

19. Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes

Author

Reinthaler, Eva M., Dejanovic, Borislav, Lal, Dennis, Semtner, Marcus, Merkler, Yvonne, Reinhold, Annika, Pittrich, Dorothea A., Hotzy, Christoph, Feucht, Martha, Steinböck, Hannelore, Gruber-Sedlmayr, Ursula, Ronen, Gabriel M., Neophytou, Birgit, Geldner, Julia, Haberlandt, Edda, Muhle, Hiltrud, Ikram, Arfan M., van Duijn, Cornelia M., Uitterlinden, Andre G., Hofman, Albert, Altmüller, Janine, Kawalia, Amit, Toliat, Mohammad R., Nürnberg, Peter, Lerche, Holger, Nothnagel, Michael, Thiele, Holger, Sander, Thomas, Meier, Jochen C., Schwarz, Günter, Neubauer, Bernd A., and Zimprich, Fritz

Published
2015
Full Text
View/download PDF

20. SORL1 ‐variant carriers in ADES‐ADSP: A higher level of variant pathogenicity associates with earlier age at onset of Alzheimer's disease

Author

Rebecca Sims, Detelina Grozeva, John Hardy, Jordi Clarimón, Cornelia M. van Duijn, Gaël Nicolas, Kin Y. Mok, Najaf Amin, Maryam Shoai, Benjamin Grenier-Boley, Jeroen van Rooij, Philippe Amouyel, Oriol Dols-Icardo, Holger Hummerich, Shahzad Ahmad, Penny Norsworthy, Henne Holstege, Olivier Quenez, Amit Kawalia, Marc Hulsman, Camille Charbonnier, Alfredo Ramirez, Julie Williams, Simon Mead, Céline Bellenguez, John C. van Swieten, Jean-Charles Lambert, and Wiesje M. van der Flier

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, SORL1, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Pathogenicity
Published
2020

21. Exome sequencing identifies three novel AD‐associated genes

Author

Jean-Charles Lambert, Kin Y. Mok, Olivier Quenez, Cornelia M. van Duijn, Wiesje M. van der Flier, Alfredo Ramirez, Philippe Amouyel, Gaël Nicolas, Amit Kawalia, Shahzad Ahmad, Simon Mead, Marc Hulsman, Detelina Grozeva, Penny Norsworthy, Holger Hummerich, John C. van Swieten, Henne Holstege, Rebecca Sims, Julie Williams, Céline Bellenguez, Jordi Clarimón, Najaf Amin, Maryam Shoai, Jeroen van Rooij, Oriol Dols-Icardo, Camille Charbonnier, Benjamin Grenier-Boley, and John Hardy

Subjects
Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Gene, Exome sequencing
Published
2020

22. DEPDC5 mutations in genetic focal epilepsies of childhood

Author

Lal, Dennis, Reinthaler, Eva M., Schubert, Julian, Muhle, Hiltrud, Riesch, Erik, Kluger, Gerhard, Jabbari, Kamel, Kawalia, Amit, Bäumel, Christine, Holthausen, Hans, Hahn, Andreas, Feucht, Martha, Neophytou, Birgit, Haberlandt, Edda, Becker, Felicitas, Altmüller, Janine, Thiele, Holger, Lemke, Johannes R., Lerche, Holger, Nürnberg, Peter, Sander, Thomas, Weber, Yvonne, Zimprich, Fritz, and Neubauer, Bernd A.

Published
2014
Full Text
View/download PDF

23. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as novel risk factors for Alzheimer’s Disease

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier-Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen G.J., Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny J., Dols-Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W., Berr, Claudine, Bis, Joshua C., Boland, Anne, Bossù, Paola, Bouwman, Femke, Bras, Jose, Campion, Dominique, Cochran, J. Nicholas, Daniele, Antonio, Dartigues, Jean-François, Debette, Stéphanie, Deleuze, Jean-François, Denning, Nicola, DeStefano, Anita L, Farrer, Lindsay A., Fernandez, Maria Victoria, Fox, Nick C., Galimberti, Daniela, Genin, Emmanuelle, Gille, Hans, Guen, Yann Le, Guerreiro, Rita, Haines, Jonathan L., Holmes, Clive, Ikram, M. Arfan, Ikram, M. Kamran, Jansen, Iris E., Kraaij, Robert, Lathrop, Marc, Lemstra, Afina W., Lleó, Alberto, Luckcuck, Lauren, Mannens, Marcel M. A. M., Marshall, Rachel, Martin, Eden R, Masullo, Carlo, Mayeux, Richard, Mecocci, Patrizia, Meggy, Alun, Mol, Merel O., Morgan, Kevin, Myers, Richard M., Nacmias, Benedetta, Naj, Adam C, Napolioni, Valerio, Pasquier, Florence, Pastor, Pau, Pericak-Vance, Margaret A., Raybould, Rachel, Redon, Richard, Reinders, Marcel J.T., Richard, Anne-Claire, Riedel-Heller, Steffi G, Rivadeneira, Fernando, Rousseau, Stéphane, Ryan, Natalie S., Saad, Salha, Sanchez-Juan, Pascual, Schellenberg, Gerard D., Scheltens, Philip, Schott, Jonathan M., Seripa, Davide, Seshadri, Sudha, Sie, Daoud, Sistermans, Erik, Sorbi, Sandro, van Spaendonk, Resie, Spalletta, Gianfranco, Tesi, Niccólo, Tijms, Betty, Uitterlinden, André G, van der Lee, Sven J., de Visser, Pieter Jelle, Wagner, Michael, Wallon, David, Wang, Li-San, Zarea, Aline, Clarimon, Jordi, van Swieten, John C., Greicius, Michael D., Yokoyama, Jennifer S., Cruchaga, Carlos, Hardy, John, Ramirez, Alfredo, Mead, Simon, van der Flier, Wiesje M., van Duijn, Cornelia M, Williams, Julie, Nicolas, Gaël, Bellenguez, Céline, and Lambert, Jean-Charles

Subjects
Genetics, symbols.namesake, TREM2, SORL1, Mendelian inheritance, symbols, Disease, Allele, Biology, Genome, Gene, Exome sequencing
Abstract

Background With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimer’s Disease (AD), reaching odds ratios comparable with the APOE-e4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenize and analyze these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analyzed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritized using REVEL. Result We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion With our newly developed homogenization methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuroinflammatory processes in AD pathophysiology.

Published
2020

24. Comprehensive molecular analysis of 61 Egyptian families with hereditary nonsyndromic hearing loss

Author

Budde, B.S., Aly, M.A., Mohamed, M.R., Breß, A., Altmüller, J., Motameny, S., Kawalia, A., Thiele, H., Konrad, K., Becker, C., Toliat, M.R., Nürnberg, G., Sayed, E.A.F., Mohamed, E.S., Pfister, M., and Nürnberg, P.

Subjects
Technology Platforms
Abstract

Nonsyndromic hearing loss is an extremely heterogeneous disorder. Thus, clinical diagnostics is challenging, in particular due to differences in the etiology of hearing loss between populations. With this study, we wanted to elucidate the genetic basis of hearing loss in 61 consanguineous Egyptian families. In 25 families, linkage analysis was used as a prescreening to identify regions for targeted sequencing of candidate genes. Initially, the coding regions of 12 and later of 94 genes associated with hearing loss were enriched and subjected to massively parallel sequencing (MPS) with diagnostic yields of 36% and 75%, respectively. Causative variants were identified in 48 families (79%). They were found in 23 different genes with the majority being located in MYO15A (15.3%), SLC26A4 (9.7%), GJB2 (8.3%), and MYO7A (6.4%). As many as 32 variants were novel ones at the time of detection. Five variants were shared by two, three, or even four families. Our study provides a first survey of the mutational spectrum of deaf patients in Egypt revealing less GJB2 variants than in many European populations. It underlines the value of targeted enrichment of well-selected deafness genes in combination with MPS in the diagnostics of this frequent and genetically heterogeneous disorder.

Published
2020

25. Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

Author

Jeshurun C Kalanithy, Heiko Reutter, Oliver Münsterer, Katharina Kleine, Oliver Johannes Deffaa, Andreas Heydweiller, Beno Ure, Andreas Leutner, Alina C. Hilger, Stefanie Heilmann-Heimbach, Rong Zhang, Maria-Theodora Melissari, Nicole Spychalski, Ralf Kurz, Barbara Ludwikowski, Markus Pauly, Jörg Fuchs, Amit Kawalia, Jochen Hubertus, Eberhard Schmiedeke, Holger Thiele, Korbinian M. Riedhammer, Stefanie Märzheuser, Ferdinand Kosch, Jan Gehlen, Alice Hölscher, Ekkehart Jenetzky, Amit Sharma, Johannes Leonhardt, Julia Fabian, Michael Ludwig, Athira M. Menon, Guido Seitz, Barbara Gomez, Tikam Chand Dakal, Mattias Schäfer, Julia Höfele, Jan-Hendrik Gosemann, Johannes Schumacher, Lea Waffenschmidt, Nadine Zwink, Jörg Neser, Thomas M. Boemers, Phillip Grote, Martin Lacher, Petra Degenhardt, Stefan Holland-Cunz, Katinka Breuer, and Pastor Santos-Cortez, Regie Lyn

Subjects
Embryology, Candidate gene, Gene Expression, Transcriptome, Mice, Database and Informatics Methods, Medicine and Health Sciences, Exome, Exome sequencing, Genetics, 0303 health sciences, Multidisciplinary, Computer-Aided Drug Design, 030305 genetics & heredity, Sequence analysis, Genomics, Congenital Anomalies, DNA-Binding Proteins, embryonic structures, Amino Acid Analysis, Medicine, Transcriptome Analysis, Tracheoesophageal Fistula, Research Article, Drug Research and Development, Bioinformatics, Science, In silico, Biology, Research and Analysis Methods, 03 medical and health sciences, Exome Sequencing, Congenital Disorders, Animals, Humans, ddc:610, Molecular Biology Techniques, Esophageal Atresia, Molecular Biology, DNA sequence analysis, 030304 developmental biology, Homeodomain Proteins, Pharmacology, Molecular Biology Assays and Analysis Techniques, Gene Expression Profiling, Embryos, DNA Helicases, Biology and Life Sciences, Computational Biology, Embryo, Mammalian, Genome Analysis, FANCB, Repressor Proteins, Gene expression profiling, Biological Databases, Drug Design, Mutation Databases, Mutation, Developmental Biology
Abstract

Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.

Published
2020

26. 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 (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

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 F.M., 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 N.M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodríguez Rodríguez, Eloy, Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B.J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Nilsson, K., Nilsson, C., Mackenzie, I. R.A., Hsiung, G. Y.R., Mann, D. M.A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C.M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G.P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J.T., 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 A.L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A., Sørensen, Thorkild I.A., Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Geschwind, D. H., Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M., and Holstege, Henne

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

27. 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 (Acta Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author

van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernandez, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleo, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J., Moreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illan-Gala, I., Wei, W., Jeune, B., Orellana, A., Then Bergh, F., Wang, X., Hulsman, M., Beker, N., Tesi, N., Morris, C. M., Indakoetxea, B., Collij, L. E., Scherer, M., Morenas-Rodriguez, E., Ironside, J. W., van Berckel, B. N. M., Alcolea, D., Wiendl, H., Strickland, S. L., Pastor, P., Rodriguez Rodriguez, E., Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldo, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, B. F., Petersen, R. C., Ferman, T. J., van Gerpen, J. A., Reinders, M. J. T., Uitti, R. J., Tarraga, L., Maier, W., Dols-Icardo, O., Kawalia, A., Dalmasso, M. C., Boada, M., Zettl, U. K., van Schoor, N. M., Beekman, M., Allen, M., Masliah, E., de Munain, A. L., Pantelyat, A., Wszolek, Z. K., Ross, O. A., Dickson, D. W., Graff-Radford, N. R., Knopman, D., Rademakers, R., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Gasser, T., Chinnery, P. F., Hemmer, B., Huisman, M. A., Troncoso, J., Moreno, F., Nohr, E. A., Sorensen, T. I. A., Heutink, P., Sanchez-Juan, P., Posthuma, D., Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., Decarli, C., Geschwind, D. H., Clarimon, J., Christensen, K., Ertekin-Taner, N., Scholz, S. W., Ramirez, A., Ruiz, A., Slagboom, E., van der Flier, W. M., Holstege, H., Neurology, Epidemiology and Data Science, Human genetics, APH - Societal Participation & Health, APH - Aging & Later Life, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, and APH - Methodology

Subjects
education
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

28. Author response for 'Comprehensive molecular analysis of 61 Egyptian families with hereditary nonsyndromic hearing loss'

Author

Birgit Budde, Christian Becker, Markus Pfister, Kathryn Konrad, Mohammad R. Toliat, Maha Abdelgaber Aly, Mostafa R. Mohamed, Holger Thiele, Andreas Breß, Enass S. Mohamed, Amit Kawalia, Susanne Motameny, Peter Nürnberg, Janine Altmüller, Gudrun Nürnberg, and Eman Abdel-Fattah Said

Subjects
medicine.medical_specialty, business.industry, Hearing loss, medicine, Audiology, medicine.symptom, business, Molecular analysis
Published
2020

29. Exome sequencing identifies novel AD-associated genes

Author

Henne Holstege, Marc Hulsman, Camille Charbonnier, Benjamin Grenier-Boley, Olivier Quenez, Detelina Grozeva, Jeroen G.J. van Rooij, Rebecca Sims, Shahzad Ahmad, Najaf Amin, Penny J. Norsworthy, Oriol Dols-Icardo, Holger Hummerich, Amit Kawalia, Philippe Amouyel, Gary W. Beecham, Claudine Berr, Joshua C. Bis, Anne Boland, Paola Bossù, Femke Bouwman, Dominique Campion, Antonio Daniele, Jean-Franço

Published
2020
Full Text
View/download PDF

30. 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 (vol 138, pg 237, 2019)

Author

van der Lee, SJ, Conway, OJ, Jansen, I, Carrasquillo, MM, Kleineidam, L, van den Akker, E, Hernandez, I, van Eijk, KR, Stringa, N, Chen, JSA, Zettergren, A, Andlauer, TFM, Diez-Fairen, M, Simon-Sanchez, J, Lleo, 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, Illan-Gala, I, Wei, W, Jeune, B, Orellana, A, Bergh, FT, Wang, X, Hulsman, M, Beker, N, Tesi, N, Morris, CM, Indakoetxea, B, Collij, LE, Scherer, M, Morenas-Rodriguez, E, Ironside, JW, van Berckel, BNM, Alcolea, D, Wiendl, H, Strickland, SL, Pastor, P, Rodriguez, ER, Boeve, BF, Petersen, RC, Ferman, TJ, van Gerpen, JA, Reinders, MJT, Uitti, RJ, Tarraga, 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, Sorensen, TIA, Heutink, P, Sanchez-Juan, P, Posthuma, D, Clarim?on, J, Christensen, K, Ertekin-Taner, N, Scholz, SW, Ramirez, A, Ruiz, A, Slagboom, E, van der Flier, WM, and Holstege, H

Subjects
education
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

31. Comprehensive molecular analysis of 61 Egyptian families with hereditary nonsyndromic hearing loss

Author

Budde, Birgit S., Aly, Maha Abdelgaber, Mohamed, Mostafa R., Bress, Andreas, Altmueller, Janine, Motameny, Susanne, Kawalia, Amit, Thiele, Holger, Konrad, Kathryn, Becker, Christian, Toliat, Mohammad R., Nuernberg, Gudrun, Sayed, Eman Abdel Fattah, Mohamed, Enass Sayed, Pfister, Markus, Nuernberg, Peter, Budde, Birgit S., Aly, Maha Abdelgaber, Mohamed, Mostafa R., Bress, Andreas, Altmueller, Janine, Motameny, Susanne, Kawalia, Amit, Thiele, Holger, Konrad, Kathryn, Becker, Christian, Toliat, Mohammad R., Nuernberg, Gudrun, Sayed, Eman Abdel Fattah, Mohamed, Enass Sayed, Pfister, Markus, and Nuernberg, Peter

Abstract

Nonsyndromic hearing loss is an extremely heterogeneous disorder. Thus, clinical diagnostics is challenging, in particular due to differences in the etiology of hearing loss between populations. With this study, we wanted to elucidate the genetic basis of hearing loss in 61 consanguineous Egyptian families. In 25 families, linkage analysis was used as a prescreening to identify regions for targeted sequencing of candidate genes. Initially, the coding regions of 12 and later of 94 genes associated with hearing loss were enriched and subjected to massively parallel sequencing (MPS) with diagnostic yields of 36% and 75%, respectively. Causative variants were identified in 48 families (79%). They were found in 23 different genes with the majority being located in MYO15A (15.3%), SLC26A4 (9.7%), GJB2 (8.3%), and MYO7A (6.4%). As many as 32 variants were novel ones at the time of detection. Five variants were shared by two, three, or even four families. Our study provides a first survey of the mutational spectrum of deaf patients in Egypt revealing less GJB2 variants than in many European populations. It underlines the value of targeted enrichment of well-selected deafness genes in combination with MPS in the diagnostics of this frequent and genetically heterogeneous disorder.

Published
2020

32. 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 (vol 138, pg 237, 2019)

Author

van der Lee, Sven J., Conway, Olivia J., Jansen, Iris, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernandez, Isabel, van Eijk, Kristel R., Stringa, Najada, Chen, Jason A., Zettergren, Anna, Andlauer, Till F. M., Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleo, 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, Illan-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begona, Collij, Lyduine E., Scherer, Martin, Morenas-Rodriguez, Estrella, Ironside, James W., van Berckel, Bart N. M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodriguez Rodriguez, Eloy, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J. T., Uitti, Ryan J., Tarraga, Lluis, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Merce, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo Lopez, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A. L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin., Nohr, Ellen A., Sorensen, Thorkild I. A., Heutink, Peter, Sanchez-Juan, Pascual, Posthuma, Danielle, Clarimon, Jordi, Christensen, Kaare, Ertekin-Taner, Nilufer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustin, Slagboom, Eline, van der Flier, Wiesje M., Holstege, Henne, van der Lee, Sven J., Conway, Olivia J., Jansen, Iris, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernandez, Isabel, van Eijk, Kristel R., Stringa, Najada, Chen, Jason A., Zettergren, Anna, Andlauer, Till F. M., Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleo, 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, Illan-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begona, Collij, Lyduine E., Scherer, Martin, Morenas-Rodriguez, Estrella, Ironside, James W., van Berckel, Bart N. M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodriguez Rodriguez, Eloy, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J. T., Uitti, Ryan J., Tarraga, Lluis, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Merce, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo Lopez, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A. L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin., Nohr, Ellen A., Sorensen, Thorkild I. A., Heutink, Peter, Sanchez-Juan, Pascual, Posthuma, Danielle, Clarimon, Jordi, Christensen, Kaare, Ertekin-Taner, Nilufer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustin, Slagboom, Eline, van der Flier, Wiesje M., and Holstege, Henne

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

33. Human exome and mouse embryonic expression data implicateZFHX3,TRPS1, andCHD7in human esophageal atresia

Author

Zhang, Rong, Gehlen, Jan, Kawalia, Amit, Melissari, Maria-Theodora, Dakal, Tikam Chand, Menon, Athira M., Hoefele, Julia, Riedhammer, Korbinian, Waffenschmidt, Lea, Fabian, Julia, Breuer, Katinka, Kalanithy, Jeshurun, Hilger, Alina Christine, Sharma, Amit, Hoelscher, Alice, Boemers, Thomas M., Pauly, Markus, Leutner, Andreas, Fuchs, Joerg, Seitz, Guido, Ludwikowski, Barbara M., Gomez, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Kurz, Ralf, Leonhardt, Johannes, Kosch, Ferdinand, Holland-Cunz, Stefan, Muensterer, Oliver, Ure, Beno, Schmiedeke, Eberhard, Neser, Joerg, Degenhardt, Petra, Maerzheuser, Stefanie, Kleine, Katharina, Schaefer, Mattias, Spychalski, Nicole, Deffaa, Oliver J., Gosemann, Jan-Hendrik, Lacher, Martin, Heilmann-Heimbach, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Ludwig, Michael, Grote, Phillip, Schumacher, Johannes, Thiele, Holger, Reutter, Heiko, Zhang, Rong, Gehlen, Jan, Kawalia, Amit, Melissari, Maria-Theodora, Dakal, Tikam Chand, Menon, Athira M., Hoefele, Julia, Riedhammer, Korbinian, Waffenschmidt, Lea, Fabian, Julia, Breuer, Katinka, Kalanithy, Jeshurun, Hilger, Alina Christine, Sharma, Amit, Hoelscher, Alice, Boemers, Thomas M., Pauly, Markus, Leutner, Andreas, Fuchs, Joerg, Seitz, Guido, Ludwikowski, Barbara M., Gomez, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Kurz, Ralf, Leonhardt, Johannes, Kosch, Ferdinand, Holland-Cunz, Stefan, Muensterer, Oliver, Ure, Beno, Schmiedeke, Eberhard, Neser, Joerg, Degenhardt, Petra, Maerzheuser, Stefanie, Kleine, Katharina, Schaefer, Mattias, Spychalski, Nicole, Deffaa, Oliver J., Gosemann, Jan-Hendrik, Lacher, Martin, Heilmann-Heimbach, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Ludwig, Michael, Grote, Phillip, Schumacher, Johannes, Thiele, Holger, and Reutter, Heiko

Abstract

Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutationalde novoevents in genes involved in foregut development. Methods To identify mutationalde novoevents in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmedde novovariants were prioritized usingin silicoprediction tools. To investigate the embryonic role of genes harboring prioritizedde novovariants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results In total we prioritized 14 novelde novovariants in 14 different genes (APOL2,EEF1D,CHD7,FANCB,GGT6,KIAA0556,NFX1,NPR2,PIGC,SLC5A2,TANC2,TRPS1,UBA3, andZFHX3) and eight rarede novovariants in eight additional genes (CELSR1,CLP1,GPR133,HPS3,MTA3,PLEC,STAB1, andPPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rarede novovariant inZFHX3.In silicoprediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritizedCHD7,TRPS1, andZFHX3as EA/TEF candidate genes. Re-sequencing ofZFHX3in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion Our study suggests that rare mutationalde novoevents in genes involved in foregut development contribute to the development of EA/TEF.

Published
2020

34. A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2

Author

Karsak, Meliha, Glebov, Konstantin, Scheffold, Marina, Bajaj, Thomas, Kawalia, Amit, Karaca, Ilker, Rading, Sebastian, Kornhuber, Johannes, Peters, Oliver, Diez-Fairen, Monica, Froelich, Lutz, Huell, Michael, Wiltfang, Jens, Scherer, Martin, Riedel-Heller, Steffi, Schneider, Anja, Heneka, Michael T., Fliessbach, Klaus, Sharaf, Ahmed, Thiele, Holger, Lennarz, Martina, Jessen, Frank, Maier, Wolfgang, Kubisch, Christian, Ignatova, Zoya, Nuernberg, Peter, Pastor, Pau, Walter, Jochen, Ramirez, Alfredo, Karsak, Meliha, Glebov, Konstantin, Scheffold, Marina, Bajaj, Thomas, Kawalia, Amit, Karaca, Ilker, Rading, Sebastian, Kornhuber, Johannes, Peters, Oliver, Diez-Fairen, Monica, Froelich, Lutz, Huell, Michael, Wiltfang, Jens, Scherer, Martin, Riedel-Heller, Steffi, Schneider, Anja, Heneka, Michael T., Fliessbach, Klaus, Sharaf, Ahmed, Thiele, Holger, Lennarz, Martina, Jessen, Frank, Maier, Wolfgang, Kubisch, Christian, Ignatova, Zoya, Nuernberg, Peter, Pastor, Pau, Walter, Jochen, and Ramirez, Alfredo

Abstract

Rare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) epsilon 4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.

Published
2020

35. Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

Author

Pastor Santos-Cortez, Regie Lyn, Zhang, Rong, Gehlen, Jan, Kawalia, Amit, Melissari, Maria-Theodora, Dakal, Tikam Chand, Menon, Athira M., Höfele, Julia, Riedhammer, Korbinian, Waffenschmidt, Lea, Fabian, Julia, Breuer, Katinka, Kalanithy, Jeshurun, Hilger, Alina Christine, Sharma, Amit, Hölscher, Alice, Boemers, Thomas M., Pauly, Markus, Leutner, Andreas, Fuchs, Jörg, Seitz, Guido, Ludwikowski, Barbara, Gomez, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Kurz, Ralf, Leonhardt, Johannes, Kosch, Ferdinand, Holland-Cunz, Stefan, Münsterer, Oliver, Ure, Beno, Schmiedeke, Eberhard, Neser, Jörg, Degenhardt, Petra, Märzheuser, Stefanie, Kleine, Katharina, Schäfer, Mattias, Spychalski, Nicole, Deffaa, Oliver J., Gosemann, Jan-Hendrik, Lacher, Martin, Heilmann-Heimbach, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Ludwig, Michael, Grote, Phillip, Schumacher, Johannes, Thiele, Holger, Reutter, Heiko, Pastor Santos-Cortez, Regie Lyn, Zhang, Rong, Gehlen, Jan, Kawalia, Amit, Melissari, Maria-Theodora, Dakal, Tikam Chand, Menon, Athira M., Höfele, Julia, Riedhammer, Korbinian, Waffenschmidt, Lea, Fabian, Julia, Breuer, Katinka, Kalanithy, Jeshurun, Hilger, Alina Christine, Sharma, Amit, Hölscher, Alice, Boemers, Thomas M., Pauly, Markus, Leutner, Andreas, Fuchs, Jörg, Seitz, Guido, Ludwikowski, Barbara, Gomez, Barbara, Hubertus, Jochen, Heydweiller, Andreas, Kurz, Ralf, Leonhardt, Johannes, Kosch, Ferdinand, Holland-Cunz, Stefan, Münsterer, Oliver, Ure, Beno, Schmiedeke, Eberhard, Neser, Jörg, Degenhardt, Petra, Märzheuser, Stefanie, Kleine, Katharina, Schäfer, Mattias, Spychalski, Nicole, Deffaa, Oliver J., Gosemann, Jan-Hendrik, Lacher, Martin, Heilmann-Heimbach, Stefanie, Zwink, Nadine, Jenetzky, Ekkehart, Ludwig, Michael, Grote, Phillip, Schumacher, Johannes, Thiele, Holger, and Reutter, Heiko

Abstract

Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.

Published
2020

36. Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia

Author

Zhang, Rong, primary, Gehlen, Jan, additional, Kawalia, Amit, additional, Melissari, Maria-Theodora, additional, Dakal, Tikam Chand, additional, Menon, Athira M., additional, Höfele, Julia, additional, Riedhammer, Korbinian, additional, Waffenschmidt, Lea, additional, Fabian, Julia, additional, Breuer, Katinka, additional, Kalanithy, Jeshurun, additional, Hilger, Alina Christine, additional, Sharma, Amit, additional, Hölscher, Alice, additional, Boemers, Thomas M., additional, Pauly, Markus, additional, Leutner, Andreas, additional, Fuchs, Jörg, additional, Seitz, Guido, additional, Ludwikowski, Barbara M., additional, Gomez, Barbara, additional, Hubertus, Jochen, additional, Heydweiller, Andreas, additional, Kurz, Ralf, additional, Leonhardt, Johannes, additional, Kosch, Ferdinand, additional, Holland-Cunz, Stefan, additional, Münsterer, Oliver, additional, Ure, Beno, additional, Schmiedeke, Eberhard, additional, Neser, Jörg, additional, Degenhardt, Petra, additional, Märzheuser, Stefanie, additional, Kleine, Katharina, additional, Schäfer, Mattias, additional, Spychalski, Nicole, additional, Deffaa, Oliver J., additional, Gosemann, Jan-Hendrik, additional, Lacher, Martin, additional, Heilmann-Heimbach, Stefanie, additional, Zwink, Nadine, additional, Jenetzky, Ekkehart, additional, Ludwig, Michael, additional, Grote, Phillip, additional, Schumacher, Johannes, additional, Thiele, Holger, additional, and Reutter, Heiko, additional

Published
2020
Full Text
View/download PDF

37. Comprehensive molecular analysis of 61 Egyptian families with hereditary nonsyndromic hearing loss

Author

Budde, Birgit S., primary, Aly, Maha Abdelgaber, additional, Mohamed, Mostafa R., additional, Breß, Andreas, additional, Altmüller, Janine, additional, Motameny, Susanne, additional, Kawalia, Amit, additional, Thiele, Holger, additional, Konrad, Kathryn, additional, Becker, Christian, additional, Toliat, Mohammad R., additional, Nürnberg, Gudrun, additional, Sayed, Eman Abdel Fattah, additional, Mohamed, Enass Sayed, additional, Pfister, Markus, additional, and Nürnberg, Peter, additional

Published
2020
Full Text
View/download PDF

38. Exome sequencing identifies rare damaging variants in the ATB8B4 and ABCA1 genes as novel risk factors for Alzheimer's disease.

Author

Holstege, Henne, Hulsman, Marc, Charbonnier, Camille, Grenier‐Boley, Benjamin, Quenez, Olivier, Grozeva, Detelina, van Rooij, Jeroen G.J., Sims, Rebecca, Ahmad, Shahzad, Amin, Najaf, Norsworthy, Penny, Dols‐Icardo, Oriol, Hummerich, Holger, Kawalia, Amit, Amouyel, Philippe, Beecham, Gary W., Berr, Claudine, Bis, Josh C, Boland, Anne, and Bossù, Paola

Abstract

Background: Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer's Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE‐ε4 allele. Here, we aimed to identify additional AD‐associated genes by investigating the burden of rare damaging variants in the exomes of AD cases and controls. Method: On a single server, we analyzed in two stages, the data from 52,270 exome sequences from several independent datasets from Europe and the United States. After comprehensive QC, Stage‐1 and Stage‐2 datasets comprised in total 16,396 AD cases (5,672 EOAD) and 18,107 controls with European ancestry. All detected non‐synonymous and loss‐of‐function rare variants were prioritized by REVEL and LOFTEE, and analyzed in a per‐gene burden analysis. After a Stage‐1 discovery analysis, we replicated findings in an independent dataset (Stage‐2). We combined the Stage‐1 and Stage‐2 datasets and determined, for each gene, the features of the variants that drive the burden‐associations. Results: We confirmed the AD‐association of rare damaging variants SORL1, TREM2, ABCA7, and newly identified a significant AD‐association of rare damaging variants in the ATP8B4 and ABCA1 genes. In addition, we find a strong indication for the AD‐association of ADAM10 and SRC genes (Stage‐2 p<0.05). For most genes, we observed a larger effect size for LOF variants compared to missense variants (Figure‐A). High‐impact variants in these genes are mostly extremely rare and enriched in AD patients with early ages at onset (Figure‐B). Conclusion: We identified, for the first time, the AD‐association of rare damaging variants in two genes: (i) microglial ATP8B4 which is involved in phospholipid transport, and (ii) ABCA1 which plays a critical role in lipidation of apoE thereby supporting Aβ processing. Further, we found strong evidence for the AD‐association of damaging variants in ADAM10 and SRC genes. ADAM10 is involved in the proteolytic processing of APP, while SRC is a Non‐Receptor Tyrosine Kinase which binds PTK2B/Pyk2, a known AD risk factor. Together, our study provides further evidence for the role of Aβ and microglia in AD pathophysiology. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

39. 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, Zettergren, Anna, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Mead, S., Synofzik, M., Andlauer, Till F M, van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Diez-Fairen, Monica, Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Simon-Sanchez, Javier, Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldö, M., Lleó, Alberto, Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G-Y R, Mann, D. M. A., Grafman, J., Morris, C. M., Attems, J., Griffiths, T. D., McKeith, I. G., Zetterberg, Henrik, Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Nygaard, Marianne, Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Blauwendraat, Cornelis, Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., Savage, Jeanne E, van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Mengel-From, Jonas, Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Jansen, Iris, Moreno-Grau, Sonia, Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Wagner, Michael, Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Fortea, Juan, Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Keogh, Michael J, Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H-H, Graff, C., Pasquier, F., Rollin, A., Blennow, Kaj, Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Coppola, G., Skoog, Ingmar, Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., DeCarli, C., Friese, Manuel A, Geschwind, D. H., Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, Carrasquillo, Minerva M, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Kleineidam, Luca, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, van den Akker, Erik, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Bank, Netherlands Brain, Boeve, Bradley F, Hernández, Isabel, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, van Eijk, Kristel R, 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, Stringa, Najada, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Chen, Jason A, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT, and Clarimón, Jordi

Subjects
0301 basic medicine, Dementia with Lewy bodies, Disease, Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, Missense mutation, media_common, 2. Zero hunger, Longevity, Brain, Parkinson Disease, Phospholipase C Gamma 2, Biobank, 3. Good health, ddc, Frontotemporal Dementia, Microglia, Alzheimer's disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, Multiple Sclerosis, media_common.quotation_subject, education, Neuroimaging, Genomics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Phospholipase C gamma, business.industry, Amyotrophic Lateral Sclerosis, Correction, medicine.disease, 030104 developmental biology, Mutation, Dementia, Neurology (clinical), business, 030217 neurology & neurosurgery, 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. 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

40. Alzheimer’s disease-associated (hydroxy)methylomic changes in the brain and blood

Author

Amit Kawalia, Antonio del Sol, Tobias Luck, Per Hoffmann, Bart P. F. Rutten, Michael Wagner, Markus Leber, Roy Lardenoije, Muhammad Ali, Diego Mastroeni, Luca Kleineidam, Lars M. T. Eijssen, Wolfgang Maier, Steffi G. Riedel-Heller, René Hurlemann, Janou A. Y. Roubroeks, Frank Jessen, Adam Smith, Ehsan Pishva, Jonathan Mill, Alfredo Ramirez, Paul D. Coleman, Elaine Delvaux, Gunter Kenis, Daniel L.A. van den Hove, Rebecca G. Smith, Artemis Iatrou, Holger Wagner, Katie Lunnon, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, Promovendi MHN, Bioinformatica, MUMC+: MA Niet Med Staf Psychiatrie (9), and MUMC+: MA Psychiatrie (3)

Subjects
Male, Oncology, genetics [Alzheimer Disease], Genome-wide association study, Disease, Receptors, Nicotinic, Epigenesis, Genetic, Pathogenesis, chemistry.chemical_compound, DNA hydroxymethylation, 0302 clinical medicine, blood [5-Methylcytosine], Age of Onset, Genetics (clinical), Aged, 80 and over, 0303 health sciences, DNA methylation, ROLES, metabolism [5-Methylcytosine], DEMENTIA, Intracellular Signaling Peptides and Proteins, Brain, Alzheimer's disease, Temporal Lobe, genetics [Oxytocin], OXYTOCIN, Blood, 5-Methylcytosine, Disease Progression, 5-HYDROXYMETHYLCYTOSINE, Female, Epigenetics, HEALTH, Alzheimer’s disease, genetics [Receptors, Nicotinic], medicine.medical_specialty, HYDROXYMETHYLATION, chemistry [Temporal Lobe], 03 medical and health sciences, Alzheimer Disease, Internal medicine, analysis [5-Methylcytosine], Genetics, medicine, Humans, Dementia, GLOBAL CHANGES, ddc:610, GENOME-WIDE ASSOCIATION, Molecular Biology, Middle temporal gyrus, Aged, 030304 developmental biology, Brain Chemistry, 5-Hydroxymethylcytosine, business.industry, Research, Epigenome, DNA Methylation, medicine.disease, chemistry, analogs & derivatives [5-Methylcytosine], COGNITION, genetics [Intracellular Signaling Peptides and Proteins], business, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Background Late-onset Alzheimer’s disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (− 3.76% 5mC, pŠidák = 1.07E−06), CHRNB1 (+ 1.46% 5hmC, pŠidák = 4.01E−04), RHBDF2 (− 3.45% UC, pŠidák = 4.85E−06), and C3 (− 1.20% UC, pŠidák = 1.57E−03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, pŠidák = 7.14E−04). Conclusions The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

Published
2019

41. Novel mutations in

Author

Hormos Salimi, Dafsari, Amit, Kawalia, Rosanne, Sprute, Mert, Karakaya, Anna, Malenica, Peter, Herkenrath, Peter, Nürnberg, Susanne, Motameny, Holger, Thiele, and Sebahattin, Cirak

Subjects
Male, Hyperekplexia, apneic episodes in infancy, Apnea, Glycine Plasma Membrane Transport Proteins, equinovarus deformity, Child, Preschool, Mutation, Exome Sequencing, exaggerated startle response, Humans, Infant, Research Article
Abstract

Infants suffering from life-threatening apnea, stridor, cyanosis, and increased muscle tone may often be misdiagnosed with infantile seizures and inappropriately treated because of lack and delay in genetic diagnosis. Here, we report a patient with increased muscle tone after birth and hypertonic attacks with life-threatening apnea but no epileptiform patterns in EEG recordings. We identified novel compound heterozygous variants in SLC6A5 (NM_004211.4:c.[1429T > C];[1430delC]) by trio whole-exome sequencing, containing a base deletion inherited by the asymptomatic mother leading to a frameshift (c.1430delC, p.Ser477PhefsTer9) and a de novo base exchange leading to an amino acid change (c.1429T > C, p.Ser477Pro). To date, there are four known disease-associated genes for primary hyperekplexia, all of which are involved in the functioning of glycinergic synapses. SLC6A5 encodes the sodium- and chloride-dependent glycine transporter 2 (GlyT2), which recaptures glycine, a major inhibitory transmitter in the brainstem and spinal cord. The diagnosis altered the patient's medical care to his benefit because SLC6A5 mutations with rather benign courses of hyperekplexia may be spared of needless pharmacotherapy. Symptoms eventually decreased in frequency until about once in 2 mo at 2 yr age. We present the first report of halting hyperekplexia episodes by maternal soothing in multiple instances. We highlight the importance of clarifying the genetic diagnosis by rapid next-generation sequencing techniques in this group of infantile apneic attacks with hyperekplexia due to the broad differential diagnoses.

Published
2019

42. Die genomische Ätiologie fetaler Akinesie

Author

Sebahattin Cirak, Peter Nürnberg, Hülya-Sevcan Daimagüler, Haluk Topaloglu, Janine Altmüller, Katharina Schoner, î Duman, Cho-Ming Chao, R. Heller, S Montameny, S Ostojic, Nursel Elcioglu, M Kreutzer, Kerstin Becker, Amit Kawalia, Goknur Haliloglu, M Pergande, Holger Thiele, Mert Karakaya, A Koy, and Haicui Wang

Published
2019

43. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing (vol 51, pg 414, 2019)

Author

Kunkle, BW, Grenier-Boley, B, Sims, R, Bis, JC, Damotte, V, Naj, AC, Boland, A, Vronskaya, M, van der Lee, SJ, Amlie-Wolf, A, Bellenguez, C, Frizatti, A, Chouraki, V, Martin, ER, Sleegers, K, Badarinarayan, N, Jakobsdottir, J, Hamilton-Nelson, KL, Moreno-Grau, S, Olaso, R, Raybould, R, Chen, YN, Kuzma, AB, Hiltunen, M, Morgan, T, Ahmad, S, Vardarajan, BN, Epelbaum, J, Hoffmann, P, Boada, M, Beecham, GW, Garnier, JG, Harold, D, Fitzpatrick, AL, Valladares, O, Moutet, ML, Gerrish, A, Smith, AV, Qu, LM, Bacq, D, Denning, N, Jian, XQ, Zhao, Y, Del Zompo, M, Fox, NC, Choi, SH, Mateo, I, Hughes, JT, Adams, HH, Malamon, J, Sanchez-Garcia, F, Patel, Y, Brody, JA, Dombroski, BA, Naranjo, MCD, Daniilidou, M, Eiriksdottir, G, Mukherjee, S, Wallon, D, Uphill, J, Aspelund, T, Cantwell, LB, Garzia, F, Galimberti, D, Hofer, E, Butkiewicz, M, Fin, B, Scarpini, E, Sarnowski, C, Bush, WS, Meslage, S, Kornhuber, J, White, CC, Song, Y, Barber, RC, Engelborghs, S, Sordon, S, Voijnovic, D, Adams, PM, Vandenberghe, R, Mayhaus, M, Cupples, LA, Albert, MS, De Deyn, PP, Gu, W, Himali, JJ, Beekly, D, Squassina, A, Hartmann, AM, Orellana, A, Blacker, D, Rodriguez-Rodriguez, E, Lovestone, S, Garcia, ME, Doody, RS, Munoz-Fernadez, C, Sussams, R, Lin, HH, Fairchild, TJ, Benito, YA, Holmes, C, Karamujic-Comic, H, Frosch, MP, Thonberg, H, Maier, W, Roshchupkin, G, Ghetti, B, Giedraitis, V, Kawalia, A, Li, S, Huebinger, RM, Kilander, L, Moebus, S, Hernandez, I, Kamboh, MI, Brundin, R, Turton, J, Yang, Q, Katz, MJ, Concari, L, Lord, J, Beiser, AS, Keene, CD, Helisalmi, S, Kloszewska, I, Kukull, WA, Koivisto, AM, Lynch, A, Tarraga, L, Larson, EB, Haapasalo, A, Lawlor, B, Mosley, TH, Lipton, RB, Solfrizzi, V, Gill, M, Longstreth, WT, Montine, TJ, Frisardi, V, Diez-Fairen, M, Rivadeneira, F, Petersen, RC, Deramecourt, V, Alvarez, I, Salani, F, Ciaramella, A, Boerwinkle, E, Reiman, EM, Fievet, N, Rotter, JI, Reisch, JS, Hanon, O, Cupidi, C, Uitterlinden, AGA, Royall, DR, Dufouil, C, Maletta, RG, de Rojas, I, Sano, M, Brice, A, Cecchetti, R, St George-Hyslop, P, Ritchie, K, Tsolaki, M, Tsuang, DW, Dubois, B, Craig, D, Wu, CK, Soininen, H, Avramidou, D, Albin, RL, Fratiglioni, L, Germanou, A, Apostolova, LG, Keller, L, Koutroumani, M, Arnold, SE, Panza, F, Gkatzima, O, Asthana, S, Hannequin, D, Whitehead, P, Atwood, CS, Caffarra, P, Hampel, H, Quintela, I, Carracedo, A, Lannfelt, L, Rubinsztein, DC, Barnes, LL, Pasquier, F, Frolich, L, Barral, S, McGuinness, B, Beach, TG, Johnston, JA, Becker, JT, Passmore, P, Bigio, EH, Schott, JM, Bird, TD, Warren, JD, Boeve, BF, Lupton, MK, Bowen, JD, Proitsi, P, Boxer, A, Powell, JF, Burke, JR, Kauwe, JSK, Burns, JM, Mancuso, M, Buxbaum, JD, Bonuccelli, U, Cairns, NJ, McQuillin, A, Cao, CH, Livingston, G, Carlson, CS, Bass, NJ, Carlsson, CM, Hardy, J, Carney, RM, Bras, J, Carrasquillo, MM, Guerreiro, R, Allen, M, Chui, HC, Fisher, E, Masullo, C, Crocco, EA, DeCarli, C, Bisceglio, G, Dick, M, Ma, L, Duara, R, Graff-Radford, NR, Evans, DA, Hodges, A, Faber, KM, Scherer, M, Fallon, KB, Riemenschneider, M, Fardo, DW, Heun, R, Farlow, MR, Kolsch, H, Ferris, S, Leber, M, Foroud, TM, Heuser, I, Galasko, DR, Giegling, I, Gearing, M, Hull, M, Geschwind, DH, Gilbert, JR, Morris, J, Green, RC, Mayo, K, Growdon, JH, Feulner, T, Hamilton, RL, Harrell, LE, Drichel, D, Honig, LS, Cushion, TD, Huentelman, MJ, Hollingworth, P, Hulette, CM, Hyman, BT, Marshall, R, Jarvik, GP, Meggy, A, Abner, E, Menzies, GE, Jin, LW, Leonenko, G, Real, LM, Jun, GR, Baldwin, CT, Grozeva, D, Karydas, A, Russo, G, Kaye, JA, Kim, R, Jessen, F, Kowall, NW, Vellas, B, Kramer, JH, Vardy, E, LaFerla, FM, Jockel, KH, Lah, JJ, Dichgans, M, Leverenz, JB, Mann, D, Levey, AI, Pickering-Brown, S, Lieberman, AP, Klopp, N, Lunetta, KL, Wichmann, HE, Lyketsos, CG, Morgan, K, Marson, DC, Brown, K, Martiniuk, F, Medway, C, Mash, DC, Nothen, MM, Masliah, E, Hooper, NM, McCormick, WC, Daniele, A, McCurry, SM, Bayer, A, McDavid, AN, Gallacher, J, Mckee, AC, van den Bussche, H, Mesulam, M, Brayne, C, Miller, BL, Riedel-Heller, S, Miller, CA, Miller, JW, Al-Chalabi, A, Morris, JC, Shaw, CE, Myers, AJ, Wiltfang, J, O'Bryant, S, Olichney, JM, Alvarez, V, Parisi, JE, Singleton, AB, Paulson, HL, Collinge, J, Perry, WR, Mead, S, Peskind, E, Cribbs, DH, Rossor, M, Pierce, A, Ryan, NS, Poon, WW, Nacmias, B, Potter, H, Sorbi, S, Quinn, JF, Sacchinelli, E, Raj, A, Spalletta, G, Raskind, M, Caltagirone, C, Bossu, P, Orfei, MD, Reisberg, B, Clarke, R, Reitz, C, Smith, AD, Ringman, JM, Warden, D, Roberson, ED, Wilcock, G, Rogaeva, E, Bruni, AC, Rosen, HJ, Gallo, M, Rosenberg, RN, Ben-Shlomo, Y, Sager, MA, Mecocci, P, Saykin, AJ, Pastor, P, Cuccaro, ML, Vance, JM, Schneider, JA, Schneider, LS, Slifer, S, Seeley, WW, Smith, AG, Sonnen, JA, Spina, S, Stern, RA, Swerdlow, RH, Tang, M, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Van Deerlin, VM, Van Eldik, LJ, Vinters, HV, Vonsattel, JP, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, CE, Yu, L, Saba, Y, Pilotto, A, Bullido, MJ, Peters, O, Crane, PK, Bennett, D, Bosco, P, Coto, E, Boccardi, V, De Jager, PL, Lleo, A, Warner, N, Lopez, OL, Ingelsson, M, Deloukas, P, Cruchaga, C, Graff, C, Gwilliam, R, Fornage, M, Goate, AM, Sanchez-Juan, P, Kehoe, PG, Amin, N, Ertekin-Taner, N, Berr, C, Debette, S, Love, S, Launer, LJ, Younkin, SG, Dartigues, JF, Corcoran, C, Ikram, MA, Dickson, DW, Nicolas, G, Campion, D, Tschanz, J, Schmidt, H, Hakonarson, H, Clarimon, J, Munger, R, Schmidt, R, Farrer, LA, Van Broeckhoven, C, O'Donovan, MC, DeStefano, AL, Jones, L, Haines, JL, Deleuze, JF, Owen, MJ, Gudnason, V, Mayeux, R, Escott-Price, V, Psaty, BM, Ramirez, A, Wang, LS, Ruiz, A, van Duijn, CM, Holmans, PA, Seshadri, S, Williams, J, Amouyel, P, Schellenberg, GD, Lambert, JC, Pericak-Vance, MA, ADGC, EADI, Cohorts Heart Aging Res Genomic, and Genetic Environm Risk AD Defining

Published
2019

44. Nat Genet

Author

KUNKLE, B. W., GRENIER-BOLEY, B., SIMS, R., BIS, J. C., DAMOTTE, V., NAJ, A. C., BOLAND, A., VRONSKAYA, M., VAN DER LEE, S. J., AMLIE-WOLF, A., BELLENGUEZ, C., FRIZATTI, A., CHOURAKI, V., MARTIN, E. R., SLEEGERS, K., BADARINARAYAN, N., JAKOBSDOTTIR, J., HAMILTON-NELSON, K. L., MORENO-GRAU, S., OLASO, R., RAYBOULD, R., CHEN, Y., KUZMA, A. B., HILTUNEN, M., MORGAN, T., AHMAD, S., VARDARAJAN, B. N., EPELBAUM, J., HOFFMANN, P., BOADA, M., BEECHAM, G. W., GARNIER, J. G., HAROLD, D., FITZPATRICK, A. L., VALLADARES, O., MOUTET, M. L., GERRISH, A., QU, L., BACQ, D., DENNING, N., JIAN, X., ZHAO, Y., DEL ZOMPO, M., FOX, N. C., CHOI, S. H., MATEO, I., HUGHES, J. T., ADAMS, H. H., MALAMON, J., SANCHEZ-GARCIA, F., PATEL, Y., BRODY, J. A., DOMBROSKI, B. A., NARANJO, M. C. D., DANIILIDOU, M., EIRIKSDOTTIR, G., MUKHERJEE, S., WALLON, D., UPHILL, J., ASPELUND, T., CANTWELL, L. B., GARZIA, F., GALIMBERTI, D., HOFER, E., BUTKIEWICZ, M., FIN, B., SCARPINI, E., SARNOWSKI, C., BUSH, W. S., MESLAGE, S., KORNHUBER, J., WHITE, C. C., SONG, Y., BARBER, R. C., ENGELBORGHS, S., SORDON, S., VOIJNOVIC, D., ADAMS, P. M., VANDENBERGHE, R., MAYHAUS, M., CUPPLES, L. A., ALBERT, M. S., DE DEYN, P. P., GU, W., HIMALI, J. J., BEEKLY, D., SQUASSINA, A., HARTMANN, A. M., ORELLANA, A., BLACKER, D., RODRIGUEZ-RODRIGUEZ, E., LOVESTONE, S., GARCIA, M. E., DOODY, R. S., MUNOZ-FERNADEZ, C., SUSSAMS, R., LIN, H., FAIRCHILD, T. J., BENITO, Y. A., HOLMES, C., KARAMUJIC-COMIC, H., FROSCH, M. P., THONBERG, H., MAIER, W., ROSCHUPKIN, G., GHETTI, B., GIEDRAITIS, V., KAWALIA, A., LI, S., HUEBINGER, R. M., KILANDER, L., MOEBUS, S., HERNANDEZ, I., KAMBOH, M. I., BRUNDIN, R., TURTON, J., YANG, Q., KATZ, M. J., CONCARI, L., LORD, J., BEISER, A. S., KEENE, C. D., HELISALMI, S., KLOSZEWSKA, I., KUKULL, W. A., KOIVISTO, A. M., LYNCH, A., TARRAGA, L., LARSON, E. B., HAAPASALO, A., LAWLOR, B., MOSLEY, T. H., LIPTON, R. B., SOLFRIZZI, V., GILL, M., LONGSTRETH, W. T. Jr., MONTINE, T. J., FRISARDI, V., DIEZ-FAIREN, M., RIVADENEIRA, F., PETERSEN, R. C., DERAMECOURT, V., ALVAREZ, I., SALANI, F., CIARAMELLA, A., BOERWINKLE, E., REIMAN, E. M., FIEVET, N., ROTTER, J. I., REISCH, J. S., HANON, O., CUPIDI, C., ANDRE UITTERLINDEN, A. G., ROYALL, D. R., DUFOUIL, Carole, MALETTA, R. G., DE ROJAS, I., SANO, M., BRICE, A., CECCHETTI, R., GEORGE-HYSLOP, P. S., RITCHIE, K., TSOLAKI, M., TSUANG, D. W., DUBOIS, B., CRAIG, D., WU, C. K., SOININEN, H., AVRAMIDOU, D., ALBIN, R. L., FRATIGLIONI, L., GERMANOU, A., APOSTOLOVA, L. G., KELLER, L., KOUTROUMANI, M., ARNOLD, S. E., PANZA, F., GKATZIMA, O., ASTHANA, S., HANNEQUIN, D., WHITEHEAD, P., ATWOOD, C. S., CAFFARRA, P., HAMPEL, H., QUINTELA, I., CARRACEDO, A., LANNFELT, L., RUBINSZTEIN, D. C., BARNES, L. L., PASQUIER, F., FROLICH, L., BARRAL, S., MCGUINNESS, B., BEACH, T. G., JOHNSTON, J. A., BECKER, J. T., PASSMORE, P., BIGIO, E. H., SCHOTT, J. M., BIRD, T. D., WARREN, J. D., BOEVE, B. F., LUPTON, M. K., BOWEN, J. D., PROITSI, P., BOXER, A., POWELL, J. F., BURKE, J. R., KAUWE, J. S. K., BURNS, J. M., MANCUSO, M., BUXBAUM, J. D., BONUCCELLI, U., CAIRNS, N. J., MCQUILLIN, A., CAO, C., LIVINGSTON, G., CARLSON, C. S., BASS, N. J., CARLSSON, C. M., HARDY, J., CARNEY, R. M., BRAS, J., CARRASQUILLO, M. M., GUERREIRO, R., ALLEN, M., CHUI, H. C., FISHER, E., MASULLO, C., CROCCO, E. A., DECARLI, C., BISCEGLIO, G., DICK, M., MA, L., DUARA, R., GRAFF-RADFORD, N. R., EVANS, D. A., HODGES, A., FABER, K. M., SCHERER, M., FALLON, K. B., RIEMENSCHNEIDER, M., FARDO, D. W., HEUN, R., FARLOW, M. R., KOLSCH, H., FERRIS, S., LEBER, M., FOROUD, T. M., HEUSER, I., GALASKO, D. R., GIEGLING, I., GEARING, M., HULL, M., GESCHWIND, D. H., GILBERT, J. R., GREEN, R. C., MAYO, K., GROWDON, J. H., FEULNER, T., HAMILTON, R. L., HARRELL, L. E., DRICHEL, D., HONIG, L. S., CUSHION, T. D., HUENTELMAN, M. J., HOLLINGWORTH, P., HULETTE, C. M., HYMAN, B. T., MARSHALL, R., JARVIK, G. P., MEGGY, A., ABNER, E., MENZIES, G. E., JIN, L. W., LEONENKO, G., REAL, L. M., JUN, G. R., BALDWIN, C. T., GROZEVA, D., KARYDAS, A., RUSSO, G., KAYE, J. A., KIM, R., JESSEN, F., KOWALL, N. W., VELLAS, B., KRAMER, J. H., VARDY, E., LAFERLA, F. M., JOCKEL, K. H., LAH, J. J., DICHGANS, M., LEVERENZ, J. B., MANN, D., LEVEY, A. I., PICKERING-BROWN, S., LIEBERMAN, A. P., KLOPP, N., LUNETTA, K. L., WICHMANN, H. E., LYKETSOS, C. G., MORGAN, K., MARSON, D. C., BROWN, K., MARTINIUK, F., MEDWAY, C., MASH, D. C., NOTHEN, M. M., MASLIAH, E., HOOPER, N. M., MCCORMICK, W. C., DANIELE, A., MCCURRY, S. M., BAYER, A., MCDAVID, A. N., GALLACHER, J., MCKEE, A. C., VAN DEN BUSSCHE, H., MESULAM, M., BRAYNE, C., MILLER, B. L., RIEDEL-HELLER, S., MILLER, C. A., MILLER, J. W., AL-CHALABI, A., MORRIS, J. C., SHAW, C. E., MYERS, A. J., WILTFANG, J., O'BRYANT, S., OLICHNEY, J. M., ALVAREZ, V., PARISI, J. E., SINGLETON, A. B., PAULSON, H. L., COLLINGE, J., PERRY, W. R., MEAD, S., PESKIND, E., CRIBBS, D. H., ROSSOR, M., PIERCE, A., RYAN, N. S., POON, W. W., NACMIAS, B., POTTER, H., SORBI, S., QUINN, J. F., SACCHINELLI, E., RAJ, A., SPALLETTA, G., RASKIND, M., CALTAGIRONE, C., BOSSU, P., ORFEI, M. D., REISBERG, B., CLARKE, R., REITZ, C., RINGMAN, J. M., WARDEN, D., ROBERSON, E. D., WILCOCK, G., ROGAEVA, E., BRUNI, A. C., ROSEN, H. J., GALLO, M., ROSENBERG, R. N., BEN-SHLOMO, Y., SAGER, M. A., MECOCCI, P., SAYKIN, A. J., PASTOR, P., CUCCARO, M. L., VANCE, J. M., SCHNEIDER, J. A., SCHNEIDER, L. S., SLIFER, S., SEELEY, W. W., SMITH, A. V., SONNEN, J. A., SPINA, S., STERN, R. A., SWERDLOW, R. H., TANG, M., TANZI, R. E., TROJANOWSKI, J. Q., TRONCOSO, J. C., VAN DEERLIN, V. M., VAN ELDIK, L. J., VINTERS, H. V., VONSATTEL, J. P., WEINTRAUB, S., WELSH-BOHMER, K. A., WILHELMSEN, K. C., WILLIAMSON, J., WINGO, T. S., WOLTJER, R. L., WRIGHT, C. B., YU, C. E., YU, L., SABA, Y., ALZHEIMER DISEASE GENETICS, Consortium, EUROPEAN ALZHEIMER'S DISEASE, Initiative, COHORTS FOR, Heart, AGING RESEARCH IN GENOMIC EPIDEMIOLOGY, Consortium, GENETIC ENVIRONMENTAL RISK IN AD/DEFINING GENETIC, Polygenic, ENVIRONMENTAL RISK FOR ALZHEIMER'S DISEASE, Consortium, PILOTTO, A., BULLIDO, M. J., PETERS, O., CRANE, P. K., BENNETT, D., BOSCO, P., COTO, E., BOCCARDI, V., DE JAGER, P. L., LLEO, A., WARNER, N., LOPEZ, O. L., INGELSSON, M., DELOUKAS, P., CRUCHAGA, C., GRAFF, C., GWILLIAM, R., FORNAGE, M., GOATE, A. M., SANCHEZ-JUAN, P., KEHOE, P. G., AMIN, N., ERTEKIN-TANER, N., BERR, C., DEBETTE, S., LOVE, S., LAUNER, L. J., YOUNKIN, S. G., DARTIGUES, Jean-Francois, CORCORAN, C., IKRAM, M. A., DICKSON, D. W., NICOLAS, G., CAMPION, D., TSCHANZ, J., SCHMIDT, H., HAKONARSON, H., CLARIMON, J., MUNGER, R., SCHMIDT, R., FARRER, L. A., VAN BROECKHOVEN, C., M, C. O' Donovan, DESTEFANO, A. L., JONES, L., HAINES, J. L., DELEUZE, J. F., OWEN, M. J., GUDNASON, V., MAYEUX, R., ESCOTT-PRICE, V., PSATY, B. M., RAMIREZ, A., WANG, L. S., RUIZ, A., VAN DUIJN, C. M., HOLMANS, P. A., SESHADRI, S., WILLIAMS, J., AMOUYEL, P., SCHELLENBERG, G. D., LAMBERT, J. C., and PERICAK-VANCE, M. A.

Published
2019

45. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (Nature Genetics, (2019), 51, 3, (414-430), 10.1038/s41588-019-0358-2)

Author

Kunkle, B. W., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., Boland, A., Vronskaya, M., van der Lee, S. J., Amlie-Wolf, A., Bellenguez, C., Frizatti, A., Chouraki, V., Martin, E. R., Sleegers, K., Badarinarayan, N., Jakobsdottir, J., Hamilton-Nelson, K. L., Moreno-Grau, S., Olaso, R., Raybould, R., Chen, Y., Kuzma, A. B., Hiltunen, M., Morgan, T., Ahmad, S., Vardarajan, B. N., Epelbaum, J., Hoffmann, P., Boada, M., Beecham, G. W., Garnier, J. -G., Harold, D., Fitzpatrick, A. L., Valladares, O., Moutet, M. -L., Gerrish, A., Smith, A. V., Qu, L., Bacq, D., Denning, N., Jian, X., Zhao, Y., Del Zompo, M., Fox, N. C., Choi, S. -H., Mateo, I., Hughes, J. T., Adams, H. H., Malamon, J., Sanchez-Garcia, F., Patel, Y., Brody, J. A., Dombroski, B. A., Naranjo, M. C. D., Daniilidou, M., Eiriksdottir, G., Mukherjee, S., Wallon, D., Uphill, J., Aspelund, T., Cantwell, L. B., Garzia, F., Galimberti, D., Hofer, E., Butkiewicz, M., Fin, B., Scarpini, E., Sarnowski, C., Bush, W. S., Meslage, S., Kornhuber, J., White, C. C., Song, Y., Barber, R. C., Engelborghs, S., Sordon, S., Voijnovic, D., Adams, P. M., Vandenberghe, R., Mayhaus, M., Cupples, L. A., Albert, M. S., De Deyn, P. P., Gu, W., Himali, J. J., Beekly, D., Squassina, A., Hartmann, A. M., Orellana, A., Blacker, D., Rodriguez-Rodriguez, E., Lovestone, S., Garcia, M. E., Doody, R. S., Munoz-Fernadez, C., Sussams, R., Lin, H., Fairchild, T. J., Benito, Y. A., Holmes, C., Karamujic-Comic, H., Frosch, M. P., Thonberg, H., Maier, W., Roshchupkin, G., Ghetti, B., Giedraitis, V., Kawalia, A., Li, S., Huebinger, R. M., Kilander, L., Moebus, S., Hernandez, I., Kamboh, M. I., Brundin, R. M., Turton, J., Yang, Q., Katz, M. J., Concari, L., Lord, J., Beiser, A. S., Keene, C. D., Helisalmi, S., Kloszewska, I., Kukull, W. A., Koivisto, A. M., Lynch, A., Tarraga, L., Larson, E. B., Haapasalo, A., Lawlor, B., Mosley, T. H., Lipton, R. B., Solfrizzi, V., Gill, M., Longstreth, W. T., Montine, T. J., Frisardi, V., Diez-Fairen, M., Rivadeneira, F., Petersen, R. C., Deramecourt, V., Alvarez, I., Salani, F., Ciaramella, A., Boerwinkle, E., Reiman, E. M., Fievet, N., Rotter, J. I., Reisch, J. S., Hanon, O., Cupidi, C., Uitterlinden, A. G. A., Royall, D. R., Dufouil, C., Maletta, R. G., de Rojas, I., Sano, M., Brice, A., Cecchetti, R., George-Hyslop, P. S., Ritchie, K., Tsolaki, M., Tsuang, D. W., Dubois, B., Craig, D., C. -K., Wu, Soininen, H., Avramidou, D., Albin, R. L., Fratiglioni, L., Germanou, A., Apostolova, L. G., Keller, L., Koutroumani, M., Arnold, S. E., Panza, F., Gkatzima, O., Asthana, S., Hannequin, D., Whitehead, P., Atwood, C. S., Caffarra, P., Hampel, H., Quintela, I., Carracedo, A., Lannfelt, L., Rubinsztein, D. C., Barnes, L. L., Pasquier, F., Frolich, L., Barral, S., Mcguinness, B., Beach, T. G., Johnston, J. A., Becker, J. T., Passmore, P., Bigio, E. H., Schott, J. M., Bird, T. D., Warren, J. D., Boeve, B. F., Lupton, M. K., Bowen, J. D., Proitsi, P., Boxer, A., Powell, J. F., Burke, J. R., Kauwe, J. S. K., Burns, J. M., Mancuso, M., Buxbaum, J. D., Bonuccelli, U., Cairns, N. J., Mcquillin, A., Cao, C., Livingston, G., Carlson, C. S., Bass, N. J., Carlsson, C. M., Hardy, J., Carney, R. M., Bras, J., Carrasquillo, M. M., Guerreiro, R., Allen, M., Chui, H. C., Fisher, E., Masullo, Carlo, Crocco, E. A., Decarli, C., Bisceglio, G., Dick, M., Ma, L., Duara, R., Graff-Radford, N. R., Evans, D. A., Hodges, A., Faber, K. M., Scherer, M., Fallon, K. B., Riemenschneider, M., Fardo, D. W., Heun, R., Farlow, M. R., Kolsch, H., Ferris, S., Leber, M., Foroud, T. M., Heuser, I., Galasko, D. R., Giegling, I., Gearing, M., Hull, M., Geschwind, D. H., Gilbert, J. R., Morris, J., Green, R. C., Mayo, K., Growdon, J. H., Feulner, T., Hamilton, R. L., Harrell, L. E., Drichel, D., Honig, L. S., Cushion, T. D., Huentelman, M. J., Hollingworth, P., Hulette, C. M., Hyman, B. T., Marshall, R., Jarvik, G. P., Meggy, A., Abner, E., Menzies, G. E., Jin, L. -W., Leonenko, G., Real, L. M., Jun, G. R., Baldwin, C. T., Grozeva, D., Karydas, A., Russo, G., Kaye, J. A., Kim, R., Jessen, F., Kowall, N. W., Vellas, B., Kramer, J. H., Vardy, E., Laferla, F. M., Jockel, K. -H., Lah, J. J., Dichgans, M., Leverenz, J. B., Mann, D., Levey, A. I., Pickering-Brown, S., Lieberman, A. P., Klopp, N., Lunetta, K. L., Wichmann, H. -E., Lyketsos, C. G., Morgan, K., Marson, D. C., Brown, K., Martiniuk, F., Medway, C., Mash, D. C., Nothen, M. M., Masliah, E., Hooper, N. M., Mccormick, W. C., Daniele, Antonio, Mccurry, S. M., Bayer, A., Mcdavid, A. N., Gallacher, J., Mckee, A. C., van den Bussche, H., Mesulam, M., Brayne, C., Miller, B. L., Riedel-Heller, S., Miller, C. A., Miller, J. W., Al-Chalabi, A., Morris, J. C., Shaw, C. E., Myers, A. J., Wiltfang, J., O'Bryant, S., Olichney, J. M., Alvarez, V., Parisi, J. E., Singleton, A. B., Paulson, H. L., Collinge, J., Perry, W. R., Mead, S., Peskind, E., Cribbs, D. H., Rossor, M., Pierce, A., Ryan, N. S., Poon, W. W., Nacmias, B., Potter, H., Sorbi, S., Quinn, J. F., Sacchinelli, E., Raj, A., Spalletta, Gianfranco, Raskind, M., Caltagirone, C., Bossu, P., Orfei, M. D., Reisberg, B., Clarke, Ronald Victor, Reitz, C., Smith, A. D., Ringman, J. M., Warden, D., Roberson, E. D., Wilcock, G., Rogaeva, E., Bruni, A. C., Rosen, H. J., Gallo, Massimiliano, Rosenberg, R. N., Ben-Shlomo, Y., Sager, M. A., Mecocci, P., Saykin, A. J., Pastor, P., Cuccaro, M. L., Vance, J. M., Schneider, J. A., Schneider, L. S., Slifer, S., Seeley, W. W., Smith, A. G., Sonnen, J. A., Spina, S., Stern, R. A., Swerdlow, R. H., Tang, M., Tanzi, R. E., Trojanowski, J. Q., Troncoso, J. C., Van Deerlin, V. M., Van Eldik, L. J., Vinters, H. V., Vonsattel, J. P., Weintraub, S., Welsh-Bohmer, K. A., Wilhelmsen, K. C., Williamson, J., Wingo, T. S., Woltjer, R. L., Wright, C. B., C. -E., Yu, Yu, L., Saba, Y., Pilotto, A., Bullido, M. J., Peters, O., Crane, P. K., Bennett, D., Bosco, P., Coto, E., Boccardi, V., De Jager, P. L., Lleo, A., Warner, N., Lopez, O. L., Ingelsson, M., Deloukas, P., Cruchaga, C., Graff, C., Gwilliam, R., Fornage, M., Goate, A. M., Sanchez-Juan, P., Kehoe, P. G., Amin, N., Ertekin-Taner, N., Berr, C., Debette, S., Love, S., Launer, L. J., Younkin, S. G., Dartigues, J. -F., Corcoran, C., Ikram, M. A., Dickson, D. W., Nicolas, G., Campion, D., Tschanz, J. A., Schmidt, H., Hakonarson, H., Clarimon, J., Munger, R., Schmidt, R., Farrer, L. A., Van Broeckhoven, C., O'Donovan, M. C., Destefano, A. L., Jones, L., Haines, J. L., Deleuze, J. -F., Owen, M. J., Gudnason, V., Mayeux, R., Escott-Price, V., Psaty, B. M., Ramirez, A., Wang, L. -S., Ruiz, A., van Duijn, C. M., Holmans, P. A., Seshadri, S., Williams, J., Amouyel, P., Schellenberg, G. D., Lambert, J. -C., and Pericak-Vance, M. A.

Subjects
Author Correction: Alzheimer’s disease genetic meta-analysis new risk loci Aβ, tau, immunity and lipid processing, Settore MED/26 - NEUROLOGIA, Author Correction: Alzheimer’s disease genetic meta-analysis new risk loci Aβ, tau, immunity and lipid processing
Published
2019

46. Polygenic risk and hazard scores for Alzheimer's disease prediction

Author

Leonenko, G, Sims, R, Shoai, M, Frizzati, A, Bossù, P, Spalletta, G, Fox, Nc, Williams, J, for the GERAD consortium: Hardy, J, Escott-Price, V, Tsolaki, M, Craig, D, Avramidou, D, Germanou, A, Koutroumani, M, Gkatzima, O, Hampel, H, Kehoe, Pg, Love, S, Rubinsztein, Dc, Frölich, L, Mcguinness, B, Johnston, Ja, Passmore, P, Drichel, D, Rossor, M, Schott, Jm, Warren, Jd, Bras, J, Guerreiro, R, Kawalia, A, Hughes, Jt, Patel, Y, Lupton, Mk, Proitsi, P, Powell, J, Kauwe, Jsk, Mancuso, M, Bonuccelli, U, Uphill, J, Fisher, E, Masullo, C, Soininen, H, Bisceglio, G, Ma, L, Dickson, Dw, Graff‐radford, Nr, Carrasquillo, Mm, Younkin, Sg, Sandro Sorbi, S, Daniilidou, M, Hodges, A, Galimberti, D, Scarpini, E, Scherer, M, Peters, O, Ramirez, A, Leber, M, Pichler, S, Mayhaus, M, Gu, W, Riemenschneider, M, Wiltfang, J, Heun, R, Kölsch, H, Kornhuber, J, Heuser, I, Rujescu, D, Hartmann, Am, Giegling, I, Hüll, M, Lovestone, S, Cruchaga, C, Morris, J, Mayo, K, Feulner, T, Sussams, R, Holmes, C, Mann, D, Pickering‐brown, S, Hooper, Nm, Mcquillin, A, Livingston, G, Bass, Nj, Vronskaya, M, Morgan, T, Denning, N, Cushion, Td, Jones, L, Marshall, R, Meggy, A, Menzies, G, Grozeva, D, O'Donovan, Mc, Owen, Mj, Holmans, Pa, Salani, F, Russo, G, Maier, W, Jessen, F, Wichmann, H-E, Morgan, K, Goate, Am, Vellas, B, Vardy, E, Moebus, S, Jöckel, K-H, Dichgans, M, Klopp, N, Turton, J, Lord, J, Brown, K, Medway, C, Nöthen, Mm, Hoffmann, P, Daniele, A, Bayer, A, Gallacher, J, van den Bussche, H, Brayne, C, Riedel‐heller, S, Powell, Jf, Al‐chalabi, A, Shaw, Ce, Kloszewska, I, Pastor, P, Diez‐fairen, M, Lynch, A, Lawlor, B, Gill, M, Coto, E, Alvarez, V, Singleton, Ab, Collinge, J, Mead, S, Ryan, N, Nacmias, B, Ortega‐cubero, S, Rodriguez‐rodriguez, E, Sanchez‐juan, P, Shofany, J, Banaj, N, Ciullo, V, Sacchinelli, E, Robert, Clarke, A David Smith, Donald, Warden, Yoav, Ben‐shlomo, Chiara, Cupidi, Raffaele Giovanni Maletta, Runi, Gallo, M, Harold, D, Cecchetti, R, Mecocci, P, Boccardi, V, Warner, N, Wilcock, G, Deloukas, P, Gwilliam, R, Corcoran, C, Tschanz, J, Munger, R., and Consortium, Gerad

Subjects
Male, Multifactorial Inheritance, Polygenic risk, Alzheimer's disease, hazard score, Polymorphism, Single Nucleotide, Settore MED/26 - NEUROLOGIA, Apolipoproteins E, Alzheimer Disease, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Research Articles, Research Article, Genome-Wide Association Study, Proportional Hazards Models
Abstract

Objective: Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age‐specific genetic risk for AD. The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P‐value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10−12) was observed for PRS based upon genome‐wide significant SNPs (P ≤ 5 × 10−8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age‐specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10−3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10−3, the age‐specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Published
2019

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

Author

KUNKLE, B. W., GRENIER-BOLEY, B., SIMS, R., BIS, J. C., DAMOTTE, V., NAJ, A. C., BOLAND, A., VRONSKAYA, M., VAN DER LEE, S. J., AMLIE-WOLF, A., BELLENGUEZ, C., FRIZATTI, A., CHOURAKI, V., MARTIN, E. R., SLEEGERS, K., BADARINARAYAN, N., JAKOBSDOTTIR, J., HAMILTON-NELSON, K. L., MORENO-GRAU, S., OLASO, R., RAYBOULD, R., CHEN, Y., KUZMA, A. B., HILTUNEN, M., MORGAN, T., AHMAD, S., VARDARAJAN, B. N., EPELBAUM, J., HOFFMANN, P., BOADA, M., BEECHAM, G. W., GARNIER, J. G., HAROLD, D., FITZPATRICK, A. L., VALLADARES, O., MOUTET, M. L., GERRISH, A., SMITH, A. V., QU, L., BACQ, D., DENNING, N., JIAN, X., ZHAO, Y., DEL ZOMPO, M., FOX, N. C., CHOI, S. H., MATEO, I., HUGHES, J. T., ADAMS, H. H., MALAMON, J., SANCHEZ-GARCIA, F., PATEL, Y., BRODY, J. A., DOMBROSKI, B. A., NARANJO, M. C. D., DANIILIDOU, M., EIRIKSDOTTIR, G., MUKHERJEE, S., WALLON, D., UPHILL, J., ASPELUND, T., CANTWELL, L. B., GARZIA, F., GALIMBERTI, D., HOFER, E., BUTKIEWICZ, M., FIN, B., SCARPINI, E., SARNOWSKI, C., BUSH, W. S., MESLAGE, S., KORNHUBER, J., WHITE, C. C., SONG, Y., BARBER, R. C., ENGELBORGHS, S., SORDON, S., VOIJNOVIC, D., ADAMS, P. M., VANDENBERGHE, R., MAYHAUS, M., CUPPLES, L. A., ALBERT, M. S., DE DEYN, P. P., GU, W., HIMALI, J. J., BEEKLY, D., SQUASSINA, A., HARTMANN, A. M., ORELLANA, A., BLACKER, D., RODRIGUEZ-RODRIGUEZ, E., LOVESTONE, S., GARCIA, M. E., DOODY, R. S., MUNOZ-FERNADEZ, C., SUSSAMS, R., LIN, H., FAIRCHILD, T. J., BENITO, Y. A., HOLMES, C., KARAMUJIC-COMIC, H., FROSCH, M. P., THONBERG, H., MAIER, W., ROSHCHUPKIN, G., GHETTI, B., GIEDRAITIS, V., KAWALIA, A., LI, S., HUEBINGER, R. M., KILANDER, L., MOEBUS, S., HERNANDEZ, I., KAMBOH, M. I., BRUNDIN, R., TURTON, J., YANG, Q., KATZ, M. J., CONCARI, L., LORD, J., BEISER, A. S., KEENE, C. D., HELISALMI, S., KLOSZEWSKA, I., KUKULL, W. A., KOIVISTO, A. M., LYNCH, A., TARRAGA, L., LARSON, E. B., HAAPASALO, A., LAWLOR, B., MOSLEY, T. H., LIPTON, R. B., SOLFRIZZI, V., GILL, M., LONGSTRETH, W. T., Jr., MONTINE, T. J., FRISARDI, V., DIEZ-FAIREN, M., RIVADENEIRA, F., PETERSEN, R. C., DERAMECOURT, V., ALVAREZ, I., SALANI, F., CIARAMELLA, A., BOERWINKLE, E., REIMAN, E. M., FIEVET, N., ROTTER, J. I., REISCH, J. S., HANON, O., CUPIDI, C., UITTERLINDEN, A. G. A., ROYALL, D. R., DUFOUIL, Carole, MALETTA, R. G., DE ROJAS, I., SANO, M., BRICE, A., CECCHETTI, R., GEORGE-HYSLOP, P. S., RITCHIE, K., TSOLAKI, M., TSUANG, D. W., DUBOIS, B., CRAIG, D., WU, C. K., SOININEN, H., AVRAMIDOU, D., ALBIN, R. L., FRATIGLIONI, L., GERMANOU, A., APOSTOLOVA, L. G., KELLER, L., KOUTROUMANI, M., ARNOLD, S. E., PANZA, F., GKATZIMA, O., ASTHANA, S., HANNEQUIN, D., WHITEHEAD, P., ATWOOD, C. S., CAFFARRA, P., HAMPEL, H., QUINTELA, I., CARRACEDO, A., LANNFELT, L., RUBINSZTEIN, D. C., BARNES, L. L., PASQUIER, F., FROLICH, L., BARRAL, S., MCGUINNESS, B., BEACH, T. G., JOHNSTON, J. A., BECKER, J. T., PASSMORE, P., BIGIO, E. H., SCHOTT, J. M., BIRD, T. D., WARREN, J. D., BOEVE, B. F., LUPTON, M. K., BOWEN, J. D., PROITSI, P., BOXER, A., POWELL, J. F., BURKE, J. R., KAUWE, J. S. K., BURNS, J. M., MANCUSO, M., BUXBAUM, J. D., BONUCCELLI, U., CAIRNS, N. J., MCQUILLIN, A., CAO, C., LIVINGSTON, G., CARLSON, C. S., BASS, N. J., CARLSSON, C. M., HARDY, J., CARNEY, R. M., BRAS, J., CARRASQUILLO, M. M., GUERREIRO, R., ALLEN, M., CHUI, H. C., FISHER, E., MASULLO, C., CROCCO, E. A., DECARLI, C., BISCEGLIO, G., DICK, M., MA, L., DUARA, R., GRAFF-RADFORD, N. R., EVANS, D. A., HODGES, A., FABER, K. M., SCHERER, M., FALLON, K. B., RIEMENSCHNEIDER, M., FARDO, D. W., HEUN, R., FARLOW, M. R., KOLSCH, H., FERRIS, S., LEBER, M., FOROUD, T. M., HEUSER, I., GALASKO, D. R., GIEGLING, I., GEARING, M., HULL, M., GESCHWIND, D. H., GILBERT, J. R., MORRIS, J., GREEN, R. C., MAYO, K., GROWDON, J. H., FEULNER, T., HAMILTON, R. L., HARRELL, L. E., DRICHEL, D., HONIG, L. S., CUSHION, T. D., HUENTELMAN, M. J., HOLLINGWORTH, P., HULETTE, C. M., HYMAN, B. T., MARSHALL, R., JARVIK, G. P., MEGGY, A., ABNER, E., MENZIES, G. E., JIN, L. W., LEONENKO, G., REAL, L. M., JUN, G. R., BALDWIN, C. T., GROZEVA, D., KARYDAS, A., RUSSO, G., KAYE, J. A., KIM, R., JESSEN, F., KOWALL, N. W., VELLAS, B., KRAMER, J. H., VARDY, E., LAFERLA, F. M., JOCKEL, K. H., LAH, J. J., DICHGANS, M., LEVERENZ, J. B., MANN, D., LEVEY, A. I., PICKERING-BROWN, S., LIEBERMAN, A. P., KLOPP, N., LUNETTA, K. L., WICHMANN, H. E., LYKETSOS, C. G., MORGAN, K., MARSON, D. C., BROWN, K., MARTINIUK, F., MEDWAY, C., MASH, D. C., NOTHEN, M. M., MASLIAH, E., HOOPER, N. M., MCCORMICK, W. C., DANIELE, A., MCCURRY, S. M., BAYER, A., MCDAVID, A. N., GALLACHER, J., MCKEE, A. C., VAN DEN BUSSCHE, H., MESULAM, M., BRAYNE, C., MILLER, B. L., RIEDEL-HELLER, S., MILLER, C. A., MILLER, J. W., AL-CHALABI, A., MORRIS, J. C., SHAW, C. E., MYERS, A. J., WILTFANG, J., O'BRYANT, S., OLICHNEY, J. M., ALVAREZ, V., PARISI, J. E., SINGLETON, A. B., PAULSON, H. L., COLLINGE, J., PERRY, W. R., MEAD, S., PESKIND, E., CRIBBS, D. H., ROSSOR, M., PIERCE, A., RYAN, N. S., POON, W. W., NACMIAS, B., POTTER, H., SORBI, S., QUINN, J. F., SACCHINELLI, E., RAJ, A., SPALLETTA, G., RASKIND, M., CALTAGIRONE, C., BOSSU, P., ORFEI, M. D., REISBERG, B., CLARKE, R., REITZ, C., SMITH, A. D., RINGMAN, J. M., WARDEN, D., ROBERSON, E. D., WILCOCK, G., ROGAEVA, E., BRUNI, A. C., ROSEN, H. J., GALLO, M., ROSENBERG, R. N., BEN-SHLOMO, Y., SAGER, M. A., MECOCCI, P., SAYKIN, A. J., PASTOR, P., CUCCARO, M. L., VANCE, J. M., SCHNEIDER, J. A., SCHNEIDER, L. S., SLIFER, S., SEELEY, W. W., SMITH, A. G., SONNEN, J. A., SPINA, S., STERN, R. A., SWERDLOW, R. H., TANG, M., TANZI, R. E., TROJANOWSKI, J. Q., TRONCOSO, J. C., VAN DEERLIN, V. M., VAN ELDIK, L. J., VINTERS, H. V., VONSATTEL, J. P., WEINTRAUB, S., WELSH-BOHMER, K. A., WILHELMSEN, K. C., WILLIAMSON, J., WINGO, T. S., WOLTJER, R. L., WRIGHT, C. B., YU, C. E., YU, L., SABA, Y., PILOTTO, A., BULLIDO, M. J., PETERS, O., CRANE, P. K., BENNETT, D., BOSCO, P., COTO, E., BOCCARDI, V., DE JAGER, P. L., LLEO, A., WARNER, N., LOPEZ, O. L., INGELSSON, M., DELOUKAS, P., CRUCHAGA, C., GRAFF, C., GWILLIAM, R., FORNAGE, M., GOATE, A. M., SANCHEZ-JUAN, P., KEHOE, P. G., AMIN, N., ERTEKIN-TANER, N., BERR, C., DEBETTE, Stephanie, LOVE, S., LAUNER, L. J., YOUNKIN, S. G., DARTIGUES, Jean-Francois, CORCORAN, C., IKRAM, M. A., DICKSON, D. W., NICOLAS, G., CAMPION, D., TSCHANZ, J., SCHMIDT, H., HAKONARSON, H., CLARIMON, J., MUNGER, R., SCHMIDT, R., FARRER, L. A., VAN BROECKHOVEN, C., O'DONOVAN, M. C., DESTEFANO, A. L., JONES, L., HAINES, J. L., DELEUZE, J. F., OWEN, M. J., GUDNASON, V., MAYEUX, R., ESCOTT-PRICE, V., PSATY, B. M., RAMIREZ, A., WANG, L. S., RUIZ, A., VAN DUIJN, C. M., HOLMANS, P. A., SESHADRI, S., WILLIAMS, J., AMOUYEL, P., SCHELLENBERG, G. D., LAMBERT, J. C., PERICAK-VANCE, M. A., Clinical sciences, Neurology, and Pathologic Biochemistry and Physiology

Subjects
Medicine(all), MEDLINE, Medizin, Disease, Computational biology, Biology, medicine.disease, Article, Immunity, Alzheimer Disease, ddc:570, Meta-analysis, Genetics, medicine, Alzheimer's disease
Abstract

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

Published
2019

48. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, 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, Celine, 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, Stphane, 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., Benito, Yolanda A., Holmes, Clive, Karamujic-Comic, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roschupkin, Gena, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernandez, Isabel, Kamboh, M. Ilyas, Brundin, Rosemarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluis, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, W. T., Jr., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome, I, Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, St George-Hyslop, Peter, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Ines, Carracedo, Angel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Froelich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Koelsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Huell, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Joeckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan, I, Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Noethen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O'Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossu, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A. David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O'Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, Pericak-Vance, Margaret A., 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, Celine, 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, Stphane, 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., Benito, Yolanda A., Holmes, Clive, Karamujic-Comic, Hata, Frosch, Matthew P., Thonberg, Hakan, Maier, Wolfgang, Roschupkin, Gena, Ghetti, Bernardino, Giedraitis, Vilmantas, Kawalia, Amit, Li, Shuo, Huebinger, Ryan M., Kilander, Lena, Moebus, Susanne, Hernandez, Isabel, Kamboh, M. Ilyas, Brundin, Rosemarie, Turton, James, Yang, Qiong, Katz, Mindy J., Concari, Letizia, Lord, Jenny, Beiser, Alexa S., Keene, C. Dirk, Helisalmi, Seppo, Kloszewska, Iwona, Kukull, Walter A., Koivisto, Anne Maria, Lynch, Aoibhinn, Tarraga, Lluis, Larson, Eric B., Haapasalo, Annakaisa, Lawlor, Brian, Mosley, Thomas H., Lipton, Richard B., Solfrizzi, Vincenzo, Gill, Michael, Longstreth, W. T., Jr., Montine, Thomas J., Frisardi, Vincenza, Diez-Fairen, Monica, Rivadeneira, Fernando, Petersen, Ronald C., Deramecourt, Vincent, Alvarez, Ignacio, Salani, Francesca, Ciaramella, Antonio, Boerwinkle, Eric, Reiman, Eric M., Fievet, Nathalie, Rotter, Jerome, I, Reisch, Joan S., Hanon, Olivier, Cupidi, Chiara, Uitterlinden, A. G. Andre, Royall, Donald R., Dufouil, Carole, Maletta, Raffaele Giovanni, de Rojas, Itziar, Sano, Mary, Brice, Alexis, Cecchetti, Roberta, St George-Hyslop, Peter, Ritchie, Karen, Tsolaki, Magda, Tsuang, Debby W., Dubois, Bruno, Craig, David, Wu, Chuang-Kuo, Soininen, Hilkka, Avramidou, Despoina, Albin, Roger L., Fratiglioni, Laura, Germanou, Antonia, Apostolova, Liana G., Keller, Lina, Koutroumani, Maria, Arnold, Steven E., Panza, Francesco, Gkatzima, Olymbia, Asthana, Sanjay, Hannequin, Didier, Whitehead, Patrice, Atwood, Craig S., Caffarra, Paolo, Hampel, Harald, Quintela, Ines, Carracedo, Angel, Lannfelt, Lars, Rubinsztein, David C., Barnes, Lisa L., Pasquier, Florence, Froelich, Lutz, Barral, Sandra, McGuinness, Bernadette, Beach, Thomas G., Johnston, Janet A., Becker, James T., Passmore, Peter, Bigio, Eileen H., Schott, Jonathan M., Bird, Thomas D., Warren, Jason D., Boeve, Bradley F., Lupton, Michelle K., Bowen, James D., Proitsi, Petra, Boxer, Adam, Powell, John F., Burke, James R., Kauwe, John S. K., Burns, Jeffrey M., Mancuso, Michelangelo, Buxbaum, Joseph D., Bonuccelli, Ubaldo, Cairns, Nigel J., McQuillin, Andrew, Cao, Chuanhai, Livingston, Gill, Carlson, Chris S., Bass, Nicholas J., Carlsson, Cynthia M., Hardy, John, Carney, Regina M., Bras, Jose, Carrasquillo, Minerva M., Guerreiro, Rita, Allen, Mariet, Chui, Helena C., Fisher, Elizabeth, Masullo, Carlo, Crocco, Elizabeth A., DeCarli, Charles, Bisceglio, Gina, Dick, Malcolm, Ma, Li, Duara, Ranjan, Graff-Radford, Neill R., Evans, Denis A., Hodges, Angela, Faber, Kelley M., Scherer, Martin, Fallon, Kenneth B., Riemenschneider, Matthias, Fardo, David W., Heun, Reinhard, Farlow, Martin R., Koelsch, Heike, Ferris, Steven, Leber, Markus, Foroud, Tatiana M., Heuser, Isabella, Galasko, Douglas R., Giegling, Ina, Gearing, Marla, Huell, Michael, Geschwind, Daniel H., Gilbert, John R., Morris, John, Green, Robert C., Mayo, Kevin, Growdon, John H., Feulner, Thomas, Hamilton, Ronald L., Harrell, Lindy E., Drichel, Dmitriy, Honig, Lawrence S., Cushion, Thomas D., Huentelman, Matthew J., Hollingworth, Paul, Hulette, Christine M., Hyman, Bradley T., Marshall, Rachel, Jarvik, Gail P., Meggy, Alun, Abner, Erin, Menzies, Georgina E., Jin, Lee-Way, Leonenko, Ganna, Real, Luis M., Jun, Gyungah R., Baldwin, Clinton T., Grozeva, Detelina, Karydas, Anna, Russo, Giancarlo, Kaye, Jeffrey A., Kim, Ronald, Jessen, Frank, Kowall, Neil W., Vellas, Bruno, Kramer, Joel H., Vardy, Emma, LaFerla, Frank M., Joeckel, Karl-Heinz, Lah, James J., Dichgans, Martin, Leverenz, James B., Mann, David, Levey, Allan, I, Pickering-Brown, Stuart, Lieberman, Andrew P., Klopp, Norman, Lunetta, Kathryn L., Wichmann, H-Erich, Lyketsos, Constantine G., Morgan, Kevin, Marson, Daniel C., Brown, Kristelle, Martiniuk, Frank, Medway, Christopher, Mash, Deborah C., Noethen, Markus M., Masliah, Eliezer, Hooper, Nigel M., McCormick, Wayne C., Daniele, Antonio, McCurry, Susan M., Bayer, Anthony, McDavid, Andrew N., Gallacher, John, McKee, Ann C., van den Bussche, Hendrik, Mesulam, Marsel, Brayne, Carol, Miller, Bruce L., Riedel-Heller, Steffi, Miller, Carol A., Miller, Joshua W., Al-Chalabi, Ammar, Morris, John C., Shaw, Christopher E., Myers, Amanda J., Wiltfang, Jens, O'Bryant, Sid, Olichney, John M., Alvarez, Victoria, Parisi, Joseph E., Singleton, Andrew B., Paulson, Henry L., Collinge, John, Perry, William R., Mead, Simon, Peskind, Elaine, Cribbs, David H., Rossor, Martin, Pierce, Aimee, Ryan, Natalie S., Poon, Wayne W., Nacmias, Benedetta, Potter, Huntington, Sorbi, Sandro, Quinn, Joseph F., Sacchinelli, Eleonora, Raj, Ashok, Spalletta, Gianfranco, Raskind, Murray, Caltagirone, Carlo, Bossu, Paola, Orfei, Maria Donata, Reisberg, Barry, Clarke, Robert, Reitz, Christiane, Smith, A. David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia, Saykin, Andrew J., Pastor, Pau, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine, Debette, Stphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, Munger, Ron, Schmidt, Reinhold, Farrer, Lindsay A., Van Broeckhoven, Christine, O'Donovan, Michael C., DeStefano, Anita L., Jones, Lesley, Haines, Jonathan L., Deleuze, Jean-Francois, Owen, Michael J., Gudnason, Vilmundur, Mayeux, Richard, Escott-Price, Valentina, Psaty, Bruce M., Ramirez, Alfredo, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha, Williams, Julie, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles, and Pericak-Vance, Margaret A.

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 A beta 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 x 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

49. 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, Hernandez, Isabel, van Eijk, Kristel R., Stringa, Najada, Chen, Jason A., Zettergren, Anna, Andlauer, Till F. M., Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleo, 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, Illan-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Bergh, Florian Then, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begona, Collij, Lyduine E., Scherer, Martin, Morenas-Rodriguez, Estrella, Ironside, James W., van Berckel, Bart N. M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodriguez Rodriguez, Eloy, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J. T., Uitti, Ryan J., Tarraga, Lluis, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Merce, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, Lopez de Munain, Adolfo, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A. L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A., Sorensen, Thorkild I. A., Heutink, Peter, Sanchez-Juan, Pascual, Posthuma, Danielle, Clarimon, Jordi, Christensen, Kaare, Ertekin-Taner, Nilufer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustin, Slagboom, Eline, van der Flier, Wiesje M., Holstege, Henne, van der Lee, Sven J., Conway, Olivia J., Jansen, Iris, Carrasquillo, Minerva M., Kleineidam, Luca, van den Akker, Erik, Hernandez, Isabel, van Eijk, Kristel R., Stringa, Najada, Chen, Jason A., Zettergren, Anna, Andlauer, Till F. M., Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleo, 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, Illan-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Bergh, Florian Then, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M., Indakoetxea, Begona, Collij, Lyduine E., Scherer, Martin, Morenas-Rodriguez, Estrella, Ironside, James W., van Berckel, Bart N. M., Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L., Pastor, Pau, Rodriguez Rodriguez, Eloy, Boeve, Bradley F., Petersen, Ronald C., Ferman, Tanis J., van Gerpen, Jay A., Reinders, Marcel J. T., Uitti, Ryan J., Tarraga, Lluis, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Merce, Zettl, Uwe K., van Schoor, Natasja M., Beekman, Marian, Allen, Mariet, Masliah, Eliezer, Lopez de Munain, Adolfo, Pantelyat, Alexander, Wszolek, Zbigniew K., Ross, Owen A., Dickson, Dennis W., Graff-Radford, Neill R., Knopman, David, Rademakers, Rosa, Lemstra, Afina W., Pijnenburg, Yolande A. L., Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F., Hemmer, Bernhard, Huisman, Martijn A., Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A., Sorensen, Thorkild I. A., Heutink, Peter, Sanchez-Juan, Pascual, Posthuma, Danielle, Clarimon, Jordi, Christensen, Kaare, Ertekin-Taner, Nilufer, Scholz, Sonja W., Ramirez, Alfredo, Ruiz, Agustin, Slagboom, Eline, van der Flier, Wiesje M., and Holstege, Henne

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 PLC gamma 2 pathway as drug-target.

Published
2019

50. Novel mutations in SLC6A5 with benign course in hyperekplexia

Author

Dafsari, Hormos Salimi, Kawalia, Amit, Sprute, Rosanne, Karakaya, Mert, Malenica, Anna, Herkenrath, Peter, Nuernberg, Peter, Motameny, Susanne, Thiele, Holger, Cirak, Sebahattin, Dafsari, Hormos Salimi, Kawalia, Amit, Sprute, Rosanne, Karakaya, Mert, Malenica, Anna, Herkenrath, Peter, Nuernberg, Peter, Motameny, Susanne, Thiele, Holger, and Cirak, Sebahattin

Abstract

Infants suffering from life-threatening apnea, stridor, cyanosis, and increased muscle tone may often be misdiagnosed with infantile seizures and inappropriately treated because of lack and delay in genetic diagnosis. Here, we report a patient with increased muscle tone after birth and hypertonic attacks with life-threatening apnea but no epileptiform patterns in EEG recordings. We identified novel compound heterozygous variants in SLC6A5 (NM_004211.4:c.[1429T> C];[1430delC]) by trio whole-exome sequencing, containing a base deletion inherited by the asymptomatic mother leading to a frameshift (c.1430delC, p.Ser477PhefsTer9) and a de novo base exchange leading to an amino acid change (c.1429T > C, p.Ser477Pro). To date, there are four known disease-associated genes for primary hyperekplexia, all of which are involved in the functioning of glycinergic synapses. SLC6A5 encodes the sodium- and chloride-dependent glycine transporter 2 (GlyT2), which recaptures glycine, a major inhibitory transmitter in the brainstem and spinal cord. The diagnosis altered the patient's medical care to his benefit because SLC6A5 mutations with rather benign courses of hyperekplexia may be spared of needless pharmacotherapy. Symptoms eventually decreased in frequency until about once in 2 mo at 2 yr age. We present the first report of halting hyperekplexia episodes by maternal soothing in multiple instances. We highlight the importance of clarifying the genetic diagnosis by rapid next-generation sequencing techniques in this group of infantile apneic attacks with hyperekplexia due to the broad differential diagnoses.

Published
2019

Catalog

Books, media, physical & digital resources
See catalog results