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13 results on '"Carla A Ibrahim-Verbaas"'

1. Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

Author

Johanna Jakobsdottir, Sven J van der Lee, Joshua C Bis, Vincent Chouraki, David Li-Kroeger, Shinya Yamamoto, Megan L Grove, Adam Naj, Maria Vronskaya, Jose L Salazar, Anita L DeStefano, Jennifer A Brody, Albert V Smith, Najaf Amin, Rebecca Sims, Carla A Ibrahim-Verbaas, Seung-Hoan Choi, Claudia L Satizabal, Oscar L Lopez, Alexa Beiser, M Arfan Ikram, Melissa E Garcia, Caroline Hayward, Tibor V Varga, Samuli Ripatti, Paul W Franks, Göran Hallmans, Olov Rolandsson, Jan-Håkon Jansson, David J Porteous, Veikko Salomaa, Gudny Eiriksdottir, Kenneth M Rice, Hugo J Bellen, Daniel Levy, Andre G Uitterlinden, Valur Emilsson, Jerome I Rotter, Thor Aspelund, Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, Alzheimer’s Disease Genetic Consortium, Genetic and Environmental Risk in Alzheimer’s Disease consortium, Christopher J O'Donnell, Annette L Fitzpatrick, Lenore J Launer, Albert Hofman, Li-San Wang, Julie Williams, Gerard D Schellenberg, Eric Boerwinkle, Bruce M Psaty, Sudha Seshadri, Joshua M Shulman, Vilmundur Gudnason, and Cornelia M van Duijn

Subjects
Genetics, QH426-470
Abstract

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus

Published
2016
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2. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Author

Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L DeStefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, United Kingdom Brain Expression Consortium, Andrew D Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renee F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams, and Cardiovascular Health Study (CHS)

Subjects
Medicine, Science
Abstract

BACKGROUND:Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS:In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE:The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

Published
2014
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3. Human prion diseases in the Netherlands (1998-2009): clinical, genetic and molecular aspects.

Author

Casper Jansen, Piero Parchi, Sabina Capellari, Carla A Ibrahim-Verbaas, Maaike Schuur, Rosaria Strammiello, Patrizia Corrado, Matthew T Bishop, Willem A van Gool, Marcel M Verbeek, Frank Baas, Wesley van Saane, Wim G M Spliet, Gerard H Jansen, Cornelia M van Duijn, and Annemieke J M Rozemuller

Subjects
Medicine, Science
Abstract

Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998-2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrP(Sc) and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a "pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation.

Published
2012
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4. Genome-wide association study identifies risk variants for sporadic Creutzfeldt-Jakob disease in STX6 and GAL3ST1

Author

Anna Poleggi, John Collinge, Carla A. Ibrahim-Verbaas, Jean-Philippe Brandel, Emma Jones, Dimitriadis A, Anna Bartoletti-Stella, James Uphill, Christiane Stehmann, Mok Th, Gerard H. Jansen, Tracy Campbell, Zafar S, Holger Hummerich, van Duijn C, Jiri G. Safar, Ewa Golanska, Martinón-Torres F, Aili Golubjatnikov, Michael B. Coulthart, Zane Jaunmuktane, Beata Sikorska, Giuseppe Matullo, Miguel Calero, Jerome Whitfield, Sabina Capellari, Jean-Louis Laplanche, Kathleen Glisic, Gabor G. Kovacs, Richard Knight, Helen Speedy, Juan Ps, Olga Calero, Jean-Charles Lambert, Stéphane Haïk, Anna Ladogana, Akin Nihat, Stephanie A. Booth, Serena Aneli, Herbert Budka, Pawel P. Liberski, Piero Parchi, Shannon Sarros, Jacqueline M. Linehan, Sebastian Brandner, Maurizio Pocchiari, Ahmed P, Michael D. Geschwind, Fronztek K, Antonio Salas, Inga Zerr, Janis Blevins, Elodie Bouaziz-Amar, Brian S. Appleby, Steven J. Collins, P. Gambetti, Hata Karamujić-Čomić, Adriano Aguzzi, Philippe Amouyel, van der Lee S, Penny Norsworthy, Parmjit S. Jat, Liam Quinn, Emmanuelle Viré, and Simon Mead

Subjects
Genetics, 0303 health sciences, biology, animal diseases, Tau protein, STX6, Single-nucleotide polymorphism, Genome-wide association study, medicine.disease, 3. Good health, Progressive supranuclear palsy, PRNP, nervous system diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, biology.protein, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

Mammalian prions are lethal pathogens composed of fibrillar assemblies of misfolded prion protein. Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the gene that encodes prion protein (PRNP) are strong risk factors for sCJD, but although the condition has heritability similar to other neurodegenerative disorders, no other risk loci have yet been confirmed. By genome-wide association in European ancestry populations, we found three replicated loci (cases n=5208, within PRNP, STX6, and GAL3ST1) and two further unreplicated loci were significant in gene-wide tests (within PDIA4, BMERB1). Exome sequencing in 407 sCJD cases, conditional and transcription analyses suggest that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 and PDIA4 associate with increased expression of the major transcripts in disease-relevant brain regions. Alteration of STX6 expression does not modify prion propagation in a neuroblastoma cell model of mouse prion infection. We went on to analyse the proteins histologically in diseased tissue and examine the effects of risk variants on clinical phenotypes using deep longitudinal clinical cohort data. Risk SNPs in STX6, a protein involved in the intracellular trafficking of proteins and vesicles, are shared with progressive supranuclear palsy, a neurodegenerative disease associated with the misfolded protein tau. We present the first evidence of statistically robust associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism.

Published
2020
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5. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Author

Gabor G. Kovacs, Stephanie A. Booth, Sebastian Brandner, Penny Norsworthy, Anna Ladogana, Akin Nihat, Herbert Budka, Saima Zafar, Helen Speedy, Antonio Salas, Parvin Ahmed, Holger Hummerich, Gerard H. Jansen, Tze How Mok, Michael D. Geschwind, Beata Sikorska, Maurizio Pocchiari, Christiane Stehmann, Sabina Capellari, Jean-Louis Laplanche, Sven J. van der Lee, Emma Jones, Jean-Charles Lambert, Olga Calero, Pierluigi Gambetti, Ewa Golanska, Serena Aneli, Richard Knight, Giuseppe Matullo, Pawel P. Liberski, Athanasios Dimitriadis, Jerome Whitfield, Hata Karamujić-Čomić, Federico Martinón-Torres, Emmanuelle Viré, Jiri G. Safar, Tracy Campbell, Pascual Sánchez-Juan, Katie Glisic, Anna Bartoletti-Stella, Carla A. Ibrahim-Verbaas, Adriano Aguzzi, Anna Poleggi, Aili Golubjatnikov, Karl Frontzek, Jean Phillipe Brandel, Phillipe Amouyel, Parmjit S. Jat, Zane Jaunmuktane, Simon Mead, Steven J. Collins, Inga Zerr, Liam Quinn, Piero Parchi, Janis Blevins, Elodie Bouaziz-Amar, Brian S. Appleby, Shannon Sarros, Jacqueline M. Linehan, Miguel Calero, Michael B. Coulthart, Stéphane Haïk, John Collinge, James Uphill, Cornelia M. van Duijn, Diseases, Network Centre for Biomedical Research in Neurodegenerative, Jones E., Hummerich H., Vire E., Uphill J., Dimitriadis A., Speedy H., Campbell T., Norsworthy P., Quinn L., Whitfield J., Linehan J., Jaunmuktane Z., Brandner S., Jat P., Nihat A., How Mok T., Ahmed P., Collins S., Stehmann C., Sarros S., Kovacs G.G., Geschwind M.D., Golubjatnikov A., Frontzek K., Budka H., Aguzzi A., Karamujic-Comic H., van der Lee S.J., Ibrahim-Verbaas C.A., van Duijn C.M., Sikorska B., Golanska E., Liberski P.P., Calero M., Calero O., Sanchez-Juan P., Salas A., Martinon-Torres F., Bouaziz-Amar E., Haik S., Laplanche J.-L., Brandel J.-P., Amouyel P., Lambert J.-C., Parchi P., Bartoletti-Stella A., Capellari S., Poleggi A., Ladogana A., Pocchiari M., Aneli S., Matullo G., Knight R., Zafar S., Zerr I., Booth S., Coulthart M.B., Jansen G.H., Glisic K., Blevins J., Gambetti P., Safar J., Appleby B., Collinge J., Mead S., Universidad de Cantabria, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Epidemiology

Subjects
0301 basic medicine, epidemiology [Creutzfeldt-Jakob Syndrome], Tau protein, Single-nucleotide polymorphism, Genome-wide association study, diagnosis [Creutzfeldt-Jakob Syndrome], Disease, genetics [Genetic Loci], methods [Genome-Wide Association Study], Polymorphism, Single Nucleotide, Creutzfeldt-Jakob Syndrome, PRNP, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Genotyping, Exome sequencing, Genetics, biology, Odds ratio, genetics [Creutzfeldt-Jakob Syndrome], 030104 developmental biology, Genetic Loci, epidemiology [Genetic Predisposition to Disease], biology.protein, genetics [Polymorphism, Single Nucleotide], Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
Abstract

Background Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17–1·30], p=2·68 × 10 −15; heterozygous model p=1·01 × 10 −135), STX6 (rs3747957; OR 1·16 [1·10–1·22], p=9·74 × 10 −9), and GAL3ST1 (rs2267161; OR 1·18 [1·12–1·25], p=8·60 × 10 −10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Published
2020
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6. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Igor Rudan, Daniel I. Chasman, Helena Schmidt, Stefan Herms, Sharon L.R. Kardia, Oliver Stegle, Alison Pattie, Jenna Price, Gerardo Heiss, Karen A. Mather, L. J. Launer, Johan G. Eriksson, Christopher Oldmeadow, Ian Ford, Saira Saeed Mirza, Alan F. Wright, Ozren Polasek, Joshua M. Shulman, Maria K. Jonsdottir, André G. Uitterlinden, Rodney J. Scott, Kurt Lohman, Anita L. DeStefano, Peter W. Schofield, Perminder S. Sachdev, Stefania Bandinelli, Johan Wouter Jukema, John M. Starr, Rudolf S N Fehrmann, Y. C. Hsieh, William M. Meeks, Paul M. Ridker, R.G.J. Westendorp, Le Yu, J. C. van Swieten, Vilmundur Gudnason, Myriam Fornage, Melissa Garcia, Carla A. Ibrahim-Verbaas, James F. Wilson, Jean-Charles Lambert, Qiong Yang, Laura H. Coker, Stella Trompet, Lina Zgaga, Jennifer A. Smith, David J. Llewellyn, Nicole A. Kochan, Ben A. Oostra, Katja Petrovic, Peter Hoffmann, Qi Sun, James T. Becker, Najaf Amin, Vincent Chouraki, Brendan M. Buckley, D C Liewald, Jun Ding, Christiane Wolf, P. L. DeJager, Reinhold Schmidt, Chloe Fawns-Ritchie, Stéphanie Debette, Jing Wang, J. C. Bis, Nicola J. Armstrong, David J. Stott, Albert Hofman, Nazanin Karbalai, G. Eiriksdottir, Luke C. Pilling, D. S. Knopman, Maaike Schuur, Alexa S. Beiser, Annette L. Fitzpatrick, David A. Bennett, Aarno Palotie, Lude Franke, Sven Cichon, Mirna Kirin, Markus M. Nöthen, Thomas H. Mosley, Lynda M. Rose, Alan J. Gow, Caroline Hayward, Lori B. Chibnik, Ian J. Deary, Albert V. Smith, Jan Bressler, T.B. Harris, Stephen T. Turner, David J. Porteous, C M van Duijn, M. A. Ikram, Elizabeth G. Holliday, Mike A. Nalls, Luigi Ferrucci, Sudha Seshadri, Francine Grodstein, Marlene C. W. Stewart, Philip A. Wolf, Alexander Teumer, P.E. Slagboom, Jerome I. Rotter, Blair H. Smith, Juha Karjalainen, Susan M. Resnick, A.J.M. de Craen, Toshiko Tanaka, Alan D. Penman, Hans-Jörgen Grabe, Gary Davies, Oscar L. Lopez, Yongmei Liu, Kristine Yaffe, Veronique Vitart, Stela McLachlan, Katri Räikkönen, Rebecca F. Gottesman, Rhoda Au, Lynne J. Hocking, Carsten Oliver Schmidt, John Attia, Bruce M. Psaty, Wei Zhao, Jari Lahti, Epidemiology, Neurology, Clinical Genetics, Internal Medicine, [ 1 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands [ 2 ] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands [ 3 ] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA [ 4 ] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA [ 5 ] Univ Bordeaux, Epidemiol & Biostat, U897, INSERM, Bordeaux, France [ 6 ] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France [ 7 ] Iceland Heart Assoc, Kopavogur, Iceland [ 8 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 9 ] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA [ 10 ] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland [ 11 ] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands [ 12 ] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands [ 13 ] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA [ 14 ] Max Planck Inst Psychiat, RG Stat Genet, Munich, Germany [ 15 ] Brigham & Womens Hosp, Div Neurol, Program Translat Neuropsychiat Gen, Boston, MA 02115 USA [ 16 ] Wake Forest Sch Med, Dept Epidemiol, Winston Salem, NC USA [ 17 ] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland [ 18 ] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland [ 19 ] Med Univ & Gen Hosp Graz, Dept Neurol, Graz, Austria [ 20 ] Univ Split, Dept Publ Hlth, Split, Croatia [ 21 ] Trintiy Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland [ 22 ] Res Ctr Juelich, Inst Neurosci & Med INM1, Julich, Germany [ 23 ] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland [ 24 ] Univ Bonn, Inst Human Genet, Life & Brain Res Ctr, Dept Genom, Bonn, Germany [ 25 ] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands [ 26 ] Univ Helsinki, Inst Behav Sci, Helsinki, Finland [ 27 ] Folkhalsan Res Ctr, Helsinki, Finland [ 28 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 29 ] Univ Med Greifswald, Inst Community Med, Greifswald, Germany [ 30 ] Univ New S Wales, UNSW Med, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia [ 31 ] Univ Lille Nord France, Inst Pasteur Lille, U1167, INSERM, Lille, France [ 32 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 33 ] Harvard Univ, Sch Med, Boston, MA USA [ 34 ] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA [ 35 ] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA [ 36 ] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2300, Australia [ 37 ] Univ Newcastle, Fac Hlth, Newcastle, NSW 2300, Australia [ 38 ] Univ Dundee, Med Res Inst, Dundee, Scotland [ 39 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 40 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 41 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 42 ] Netherlands Consortium Hlth Ageing, Leiden, Netherlands [ 43 ] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA [ 44 ] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland [ 45 ] Wake Forest Sch Med, Div Publ Hlth Sci & Neurol, Winston Salem, NC USA [ 46 ] Max Planck Inst Intelligent Syst, Max Planck Inst Dev Biol, Tubingen, Germany [ 47 ] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA [ 48 ] Univ Med Greifswald, Interfaculty Inst Genet & Funct Genom, Greifswald, Germany [ 49 ] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland [ 50 ] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA [ 51 ] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA [ 52 ] Landspitali Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 53 ] NIA, Lab Neurogenet, Bethesda, MD 20892 USA [ 54 ] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA [ 55 ] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA [ 56 ] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA [ 57 ] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA [ 58 ] San Francisco VA Med Ctr, San Francisco, CA USA [ 59 ] Mayo Clin, Dept Neurol, Rochester, MN USA [ 60 ] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA [ 61 ] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA [ 62 ] Univ Newcastle, Fac Hlth, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia [ 63 ] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA [ 64 ] Univ Glasgow, Dept Cardiovasc & Med Sci, Glasgow, Lanark, Scotland [ 65 ] Alzheimer Scotland Res Ctr, Edinburgh, Midlothian, Scotland [ 66 ] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland [ 67 ] Garvan Inst Med Res, Canc Res Program, Sydney, NSW, Australia [ 68 ] Univ New S Wales, Sch Math & Stat, Sydney, NSW, Australia [ 69 ] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia [ 70 ] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA [ 71 ] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Dept Mol & Human Genet, Houston, TX 77030 USA [ 72 ] Univ Exeter, Sch Med, Epidemiol & Publ Hlth Grp, Exeter, Devon, England [ 73 ] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia [ 74 ] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England [ 75 ] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland [ 76 ] Univ Helsinki, Dept Med Genet, Helsinki, Finland [ 77 ] Univ Cent Hosp, Helsinki, Finland [ 78 ] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan [ 79 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 80 ] Natl Inst Hlth & Welf, Helsinki, Finland [ 81 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 82 ] Vasa Cent Hosp, Vaasa, Finland [ 83 ] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA [ 84 ] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA [ 85 ] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA [ 86 ] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA [ 87 ] Harbor UCLA Med Ctr, Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA [ 88 ] Harbor UCLA Med Ctr, Dept Pediat, Div Genet Outcomes, Torrance, CA 90509 USA [ 89 ] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany [ 90 ] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands [ 91 ] Leiden Acad Vital & Ageing, Leiden, Netherlands [ 92 ] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland [ 93 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 94 ] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA [ 95 ] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA [ 96 ] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA [ 97 ] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, Stralsund, Germany [ 98 ] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy [ 99 ] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland [ 100 ] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA [ 101 ] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA [ 102 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 103 ] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands [ 104 ] Univ Mississippi, Med Ctr, Dept Med & Neurol, Jackson, MS 39216 USA, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
0301 basic medicine, Male, DISORDER, Trail Making Test, LOCI, Genome-wide association study, INTELLIGENCE, Neuropsychological Tests, Cohort Studies, Exon, Executive Function, 0302 clinical medicine, Cognition, SCHIZOPHRENIA, ONSET ALZHEIMERS-DISEASE, CADM2 protein, human, genetics [Cell Adhesion Molecules], gamma-Aminobutyric Acid, Genetics, Aged, 80 and over, PSC12, physiology [Cognition], COMMON VARIANTS, Genomics, Middle Aged, genetics [Genetic Variation], 3. Good health, physiology [Executive Function], Psychiatry and Mental health, genetics [European Continental Ancestry Group], Schizophrenia, Female, Psychology, EXPRESSION, genetics [White People], physiology [Cell Adhesion Molecules], Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetic variation, medicine, SNP, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Genetic Association Studies, Aged, LINKAGE ANALYSIS, 9. Industry and infrastructure, Genetic Variation, medicine.disease, COGNITIVE FUNCTION, Introns, 030104 developmental biology, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Stroop effect, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. National Foundation for Alzheimer's disease and related disorders Institut Pasteur de Lille Centre National de Genotypage Inserm FRC (fondation pour la recherche sur le cerveau) Rotary LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) MEDIALZ Project - ERDF (European Regional Development Fund) 11001003 Conseil Regional Nord Pas de Calais Fondation pour la Recherche Medicale Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante MGEN Institut de la Longevite Agence Francaise de Securite Sanitaire des Produits de Sante Aquitaine and Bourgogne Regional Councils Fondation de France joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program Eisai Wellcome Trust British Heart Foundation Chief Scientist Office of the Scottish Executive NIA N01-AG-12100 National Heart, Lung and Blood Institute Contracts HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C R01HL70825 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute U01HG004402 NIH Roadmap for Medical Research Austrian Science Fond (FWF) P20545-P05 P13180 Intramural Research Program of the NIH, National Institute on Aging NHLBI HHSN268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC850863 U01HL080295 R01HL087652 R01HL105756 R01HL103612 R01HL120393 National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Aging (NIA) R01AG023629 R01AG15928 R01AG20098 R01AG027058 National Center for Advancing Translational Sciences CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 Medical Research Council (UK) European Commission Framework 6 project EUROSPAN LSHG-CT-2006-018947 Republic of Croatia Ministry of Science, Education and Sports 108-1080315-0302 Netherlands Organization for Scientific Research (NWO) Internationale Stichting Alzheimer Onderzoek (ISAO) Hersenstichting Nederland (HSN) Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) Russian Foundation for Basic Research (RFBR) National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 U01 HL096917 R01 HL093029 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Neurological Disorders and Stroke NS17950 National Institute of Aging U01 AG049505 AG033193 AG008122 AG16495 Agence National de la Recherche Leducq Foundation National Heart, Lung and Blood Institute HL054464 HL054457 HL054481 HL071917 HL87660 HL043851 HL080467 National Institute of Neurological Disorders and Stroke of the National Institutes of Health NS041558 Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 Scottish Funding Council HR03006 Academy of Finland Finnish Diabetes Research Society Folkhalsan Research Foundation Novo Nordisk Foundation Finska Lakaresallskapet Signe and Ane Gyllenberg Foundation University of Helsinki Ministry of Education Ahokas Foundation Emil Aaltonen Foundation Juho Vainio Foundation Wellcome Trust WT089062 University of Newcastle's Strategic Initiative Fund Vincent Fairfax Family Foundation Hunter Medical Research Institute Italian Ministry of Health ICS 110.1RS97.71 US National Institute on Aging N01[AG]916413 N01[AG]821336 263 MD 9164 13 263 MD 821336 Intramural Research Program, National Institute on Aging, National Institutes of Health BBSRC Royal Society Chief Scientist Office of the Scottish Government Research Into Ageing UK Biotechnology and Biological Sciences Research Council (BBSRC) Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research Council (ESRC) MRC NHMRC 401184 Australian National Health & Medical Research Council 350833 568969 Capacity Building Grant 568940 NHMRC Project 525453 National Institutes of Health CA87969 CA49449 HL34594 U01HG004399 DK058845 CA65725 CA67262 CA50385 5UO1CA098233 EY09611 EY015473 HG004728 HL35464 CA55075 CA134958 DK070756 MRC Human Genetics Unit Arthritis Research UK European Union LSHG-CT-2006-018947 Bristol-Myers Squibb Netherlands Heart Foundation 2001 D 032 European commission 223004 Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) 050-060-810 Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission 49 (DG XII) Municipality of Rotterdam ZonMW Veni Grant 916.13.054 NIA Grants P30AG10161 R01AG15819 R01AG17917 R01AG30146 K08AG34290 K25AG41906 Federal Ministry of Education and Research 01ZZ9603 01ZZ0103 01ZZ0403 Ministry of Cultural Affairs Social Ministry of the Federal State of Mecklenburg-West Pomerania National Cancer Institute CA047988 Donald W Reynolds Foundation Fondation Leducq Amgen info:eu-repo/grantAgreement/EC/FP7/223004

Published
2016
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7. A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Author

Anais Mounier, James T. Becker, Vincent Chouraki, Robert S. Rogers, P. Amouyel, Florie Demiautte, R. F. A. G. de Bruijn, Richard Mayeux, Annette L. Fitzpatrick, J. C. Bis, J. F. Dartigues, Carla A. Ibrahim-Verbaas, A. Hofman, Christophe Tzourio, Benjamin Grenier-Boley, M. A. Ikram, Mark Lathrop, A.G. Uitterlinden, Oscar L. Lopez, Claudine Berr, Nicole Schupf, M.M.B. Breteler, Christiane Reitz, Annick Alpérovitch, J-C Lambert, C M van Duijn, Susanna Schraen, Luc Buée, Charlotte Delay, and Julien Chapuis

Subjects
Aging, Amyloid beta, Locus (genetics), Genome-wide association study, Biology, Polymorphism, Single Nucleotide, APP protein, human, White People, Article, Cellular and Molecular Neuroscience, Amyloid beta-Protein Precursor, SDG 3 - Good Health and Well-being, blood [Amyloid beta-Peptides], metabolism [Amyloid beta-Protein Precursor], blood [Aging], medicine, Humans, ddc:610, Senile plaques, Molecular Biology, Gene, Amyloid beta-Peptides, CTXN3 protein, human, HEK 293 cells, Membrane Proteins, amyloid beta-protein (1-40), amyloid beta-protein (1-42), medicine.disease, Peptide Fragments, genetics [European Continental Ancestry Group], genetics [Membrane Proteins], Psychiatry and Mental health, HEK293 Cells, Membrane protein, Biochemistry, genetics [Amyloid beta-Protein Precursor], blood [Peptide Fragments], genetics [Aging], biology.protein, Alzheimer's disease, metabolism [Membrane Proteins], Genome-Wide Association Study
Abstract

Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ 1-40 and Aβ 1 -42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P

Published
2014
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8. The association between lower educational attainment and depression owing to shared genetic effects?: Results in ~25,000 subjects

Author

Patricia A. Peyser, Jessica D. Faul, Patrik K. E. Magnusson, Nicholas D. Hastie, Beate St Pourcain, Marcus Ising, Gérard Waeber, Behrooz Z. Alizadeh, Judith M. Vonk, Lawrence F. Bielak, Sang Hong Lee, Wouter J. Peyrot, Thomas Illig, M. M. Weissman, Nicholas J. Timpson, George Dedoussis, Nicholas G. Martin, Tomi E. Mäkinen, Jorma Viikari, Lili Milani, Harold Snieder, Laura J. Bierut, A. C. Heath, Reinhold E. Schmidt, Mariza de Andrade, Vilmundur Gudnason, K. Petrovic, Robert M. Kirkpatrick, Marcela González Gross, William G. Iacono, Michelle N. Meyer, Henry Völzke, Marisa Loitfelder, Maria Dimitriou, Lude Franke, Robert F. Krueger, E. J. C. G. van den Oord, Sven Cichon, Michael Conlon O'Donovan, Ian W. Craig, Shawn N. Murphy, Danielle Posthuma, Brenda W.J.H. Penninx, Aarno Palotie, Roy Thurik, Panos Deloukas, Matt McGue, M. Preisig, Patricia A. Boyle, Osorio Meirelles, Ben A. Oostra, Klaus Berger, G. M. Montgomery, Sharon L.R. Kardia, Peter K. Joshi, K. Stefansson, Paul Lichtenstein, Andrew Heath, Andrea Schulz, Dena G. Hernandez, Debbie A Lawlor, S. P. Hamilton, James B. Potash, Z. Kutalik, Elisabeth Widen, Emil L. Sigurdsson, Rudolf S N Fehrmann, Matthias Nauck, Mikael Landén, Kurt Lohman, S.D. Gordon, Lefkos T. Middleton, Caroline Hayward, Anjali K. Henders, Philipp Koellinger, Jeffrey A. Boatman, G van Grootheest, M. Daly, Jian Yang, Peter Vollenweider, Penelope A. Lind, Stacy Steinberg, Frank J. A. van Rooij, Florian Holsboer, Hkon K. Gjessing, Erkki Vartiainen, Magnus Johannesson, Jingmei Li, David Laibson, Henrik Grönberg, Tõnu Esko, Ivana Kolcic, Niina Eklund, Kelly S. Benke, Henning Tiemeier, Isaac S. Kohane, Nicolas W. Martin, Ronny Myhre, Frans G. Zitman, Arpana Agrawal, James F. Wilson, Michael R. Barnes, Lei Yu, Thorgeir E. Thorgeirsson, Franois Bastardot, Katri Räikkönen, William Lawson, Willem A. Nolen, M. Rietschel, René Breuer, Bertram Müller-Myhsok, James A. Knowles, Grant W. Montgomery, Eva Reinmaa, Rudolf Uher, Andreas Mielck, Luigi Ferrucci, S. E. Medland, Yuri Milaneschi, Philip L. De Jager, Manfred Uhr, A. E. Farmer, Cornelia M. van Duijn, Samuli Ripatti, Marja-Liisa Nuotio, Manuel Mattheisen, Sebastian E. Baumeister, David R. Van Wagoner, Martin Preisig, Fernando Rivadeneira, Peter Lichtner, Christopher Oldmeadow, Hreinn Stefansson, Ian B. Hickie, Darina Czamara, Elizabeth G. Holliday, Astanand Jugessur, Carla A. Ibrahim-Verbaas, Jaime Derringer, Vivian S. Gainer, P. Muglia, Daniel J. Benjamin, Patrick K.E. Magnusson, Patience J. Gallagher, Jennifer A. Smith, Lynn Cherkas, Pamela A. F. Madden, David A. Bennett, Zoltán Kutalik, George Davey-Smith, Gudny Eiriksdottir, Jens Treutlein, N. Craddock, Juliette Harris, Antti Latvala, Roy H. Perlis, Markus M. Noethen, Jan-Emmanuel De Neve, Stanley I. Shyn, J.H. Smit, Dalton Conley, Adriaan Hofman, Jari Lahti, Patrick J. F. Groenen, Jüri Allik, Albert V. Smith, Ozren Polasek, Susan M. Ring, Thomas Bettecken, Michele L. Pergadia, Patrick J. McGrath, Katherine E. Tansey, Stephan Ripke, Hogni Oskarsson, Peng Lin, Douglas F. Levinson, Matthijs J. H. M. van der Loos, Melissa E. Garcia, Jonathan P. Beauchamp, Rodney J. Scott, Zhihong Zhu, Michel Guipponi, Lyle J. Palmer, Alexander Teumer, William Coryell, Stefan Kloiber, Gonneke Willemsen, John Frank, Victor M. Castro, Andrew M. McIntosh, John M. Starr, Antonio Terracciano, Mika Kähönen, Marco Masala, Markus Perola, André G. Uitterlinden, Sutapa Mukherjee, Alexander Viktorin, Lenore J. Launer, Elisabeth B. Binder, William A. Scheftner, Christel M. Middeldorp, D. H. R. Blackwood, I. Jones, Thais S. Rizzi, A. Teumer, Cornelius A. Rietveld, Aldo Rustichini, Guy Lewis, Susan L. Slager, David M. Evans, Dorret I. Boomsma, Harry Campbell, Susanne Churchill, Johan G. Eriksson, Alan F. Wright, Dan V. Iosifescu, W. Maier, Francesco Cucca, Federica Tozzi, David R. Weir, Eva Albrecht, L. Milani, Jennifer R. Harris, Min A. Jhun, Marjo-Riitta Järvelin, Martin F. Elderson, Ute Bültmann, Olli T. Raitakari, Konstantin Shakhbazov, Krista Fischer, Thomas G. Schulze, T. Jung-Ying, P. Lichtenstein, Terho Lethimäki, Jeffrey B. Weilburg, Rolf Holle, Bo Jacobsson, Pedro Marques Vidal, Jordan W. Smoller, Stavroula Kanoni, Kati Kristiansson, Sergey Goryachev, Michael Steffens, Peter M. Visscher, Toshiko Tanaka, Donald J. MacIntyre, Witte J.G. Hoogendijk, David Schlessinger, Ian J. Deary, Harm-Jan Westra, Erik Ingelsson, E.J.C. de Geus, Franziska Degenhardt, Lydia Quaye, John Barnard, David C. Liewald, John P. Rice, Christopher F. Chabris, P. McGuffin, Tamara B. Harris, C. M. Lewis, Gail Davies, Enda M. Byrne, H.-Erich Wichmann, Sara Hägg, David Cesarini, Najaf Amin, Juha Karjalainen, Dale R. Nyholt, Christian Gieger, Per Hall, Ania Korszun, Neale Bm, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Christina Holzapfel, Jae Hoon Sul, Christiaan de Leeuw, Antti-Pekka Sarin, Ida Surakka, Veikko Salomaa, Mina K. Chung, N. L. Pedersen, Gerome Breen, P. A. F. Madden, Martin A. Kohli, J Kaprio, John Attia, Jing Shi, Gibran Hemani, Rauli Svento, Veronique Vitart, Susanne Lucae, L. A. Jones, Jouke-Jan Hottenga, Daniel S. Evans, Hans-Jörgen Grabe, Yongmei Liu, Danyu Lin, Albert Hofman, George McMahon, Naomi R. Wray, Stefan Herms, Stefania Bandinelli, W. Hoffmann, P.F. Sullivan, Susanne Hoefels, Michael B. Miller, Alan W. McLean, Igor Rudan, Jürgen Wellmann, Anu Realo, Maurizio Fava, Matthew Kowgier, Marika Kaakinen, Helena Schmidt, Faculteit Medische Wetenschappen/UMCG, Peyrot, WJ, Lee, SH, Milaneschi, Y, Abdellaoui, A, Penninx, BWJH, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium, Social Science Genetic Association Consortium, Psychiatry, NCA - Neurobiology of mental health, EMGO - Mental health, Applied Economics, Biological Psychology, Complex Trait Genetics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (Corporate Collaborator), Social Science Genetic Association Consortium Corporate Collaborator, Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium Corporate Collaborator, Lewis, C.M., Hamilton, S.P., Weissman, M.M., Breen, G., Blackwood, D.H., Cichon, S., Heath, A.C., Holsboer, F., Madden, P.A., McGuffin, P., Muglia, P., Pergadia, M.L., Lin, D., Müller-Myhsok, B., Steinberg, S., Grabe, H.J., Lichtenstein, P., Magnusson, P., Perlis, R.H., Preisig, M., Smoller, J.W., Stefansson, K., Uher, R., Kutalik, Z., Tansey, K.E., Teumer, A., Viktorin, A., Barnes, M.R., Bettecken, T., Binder, E.B., Breuer, R., Castro, V.M., Churchill, S.E., Coryell, W.H., Craddock, N., Craig, I.W., Czamara, D., Degenhardt, F., Farmer, A.E., Fava, M., Frank, J., Gainer, V.S., Gallagher, P.J., Gordon, S.D., Goryachev, S., Gross, M., Guipponi, M., Henders, A.K., Herms, S., Hickie, I.B., Hoefels, S., Hoogendijk, W., Iosifescu, D.V., Ising, M., Jones, I., Jones, L., Jung-Ying, T., Knowles, J.A., Kohane, I.S., Kohli, M.A., Korszun, A., Landen, M., Lawson, W.B., Lewis, G., Macintyre, D., Maier, W., Mattheisen, M., McGrath, P.J., McIntosh, A., McLean, A., Middeldorp, C.M., Middleton, L., Montgomery, G.M., Murphy, S.N., Nauck, M., Nolen, W.A., Nyholt, D.R., O'Donovan, M., Oskarsson, H., Pedersen, N., Scheftner, W.A., Schulz, A., Schulze, T.G., Shyn, S.I., Sigurdsson, E., Slager, S.L., Smit, J.H., Stefansson, H., Steffens, M., Thorgeirsson, T., Tozzi, F., Treutlein, J., Uhr, M., van den Oord, E.J., Van Grootheest, G., Völzke, H., Weilburg, J.B., Willemsen, G., Zitman, F.G., Neale, B., Daly, M., Sullivan, P.F., Agrawal, A., Albrecht, E., Alizadeh, B.Z., Allik, J., Amin, N., Attia, J.R., Bandinelli, S., Barnard, J., Bastardot, F., Baumeister, S.E., Beauchamp, J., Benjamin, D.J., Benke, K.S., Bennett, D.A., Berger, K., Bielak, L.F., Bierut, L.J., Boatman, J.A., Boyle, P.A., Bültmann, U., Campbell, H., Cesarini, D., Chabris, C.F., Cherkas, L., Chung, M.K., Conley, D., Cucca, F., Davey-Smith, G., Davies, G., de Andrade, M., De Jager, P.L., de Leeuw, C., De Neve, J.E., Deary, I.J., Dedoussis, G.V., Deloukas, P., Derringer, J., Dimitriou, M., Eiriksdottir, G., Eklund, N., Elderson, M.F., Eriksson, J.G., Evans, D.S., Evans, D.M., Faul, J.D., Fehrmann, R., Ferrucci, L., Fischer, K., Franke, L., Garcia, M.E., Gieger, C., Gjessing, H.K., Groenen, P.J., Grönberg, H., Gudnason, V., Hägg, S., Hall, P., Harris, J.R., Harris, J.M., Harris, T.B., Hastie, N.D., Hayward, C., Hernandez, D.G., Hoffmann, W., Hofman, A., Holle, R., Holliday, E.G., Holzapfel, C., Iacono, W.G., Ibrahim-Verbaas, C.A., Illig, T., Ingelsson, E., Jacobsson, B., Järvelin, M.R., Jhun, M.A., Johannesson, M., Joshi, P.K., Jugessur, A., Kaakinen, M., Kähönen, M., Kanoni, S., Kaprio, J., Kardia, S.L., Karjalainen, J., Kirkpatrick, R.M., Koellinger, P.D., Kolcic, I., Kowgier, M., Kristiansson, K., Krueger, R.F., Lahti, J., Laibson, D., Latvala, A., Launer, L.J., Lawlor, D.A., Lethimäki, T., Li, J., Lichtner, P.K., Liewald, D.C., Lin, P., Lind, P.A., Liu, Y., Lohman, K., Loitfelder, M., Magnusson, P.K., Mäkinen, T.E., Vidal, P.M., Martin, N.W., Masala, M., McGue, M., McMahon, G., Meirelles, O., Meyer, M.N., Mielck, A., Milani, L., Miller, M.B., Montgomery, G.W., Mukherjee, S., Myhre, R., Nuotio, M.L., Oldmeadow, C.J., Oostra, B.A., Palmer, L.J., Palotie, A., Perola, M., Petrovic, K.E., Peyser, P.A., Polašek, O., Posthuma, D., Quaye, L., Räikkönen, K., Raitakari, O.T., Realo, A., Reinmaa, E., Rice, J.P., Ring, S.M., Ripatti, S., Rivadeneira, F., Rizzi, T.S., Rudan, I., Rustichini, A., Salomaa, V., Sarin, A.P., Schlessinger, D., Schmidt, H., Schmidt, R., Scott, R.J., Shakhbazov, K., Smith, A.V., Smith, J.A., Snieder, H., Pourcain, B.S., Starr, J.M., Sul, J.H., Surakka, I., Svento, R., Tanaka, T., Terracciano, A., Thurik, A.R., Tiemeier, H., Timpson, N.J., Uitterlinden, A.G., van der Loos, M.J., van Duijn, C.M., van Rooij, F.J., Van Wagoner, D.R., Vartiainen, E., Viikari, J., Visscher, P.M., Vitart, V., Vollenweider, P.K., Vonk, J.M., Waeber, G., Weir, D.R., Wellmann, J., Westra, H.J., Wichmann, H.E., Widen, E., Wilson, J.F., Wright, A.F., Yang, J., Yu, L., and Zhao, W.

Subjects
Netherlands Twin Register (NTR), Male, Genome-wide association study, Logistic regression, Cohort Studies, Odds Ratio, pleiotropic genetic effects, Netherlands, Psychiatry, education.field_of_study, Likelihood Functions, Single Nucleotide, Middle Aged, Psychiatry and Mental health, educational attainment, depression, Major depressive disorder, Educational Status, Regression Analysis, Female, Psychology, Adult, Estonia, medicine.medical_specialty, Biochemistry & Molecular Biology, Aged, Depressive Disorder, Major/epidemiology, Depressive Disorder, Major/genetics, Depressive Disorder, Major/psychology, Estonia/epidemiology, Gene-Environment Interaction, Genetic Association Studies, Genotype, Humans, Netherlands/epidemiology, Polymorphism, Single Nucleotide/genetics, Psychiatric Status Rating Scales, Concordance, Population, SNP, Single-nucleotide polymorphism, Genetic correlation, behavioral disciplines and activities, Polymorphism, Single Nucleotide, Article, Cellular and Molecular Neuroscience, mental disorders, medicine, Polymorphism, education, Molecular Biology, Depressive Disorder, Depressive Disorder, Major, major depressive disorder, ta1184, Neurosciences, Major, Odds ratio, medicine.disease, ta3124, Neurosciences & Neurology, polymorphisms, Demography
Abstract

An association between lower educational attainment (EA) and an increased risk for depression has been confirmed in various western countries. This study examines whether pleiotropic genetic effects contribute to this association. Therefore, data were analyzed from a total of 9662 major depressive disorder (MDD) cases and 14 949 controls (with no lifetime MDD diagnosis) from the Psychiatric Genomics Consortium with additional Dutch and Estonian data. The association of EA and MDD was assessed with logistic regression in 15 138 individuals indicating a significantly negative association in our sample with an odds ratio for MDD 0.78 (0.75-0.82) per standard deviation increase in EA. With data of 884 105 autosomal common single-nucleotide polymorphisms (SNPs), three methods were applied to test for pleiotropy between MDD and EA: (i) genetic profile risk scores (GPRS) derived from training data for EA (independent meta-analysis on similar to 120 000 subjects) and MDD (using a 10-fold leave-one-out procedure in the current sample), (ii) bivariate genomic-relationship-matrix restricted maximum likelihood (GREML) and (iii) SNP effect concordance analysis (SECA). With these methods, we found (i) that the EA-GPRS did not predict MDD status, and MDD-GPRS did not predict EA, (ii) a weak negative genetic correlation with bivariate GREML analyses, but this correlation was not consistently significant, (iii) no evidence for concordance of MDD and EA SNP effects with SECA analysis. To conclude, our study confirms an association of lower EA and MDD risk, but this association was not because of measurable pleiotropic genetic effects, which suggests that environmental factors could be involved, for example, socioeconomic status. Refereed/Peer-reviewed

Published
2015
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9. Multiethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

Author

Susan H. Blanton, Ashley Beecham, Pamela J. Schreiner, Ralph L. Sacco, Stéphanie Debette, Ben A. Oostra, Marian Beekman, M. Arfan Ikram, Edith Hofer, Anna Maria Töglhofer, Alexander Teumer, Ganesh Chauhan, Clinton B. Wright, Meike W. Vernooij, Wiro J. Niessen, Aad van der Lugt, Cornelia M. van Duijn, Christophe Tzourio, Matthias Nauck, Bernard Mazoyer, Bettina von Sarnowski, Alexa S. Beiser, Susan R. Heckbert, André G. Uitterlinden, Alex P. Zijdenbos, David S. Knopman, Paul Freudenberger, Myriam Fornage, Maaike Schuur, Stephen Turner, Matthew Traylor, Qiong Yang, Fabrice Crivello, P. Eline Slagboom, Ian J. Deary, Sharon L.R. Kardia, Cora E. Lewis, Stella Trompet, Mike A. Nalls, Jennifer A. Smith, Katrin Hegenscheid, Hans J. Grabe, Lenore J. Launer, Reinhold Schmidt, Albert V. Smith, M. Kamran Ikram, Kumar B. Rajan, Mariza de Andrade, Sudha Seshadri, Lorna M. Lopez, Philip L. De Jager, Albert Hofman, Joshua C. Bis, Gerardo Heiss, Neelum T. Aggarwal, Elizabeth J. Atkinson, Carla A. Ibrahim-Verbaas, David C. Liewald, Anton J. M. de Craen, Jing Wang, David J. Stott, Sandra Barral, Adam M. Brickman, Mohamad Habes, Eric Boerwinkle, Katharina Wittfeld, Jerome I. Rotter, Saima Hilal, R. Nick Bryan, Charles C. DeCarli, Mark A. van Buchem, Mitchell S.V. Elkind, Rebecca F. Gottesman, Christiane Wolf, Vincent Chouraki, Jeroen van der Grond, Jiemin Liao, Joris Deelen, Stephen Sidney, Kenneth Rice, Vilmundur Guðnason, Hieab H.H. Adams, Benjamin F.J. Verhaaren, Tien Yin Wong, Oliver Martinez, Denis A. Evans, Helena Schmidt, W. T. Longstreth, J. Wouter Jukema, Richard Mayeux, Joanna M. Wardlaw, Thomas H. Mosley, Michelle Luciano, Sigurdur Sigurdsson, Carole Dufouil, Christopher Chen, Philippe Amouyel, Wei Zhao, John C. van Swieten, Bruce M. Psaty, Hae-Won Uh, B. Gwen Windham, Erasmus University Medical Center [Rotterdam] (Erasmus MC), INSERM U897, University of Bordeaux, France, University of Washington [Seattle], University of Michigan [Ann Arbor], University of Michigan System, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), John P. Hussman Institute for Human Genomics, University of Miami Leonard M. Miller School of Medicine (UMMSM), Rush University Medical Center [Chicago], University of Edinburgh, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands, Depts of Radiology, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Department of Materials Science and Metallurgy [Cambridge University] (DMSM), University of Cambridge [UK] (CAM), JRC Institute for Transuranium Elements [Karlsruhe] (ITU ), European Commission - Joint Research Centre [Karlsruhe] (JRC), Greifswald University Hospital, Division of Biomedical Statistics and Informatics, Mayo Clinic, Division of Biomedical Statistics and Informatics, Mayo Clinic, Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Genetics, The University of Texas Health Science Center at Houston (UTHealth), Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University [New York], Perelman School of Medicine, University of Pennsylvania, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Systèmes et Applications des Technologies de l'Information et de l'Energie (SATIE), École normale supérieure - Cachan (ENS Cachan)-Université Paris-Sud - Paris 11 (UP11)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-École normale supérieure - Rennes (ENS Rennes)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE), Department of neurology, Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dept of Psychology, Molecular Epidemiology, Harvard Medical School [Boston] (HMS), Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Columbia Mailman School of Public Health, Laboratoire pharmaceutique Lilly France [Neuilly-sur-Seine], Institute of Molecular Biology & Biochemistry, Johns Hopkins University School of Medicine [Baltimore], Faculty of Medicine, University of Iceland [Reykjavik], The Icelandic Heart Association, Kopavogur, Iceland, Institutes for Community Medicine, Department of Epidemiology, University of Washington, Group Health Research Institute, Group Health Cooperative, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), National University of Singapore (NUS), Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes - UFR Langage, lettres et arts du spectacle, information et communication - Dpt Sciences de l'information et de la communication (UGA UFR LLASIC SIC), Mayo Clinic [Rochester], Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, East China University of Science and Technology, Medstar Research Institute, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Bioinformatics, GlaxoSmithKline, National Institutes of Health [Bethesda] (NIH), Institute of Clinical Chemistry and Laboratory Medicine, Universität Greifswald - University of Greifswald, Delft University of Technology (TU Delft), Cardiovascular Health Research Unit, University of Washington, Department of Medicine, University of Washington, Department of Health Services, University of Washington, Department of Biostatistics, University of Washington, Cedars-Sinai Medical Center, Dept of Neurology, Univ Medicine of Greifswald, Germany, Department of Physics [Stockholm], Stockholm University, University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Kaiser Permanente, Broad Institute [Cambridge], Harvard University-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Uppsala University, Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, King‘s College London, Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria, Research Centre for Stroke & Dementia, St George 's Univ of London, Interuniversity Cardiology Institute Netherlands, SAC, Bush Estate, School Medicine, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Singapore Eye Research Institute, Singapore National Eye Centre, University of Oslo (UiO), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Dundee Technopole, CXR Biosciences Ltd, Department of Atmospheric, Oceanic, and Space Sciences [Ann Arbor] (AOSS), University of Michigan System-University of Michigan System, University of Miami [Coral Gables], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biospective [Montréal], Dept of Epidemiology & Public Health Sciences, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Mississippi Medical Center (UMMC), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Austrian Institute of Technology [Vienna] (AIT), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Human Genetics Center, University of Pennsylvania [Philadelphia], Université Paris-Seine-Université Paris-Seine-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Memory Aging & Cognition Centre, National Univ of Singapore, Singapore, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), Dept of Ophthalmology, National Univ of Singapore & National Univ Health System, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of California-University of California, Radboud university [Nijmegen], Epidemiology, Radiology & Nuclear Medicine, General Practice, Neurology, Medical Informatics, Clinical Genetics, Internal Medicine, Human genetics, NCA - neurodegeneration, Hal, GIN, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and HESAM Université (HESAM)-HESAM Université (HESAM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Oncology, Male, single nucleotide, Pathology, Genome-wide association study, leukoencephalopathies, polymorphisms, single nucleotide, Chromosomes, Human, Genetics (clinical), Aged, 80 and over, education.field_of_study, Continental Population Groups, cerebrovascular disorders, Middle Aged, White Matter, 3. Good health, Stroke, genetics [Stroke], Female, cerebral small vessel diseases, Alzheimer's disease, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, hypertension, Population, genetics [Chromosomes, Human], Article, Meta-Analysis as Topic, Internal medicine, Genetics, medicine, Dementia, Humans, ddc:610, 1000 Genomes Project, education, Genetic association, Aged, Intracerebral hemorrhage, genome-wide association study, Models, Genetic, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Racial Groups, medicine.disease, ethnology [Stroke], Hyperintensity, Genetic Loci, pathology [Stroke], business, polymorphisms, Genome-Wide Association Study
Abstract

Background— The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies. Methods and Results— We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 ( P =2.7×10 −19 ) and identified novel loci on chr10q24 ( P =1.6×10 −9 ) and chr2p21 ( P =4.4×10 −8 ). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 ( P =2.0×10 −8 ) and chr2p16 ( P =1.5×10 −8 ). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16). Conclusions— We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

Published
2015
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10. Predicting stroke through genetic risk functions the CHARGE risk score project

Author

João D. Fontes, James B. Meigs, Seung Hoan Choi, M. Arfan Ikram, W. T. Longstreth, Kent D. Taylor, Aaron R. Folsom, Caroline S. Fox, Myriam Fornage, Helena Schmidt, Najaf Amin, Martin Dichgans, Lenore J. Launer, Thomas H. Mosley, Cornelia M. van Duijn, Christopher J. O'Donnell, Renske G. Wieberdink, Charles DeCarli, Alexa S. Beiser, Rebecca F. Gottesman, Eric Boerwinkle, Mike A. Nalls, Philip A. Wolf, Kenneth Rice, Jerome I. Rotter, Susan R. Heckbert, Sekar Kathiresan, Sudha Seshadri, Peter J. Koudstaal, Eyal Shahar, Madhu Rao, Luting Xue, Thomas Lumley, Abbas Dehghan, Albert Hofman, André G. Uitterlinden, Georg Ehret, Wayne D. Rosamond, Rainer Malik, Carla A. Ibrahim-Verbaas, Jari Lahti, Joshua C. Bis, Stéphanie Debette, Anita L. DeStefano, Bruce M. Psaty, Neurology, Epidemiology, Internal Medicine, and Radiology & Nuclear Medicine

Subjects
Male, Aging, Cardiorespiratory Medicine and Haematology, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Risk Factors, Epidemiology, 80 and over, 10. No inequality, Stroke, ddc:616, Aged, 80 and over, Framingham Risk Score, Age Factors, Aged, Area Under Curve, Case-Control Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide/genetics, ROC Curve, Regression Analysis, Sex Factors, Stroke/epidemiology, Stroke/genetics, Single Nucleotide, stroke, Stroke/epidemiology/genetics, Cohort, Patient Safety, Cardiology and Cardiovascular Medicine, Cohort study, medicine.medical_specialty, genetic epidemiology, Clinical Sciences, and over, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Internal medicine, Genetics, medicine, cardiovascular diseases, Polymorphism, Advanced and Specialized Nursing, Neurology & Neurosurgery, Whites, Proportional hazards model, business.industry, Prevention, fungi, Neurosciences, Case-control study, medicine.disease, Brain Disorders, Genetic epidemiology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Background and Purpose— Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. Methods— The study includes 4 population-based cohorts with 2047 first incident strokes from 22 720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case–control study of ischemic stroke. Results— In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P =2.3×10 −6 ; ischemic stroke: Δjoint area under the curve=0.021, P =3.7×10 −7 ), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index ( P −4 ). Conclusions— The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

Published
2014
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11. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

Author

Magnus Johannesson, André G. Uitterlinden, Cornelius A. Rietveld, Nicholas J. Timpson, Sarah E. Medland, Tõnu Esko, Beben Benyamin, Ian J. Deary, Sven J. van der Lee, Christiaan de Leeuw, Nicholas G. Martin, Matt McGue, Cornelia M. van Duijn, David C. Liewald, Patrick Turley, Nancy L. Pedersen, Paul Lichtenstein, Jaime Derringer, Frank C. Verhulst, James J. Lee, Carla A. Ibrahim-Verbaas, Dalton Conley, Philipp Koellinger, John M. Starr, Tune H. Pers, Christopher F. Chabris, David Cesarini, David Laibson, Edward L. Glaeser, Najaf Amin, Olga Rostapshova, Maciej Trzaskowski, Juha Karjalainen, Mary E. Ward, Caroline Hayward, Valur Emilsson, Patrik K. E. Magnusson, Henning Tiemeier, Daniel J. Benjamin, Robert Plomin, David J. Porteous, George Davey Smith, Michael B. Miller, Margaret J. Wright, Fernando Rivadeneira, Vincent W. V. Jaddoe, Anna A. E. Vinkhuyzen, William G. Iacono, Lude Franke, Peter M. Visscher, Rudolf S N Fehrmann, Gail Davies, Andrew D. Johnson, Steven Pinker, Riccardo E. Marioni, Blair H. Smith, George McMahon, Danielle Posthuma, Narelle K. Hansell, Human genetics, NCA - Brain mechanisms in health and disease, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Functional Genomics, Complex Trait Genetics, Tinbergen Institute, Amsterdam Neuroscience - Complex Trait Genetics, Rietveld, Cornelius A, Esko, Tõnu, Davies, Gail, Pers, Tune H, Benyamin, Beben, Koellinger, Philipp D, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Entrepreneurship & Innovation (ABS, FEB), Epidemiology, Erasmus MC other, Child and Adolescent Psychiatry / Psychology, and Internal Medicine

Subjects
Male, Multifactorial Inheritance, Cell Adhesion Molecules, Neuronal, LOCI, Social Sciences, Single-nucleotide polymorphism, Genome-wide association study, INTELLIGENCE, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Synaptic Transmission, Corrections, Cognition, Memory, medicine, ACADEMIC-ACHIEVEMENT, Dementia, GWAS, Humans, Learning, Effects of sleep deprivation on cognitive performance, GENOME-WIDE ASSOCIATION, Neural Cell Adhesion Molecules, Genetics, Multidisciplinary, Neuronal Plasticity, proxy-phenotype method, Memoria, COMPONENTS, Calcium-Binding Proteins, medicine.disease, Multiple comparisons problem, Octamer Transcription Factors, Female, SDG 4 - Quality Education
Abstract

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. Refereed/Peer-reviewed

Published
2014
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12. GWAS of 126559 Individuals Identifies Genetic Variants Associated with Educational Attainment

Author

Maria Dimitriou, Klaus Berger, Jian Yang, Nicholas J. Timpson, George Dedoussis, Magnus Johannesson, Igor Rudan, Marisa Loitfelder, Kurt Lohman, Jürgen Wellmann, Osorio Meirelles, Johan G. Eriksson, Cornelia M. van Duijn, Francesco Cucca, Anu Realo, Gérard Waeber, David R. Van Wagoner, Samuli Ripatti, Alan F. Wright, George McMahon, Elizabeth G. Holliday, Lili Milani, Ute Bültmann, Olli T. Raitakari, Behrooz Z. Alizadeh, Reinhold Schmidt, Matthew Kowgier, André G. Uitterlinden, Sutapa Mukherjee, William G. Iacono, Judith M. Vonk, Lude Franke, John M. Starr, Antonio Terracciano, Rudolf Ferhmann, Pamela A. F. Madden, Marika Kaakinen, Helena Schmidt, Dorret I. Boomsma, Harry Campbell, Konstantin Shakhbazov, Lei Yu, Albert Hofman, Tõnu Esko, Cornelius A. Rietveld, Albert V. Smith, Arpana Agrawal, Wouter J. Peyrot, Stefania Bandinelli, David M. Evans, Nicolas W. Martin, Martin F. Elderson, Melissa E. Garcia, Danielle Posthuma, Ozren Polasek, Panos Deloukas, Pedro Marques Vidal, Sang Hong Lee, James F. Wilson, Robert F. Krueger, Paul Lichtenstein, Jan-Emmanuel De Neve, Fernando Rivadeneira, Laura J. Bierut, Sebastian E. Baumeister, Lawrence F. Bielak, Peter M. Visscher, Philipp Koellinger, Thais S. Rizzi, Rodney J. Scott, Mika Kähönen, Marco Masala, Debbie A Lawlor, Yongmei Liu, Ben A. Oostra, Jaime Derringer, Zoltán Kutalik, Carla A. Ibrahim-Verbaas, Toshiko Tanaka, Håkon K. Gjessing, Jae Hoon Sul, Marjo-Riitta Järvelin, Krista Fischer, Erik Ingelsson, David R. Weir, Kati Kristiansson, Thomas Illig, Jorma Viikari, George Davey-Smith, Antti-Pekka Sarin, Matt McGue, Ida Surakka, Andreas Mielck, Ivana Kolcic, Astanand Jugessur, Aldo Rustichini, Sarah E. Medland, Ronny Myhre, Veikko Salomaa, Mina K. Chung, H.-Erich Wichmann, Lynn Cherkas, Peter Lichtner, Michael B. Miller, Peter Vollenweider, Jüri Allik, Henning Tiemeier, Grant W. Montgomery, Eva Reinmaa, Dalton Conley, Adriaan Hofman, Patricia A. Peyser, David Schlessinger, Martin Preisig, Jessica D. Faul, Patrik K. E. Magnusson, David A. Bennett, Erkki Vartiainen, David Laibson, François Bastardot, Niina Eklund, Wolfgang Hoffmann, Terho Lehtimäki, Nicholas D. Hastie, John P. Rice, Rolf Holle, Antti Latvala, Guoný Eiríksdóttir, Luigi Ferrucci, Jennifer A. Smith, Christian Gieger, Veronique Vitart, Gail Davies, Sara Hägg, Juha Karjalainen, Matthijs J. H. M. van der Loos, Bo Jacobsson, Lydia Quaye, John Barnard, Beate St Pourcain, Jouke-Jan Hottenga, Daniel S. Evans, Jonathan P. Beauchamp, Tamara B. Harris, Ian J. Deary, Jari Lahti, Peng Lin, Markus Perola, Henry Völzke, Lenore J. Launer, David C. Liewald, Brenda W.J.H. Penninx, David Cesarini, Najaf Amin, Dale R. Nyholt, Roy Thurik, Aarno Palotie, Patrick J. F. Groenen, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Susan M. Ring, Lyle J. Palmer, Alexander Teumer, Kelly S. Benke, Christopher Oldmeadow, Katja Petrovic, Gonneke Willemsen, Andrew C. Heath, Harold Snieder, Jaakko Kaprio, Marja-Liisa Nuotio, Frank J. A. van Rooij, Robert M. Kirkpatrick, Nicholas G. Martin, Tomi E. Mäkinen, Michelle N. Meyer, Katri Räikkönen, Harm-Jan Westra, Daniel J. Benjamin, Jeffrey A. Boatman, Henrik Grönberg, Eva Albrecht, Sharon L.R. Kardia, Peter K. Joshi, Philip L. De Jager, Mariza de Andrade, Patricia A. Boyle, Jennifer R. Harris, Vilmundur Guonason, Christiaan de Leeuw, Juliette Harris, Dena G. Hernandez, Jingmei Li, Per Hall, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Christina Holzapfel, Stavroula Kanoni, Christopher F. Chabris, John Attia, Rauli Svento, Erasmus School of Economics, Epidemiology, Surgery, Neurology, Applied Economics, Research Methods and Techniques, Clinical Genetics, Internal Medicine, Child and Adolescent Psychiatry / Psychology, Econometrics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Biological Psychology, Functional Genomics, Management and Organisation, Tinbergen Institute, Amsterdam Neuroscience - Complex Trait Genetics, Rietveld, Cornelius A, Medland, Sarah E, Derringer, Jaime, Yang, Jian, Lee, Sang Hong, Koellinger, Philipp D, LifeLines Cohort Study, ABS Other Research (FEB), Reproductive Origins of Adult Health and Disease (ROAHD), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Public Health Research (PHR), Teaching and Teacher Education, Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, and EMGO - Lifestyle, overweight and diabetes

Subjects
Netherlands Twin Register (NTR), Male, medicine.medical_specialty, Multifactorial Inheritance, Endophenotypes, social-science genetics, LOCI, SNP, Single-nucleotide polymorphism, Genome-wide association study, Biology, PREFERENCES, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Cognition, Polymorphism (computer science), medicine, GWAS, Humans, Allele, Polymorphism, education, gene, attainment, 030304 developmental biology, Genetics, 0303 health sciences, ENVIRONMENT, genome-wide association study, Multidisciplinary, Data Science, Replicate, Single Nucleotide, single-nucleotide polymorphism, linear polygenic score, ta3121, Educational attainment, Multidisciplinary Sciences, Educational Status, Female, Genetic Loci, Genome-Wide Association Study, educational attainment, Endophenotype, Medical genetics, 030217 neurology & neurosurgery
Abstract

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Published
2013
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13. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author

Chauhan, Ganesh, Adams, Hieab H H, Jian, Xueqiu, Sharma, Pankaj, Sudlow, Cathie L M, Rosand, Jonathan, Woo, Daniel, Cole, John W, Meschia, James F, Slowik, Agnieszka, Thijs, Vincent, Lindgren, Arne, Melander, Olle, Malik, Rainer, Grewal, Raji P, Rundek, Tatjana, Rexrode, Kathy, Rothwell, Peter M, Arnett, Donna K, Jern, Christina, Johnson, Julie A, Benavente, Oscar R, Wasssertheil-Smoller, Sylvia, Lee, Jin-Moo, Traylor, Matthew, Wong, Quenna, Mitchell, Braxton D, Rich, Stephen S, McArdle, Patrick F, Geerlings, Mirjam I, van der Graaf, Yolanda, de Bakker, Paul I W, Asselbergs, Folkert W, Srikanth, Velandai, Thomson, Russell, Pulit, Sara L, McWhirter, Rebekah, Moran, Chris, Callisaya, Michele, Phan, Thanh, Rutten-Jacobs, Loes C A, Bevan, Steve, Tzourio, Christophe, Mather, Karen A, Sachdev, Perminder S, van Duijn, Cornelia M, Amouyel, Philippe, Worrall, Bradford B, Dichgans, Martin, Kittner, Steven J, Markus, Hugh S, Ikram, Mohammad A, Fornage, Myriam, Launer, Lenore J, Seshadri, Sudha, Longstreth, W. T., Debette, Stéphanie, Mazoyer, Bernard, Network, Stroke Genetics, Almgren, Peter, Anderson, Christopher D, Attia, John, Ay, Hakan, Brown, Robert D, Bustamante, Mariana, Zhu, Yi-Cheng, Cheng, Yu-Ching, Cotlarciuc, Ioana, Cruchaga, Carlos, de Bakker, Paul Iw, Delavaran, Hossein, Engström, Gunnar, Kaffashian, Sara, Heitsch, Laura, Holliday, Elizabeth, Ibanez, Laure, Ilinca, Andreea, Irvin, Marguerite R, Jackson, Rebecca D, Jimenez-Conde, Jordi, Jood, Katarina, Schilling, Sabrina, Kissela, Brett M, Kleindorfer, Dawn O, Labovitz, Daniel, Laurie, Cathy C, Lemmens, Robin, Levi, Christopher, Li, Linxin, Lindgren, Arne G, Beecham, Gary W, Maguire, Jane, Müller-Nurasyid, Martina, Norrving, Bo, Peddareddygari, Leema Reddy, Pera, Joanna, Satizabal, Claudia L, Montine, Thomas J, Rexrode, Kathryn, Ribasés, Marta, Roquer, Jaume, Rost, Natalia S, Sacco, Ralph L, Schmidt, Reinhold, Schellenberg, Gerard D, Soriano-Tárraga, Carolina, Stanne, Tara, Stauch, Konstantin, Stine, O. C., Sudlow, Cathie Lm, Thijs, Vincent N S, Weir, David, Williams, Stephen R, Kjartansson, Olafur, Xu, Huichun, Hyacinth, Hyacinth I, Marini, Sandro, Nyquist, Paul, Lewis, Cathryn, Hansen, Bjorn, Guðnason, Vilmundur, Biffi, Alessandro, Kourkoulis, Christina, Anderson, Chris, Giese, Anne-Katrin, Sacco, Ralph, Chung, Jong-Won, Kim, Gyeong-Moon, Knopman, David S, Lubitz, Steven, Bourcier, Romain, Howson, Joanna, Granata, Alessandra, Drazyk, Anna, Markus, Hugh, Wardlaw, Joanna, Mitchell, Braxton, Cole, John, Hopewell, Jemma, Griswold, Michael E, Walters, Robin, Turnbull, Iain, Worrall, Bradford, Bis, Josh, Reiner, Alex, Dhar, Raj, Prasad, Kameshwar, Sarnowski, Chloé, Windham, B Gwen, Aparicio, Hugo Javier, Yang, Qiong, Chasman, Daniel, Phuah, Chia-Ling, Liu, Guiyou, Elkind, Mitchell, Lange, Leslie, Rost, Natalia, James, Michael, Gottesman, Rebecca F, Stewart, Jill, Vojinovic, Dina, Parati, Eugenio, Boncoraglio, Giorgio, Zand, Ramin, Bijlenga, Philippe, Selim, Magdy, Grond-Ginsbach, Caspar, Strbian, Daniel, Mosley, Thomas H, Tomppo, Liisa, Sallinen, Hanne, Pfeiffer, Dorothea, Torres, Nuria, Barboza, Miguel, Laarman, Melanie, Carriero, Roberta, Soriano, Carolina, Gill, Dipender, Debette, Stephanie, Mishra, Aniket, Wu, Jer-Yuarn, Ko, Tai-Ming, Bione, Silvia, Tatlisumak, Turgut, Holmegaard, Lukas, Yue, Suo, Bis, Joshua C, Saba, Yasaman, Bersano, Anna, Schlicht, Kristina, Ninomiya, Toshiharu, Oberstein, Saskia Lesnik, Lee, Tsong-Hai, Schmidt, Helena, Wasselius, Johan, Drake, Mattias, Stenman, Martin, Crawford, Katherine, Lena, Umme, Mateen, Farrah, Takeuchi, Fumihiko, Wu, Ona, Schirmer, Markus, Cramer, Steve, Golland, Polina, Brown, Robert, Meschia, James, Ross, Owen A, Pare, Guillaume, Chong, Mike, Yamaguchi, Shuhei, Gwinn, Katrina, Chen, Christopher, Koenig, Jim, Giralt, Eva, Saleheen, Danish, de Leeuw, Frank-Erik, Klijn, Karin, Kamatani, Yoichiro, Kubo, Michiaki, Nabika, Toru, Okada, Yukinori, Pedersen, Annie, Olsson, Maja, Martín, Juan José, Tan, Eng King, Frid, Petrea, Lee, Chaeyoung, Tregouet, David, Leung, Thomas, Kato, Norihiro, Choy, Richard, Loo, Keat Wei, Rinkel, Gabriel, Franca, Paulo, Cendes, Iscia, Carrera, Caty, Fernandez-Cadenas, Israel, Montaner, Joan, Kim, Helen, Rajan, Kumar B, Owolabi, Mayowa, Sofat, Reecha, Bakker, Mark, Ruigrok, Ynte, Hauer, Allard, van der Laan, Sander W, Irvin, Ryan, Sargurupremraj, Murali, Pezzini, Alessandro, Aggarwal, Neelum T, Abd-Allah, Foad, Liebeskind, David, Tan, Rhea, Danesh, John, Donatti, Amanda, Avelar, Wagner, Broderick, Joseph, Sudlow, Cathie, De Jager, Philip L, Rannikmae, Kristiina, McDonough, Caitrin Wheeler, van Agtmael, Tom, Walters, Matthew, Söderholm, Martin, Lorentzen, Erik, Olsson, Sandra, Olsson, Martina, Akinyemi, Rufus, Evans, Denis A, Cotlatciuc, Ioana, McArdle, Patrick, Dave, Tushar, Kittner, Steven, Faber, James E, Millwood, Iona, Márquez, Elsa Valdés, Mancuso, Michelangelo, Vibo, Riina, Teumer, Alexander, Psaty, Bruce M, Korv, Janika, Majersik, Jennifer, DeHavenon, Adam, Alexander, Matthew, Sale, Michele, Southerland, Andrew, Owens, Debra, Psaty, Bruce, Rotter, Jerome I, Wolfe, Stacey Quintero, Langefeld, Carl, Konrad, Jan, Sheth, Kevin, Falcone, Guido, Donahue, Kathleen, Simpkins, Alexis N, Liang Byorn, Tan Wei, Rice, Kenneth, Chan, Bernard, Clatworthy, Phil, Florez, Jose, Harshfield, Eric, Hozawa, Atsushi, Hsu, Chung, Hu, Chaur-Jong, Ihara, Masafumi, Lange, Marcos, Lopez, Oscar L, Lee, Soo Ji, Lee, I-Hui, Musolino, Patricia, Nakatomi, Hirofumi, Park, Kwang-Yeol, Riley, Chris, Sung, Joohon, Suzuki, Hideaki, Vo, Katie, Liao, Jiemin, Washida, Kazuo, Ibenez, Laura Garcia, Hofman, Albert, Algra, Ale, Reiner, Alex P, Doney, Alexander S F, Gschwendtner, Andreas, Vicente, Astrid M, Nordestgaard, Børge G, Carty, Cara L, Cheng, Ching-Yu, Palmer, Colin N A, Gamble, Dale M, Ringelstein, E Bernd, Valdimarsson, Einar, Davies, Gail, Wong, Tien Y, Pasterkamp, Gerard, Kuhlenbäumer, Gregor, Thorleifsson, Gudmar, Falcone, Guido J, Pare, Guillame, Ikram, Mohammad K, Aparicio, Hugo J, Deary, Ian, Hopewell, Jemma C, Liu, Jingmin, van der Lee, Sven J, Attia, John R, Ferro, Jose M, Bis, Joshua, Furie, Karen, Stefansson, Kari, Berger, Klaus, Kostulas, Konstantinos, Rannikmae, Kristina, Ikram, M Arfan, Sargurupremraj, Muralidharan, Amin, Najaf, Benn, Marianne, Farrall, Martin, Pandolfo, Massimo, Nalls, Mike, van Zuydam, Natalie R, Chouraki, Vincent, Abrantes, Patricia, Higgins, Peter, Lichtner, Peter, DeStefano, Anita L, Clarke, Robert, Abboud, Sherine, Oliveira, Sofia A, Gretarsdottir, Solveig, Mosley, Thomas, Battey, Thomas Wk, Thorsteinsdottir, Unnur, Thijs, Vincent Ns, Zhao, Wei, Chen, Wei-Min, Romero, Jose R, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barmada, M Michael, Barnes, Lisa L, Maillard, Pauline, Barral, Sandra, Beach, Thomas G, Becker, James T, Beekly, Duane, Bennett, David A, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, DeCarli, Charles, Boxer, Adam, Burke, James R, Burns, Jeffrey M, Buxbaum, Joseph D, Byrd, Goldie S, Cai, Guiqing, Cairns, Nigel J, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Wardlaw, Joanna M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Cribbs, David H, Crocco, Elizabeth A, Hernández, Maria Del C Valdés, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Duara, Ranjan, Ertekin-Taner, Nilufer, Faber, Kelley M, Fallin, M Daniele, Fallon, Kenneth B, Fardo, David W, Luciano, Michelle, Farlow, Martin R, Farrer, Lindsay A, Ferris, Steven, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Hofer, Edith, Liewald, David, Go, Rodney C P, Goate, Alison M, Graff-Radford, Neill R, Green, Robert C, Griffith, Patrick, Growdon, John H, Haines, Jonathan L, Hakonarson, Hakon, Hamilton, Ronald L, Hamilton-Nelson, Kara L, Deary, Ian J, Haroutunian, Vahram, Harrell, Lindy E, Honig, Lawrence S, Huebinger, Ryan M, Hulette, Christine M, Hyman, Bradley T, Jicha, Gregory A, Jin, Lee-Way, Jun, Gyungah, Kamboh, M Ilyas, Starr, John M, Karydas, Anna, Kauwe, John S K, Kaye, Jeffrey A, Kim, Ronald, Kowall, Neil W, Kramer, Joel H, Kukull, Walter A, Kunkle, Brian W, LaFerla, Frank M, Lah, James J, Bastin, Mark E, Lang-Walker, Rosalyn, Larson, Eric B, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Logue, Mark W, Lunetta, Kathryn L, Lyketsos, Constantine G, Muñoz Maniega, Susana, Mack, Wendy J, Manly, Jennifer J, Marson, Daniel C, Martin, Eden R, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, Mayeux, Richard, McKee, Ann C, Mesulam, Marsel, Slagboom, P Eline, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Murrell, Jill R, Naj, Adam C, Obisesan, Thomas O, Olichney, John M, Pankratz, Vernon S, Beekman, Marian, Parisi, Joseph E, Partch, Amanda, Paulson, Henry L, Pericak-Vance, Margaret A, Perry, William, Peskind, Elaine, Petersen, Ronald C, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Deelen, Joris, Quinn, Joseph F, Raj, Ashok, Raj, Towfique, Raskind, Murray, Reiman, Eric M, Reisberg, Barry, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rosen, Howard J, Uh, Hae-Won, Rosenberg, Roger N, Sager, Mark A, Sano, Mary, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Swerdlow, Russell H, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Tsuang, Debby W, Valladares, Otto, Van Deerlin, Vivianna M, Trompet, Stella, Brodaty, Henry, Van Eldik, Linda J, Vardarajan, Badri N, Vinters, Harry V, Vonsattel, Jean Paul, Wang, Li-San, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Williamson, Jennifer, Wingo, Thomas S, Wishnek, Sarah, Wright, Margaret J, Woltjer, Randall L, Wright, Clinton B, Younkin, Steven G, Yu, Chang-En, Yu, Lei, Chu, Audrey Y, Havulinna, Aki S, Ames, David, Smith, Albert Vernon, Choi, Seung Hoan, Garcia, Melissa E, Manichaikul, Ani, Gustafsson, Stefan, Bartz, Traci M, Boncoraglio, Giorgio B, Bellenguez, Céline, Vidal, Jean Sebastien, Wiggins, Kerri L, Xue, Flora, Ripatti, Samuli, Liu, Yongmei, Hoed, Marcel den, Heckbert, Susan R, Smith, Nicholas L, Buring, Julie E, Ridker, Paul M, Berr, Claudine, Dartigues, Jean-François, Beecham, Ashley H, Hamsten, Anders, Magnusson, Patrik K, Pedersen, Nancy L, Lannfelt, Lars, Lind, Lars, Lindgren, Cecilia M, Morris, Andrew P, Koudstaal, Peter J, Portegies, Marileen Lp, Blanton, Susan H, Uitterlinden, André G, de Craen, Anton Jm, Ford, Ian, Jukema, J Wouter, Stott, David J, Allen, Norrina B, Sale, Michele M, Johnson, Andrew D, White, Charles C, Paulista Markus, Marcello Ricardo, Nalls, Michael A, Beiser, Alexa, Vartiainen, Erkki, French, Curtis R, Kurth, Tobias, Harris, Tamara B, deStefano, Anita L, Schmidt, Carsten Oliver, Salomaa, Veikko, Wen, Wei, Ingelsson, Erik, Chasman, Daniel I, Verhaaren, Benjamin F J, Hilal, Saima, Thalamuthu, Anbupalam, Smith, Jennifer A, Ikram, M Kamran, Adams, Hieab H, Lopez, Lorna M, van Buchem, Mark A, Armstrong, Nicola J, van der Grond, Jeroen, Smith, Albert V, Hegenscheid, Katrin, de Andrade, Mariza, Atkinson, Elizabeth J, Beiser, Alexa S, Boerwinkle, Eric, Chong, Elizabeth, Brickman, Adam M, Bryan, R Nick, Chen, Christopher P L H, de Craen, Anton J M, Crivello, Fabrice, Schofield, Peter R, Dufouil, Carole, Elkind, Mitchell S V, Freudenberger, Paul, Habes, Mohamad, Heiss, Gerardo, Kwok, John B, Ibrahim-Verbaas, Carla A, Lewis, Cora E, Liewald, David C M, van der Lugt, Aad, Martinez, Oliver O, Nauck, Matthias, Niessen, Wiro J, Oostra, Ben A, Rice, Kenneth M, von Sarnowski, Bettina, Schreiner, Pamela J, Schuur, Maaike, Sidney, Stephen S, Sigurdsson, Sigurdur, Stott, David J M, van Swieten, John C, Töglhofer, Anna Maria, Turner, Stephen T, Vernooij, Meike W, Wang, Jing J, Wolf, Christiane, Zijdenbos, Alex, Kardia, Sharon L R, DeCarli, Charles C, Seshadri, Sudha S, Kavousi, Maryam, Franceschini, Nora, Isaacs, Aaron, Abecasis, Gonçalo R, Schminke, Ulf, Post, Wendy, Cupples, L Adrienne, Huffman, Jennifer E, Lehtimäki, Terho, Baumert, Jens, Münzel, Thomas, Dehghan, Abbas, North, Kari, Oostra, Ben, Stoegerer, Eva-Maria, Hayward, Caroline, Raitakari, Olli, Meisinger, Christa, Schillert, Arne, Sanna, Serena, Völzke, Henry, Thorsson, Bolli, Fox, Caroline S, Wittfeld, Katharina, Rivadeneira, Fernando, Nambi, Vijay, Halperin, Eran, Petrovic, Katja E, Peltonen, Leena, Wichmann, H Erich, Schnabel, Renate B, Dörr, Marcus, Parsa, Afshin, Aspelund, Thor, Grabe, Hans J, Demissie, Serkalem, Kathiresan, Sekar, Reilly, Muredach P, Taylor, Kent, Uitterlinden, Andre, Couper, David J, Sitzer, Matthias, Kähönen, Mika, Illig, Thomas, Wild, Philipp S, Hosten, Norbert, Orru, Marco, Lüdemann, Jan, Shuldiner, Alan R, Eiriksdottir, Gudny, Seissler, Jochen, Zeller, Tanja, Usala, Gianluca, Ernst, Florian, D'Agostino, Ralph B, O'Leary, Daniel H, Ballantyne, Christie, Thiery, Joachim, Ziegler, Andreas, Lakatta, Edward G, Chilukoti, Ravi Kumar, Völker, Uwe, Wolf, Philip A, Polak, Joseph F, Li, Xia, Rathmann, Wolfgang, Uda, Manuela, Klopp, Norman, Wilson, James F, Viikari, Jorma, Koenig, Wolfgang, Blankenberg, Stefan, Newman, Anne B, Witteman, Jacqueline, van Duijn, Cornelia, Scuteri, Angelo, Homuth, Georg, Gudnason, Vilmundur, O'Donnell, Christopher J, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lund University [Lund], Stroke Genetics Network (SiGN), METASTROKE, Alzheimer’s Disease Genetics Consortium (ADGC), Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Peter Almgren, MSC, Christopher D. Anderson, MD, Donna K. Arnett, PhD, MSPH, John Attia, MD, PhD, FRACP, FRCPC, Hakan Ay, MD, Oscar R. Benavente, MD, Steve Bevan, PhD, Robert D. Brown, MD, Mariana Bustamante, PhD, Yu-Ching Cheng, PhD, John W. Cole, MD, MS, Ioana Cotlarciuc, PhD, Carlos Cruchaga, PhD, Paul IW. de Bakker, PhD, Hossein Delavaran, MD, PhD, Martin Dichgans, MD, Gunnar Engström, MD, PHD, PROF, Myriam Fornage, PhD, Raji P. Grewal, MD, Laura Heitsch, MD, Elizabeth Holliday, MSc, PhD, Laure Ibanez, PhD, Andreea Ilinca, MD, Marguerite R. Irvin, PhD, Rebecca D. Jackson, MD, Christina Jern, MD, PhD, Jordi Jimenez-Conde, MD, PhD, Julie A. Johnson, PharmD, Katarina Jood, MD, PhD, Brett M. Kissela, MD, MS, Steven J. Kittner, MD, Dawn O. Kleindorfer, MD, MS, Daniel Labovitz, MD, Cathy C. Laurie, PhD, Jin-Moo Lee, MD, PhD, Robin Lemmens, MD PhD, Christopher Levi, MBBS B Med Sci FRACP, Linxin Li, DPhil, Arne G. Lindgren, MD, PhD, Jane Maguire, PhD, Hugh S. Markus, FRCP, Patrick F. McArdle, PhD, Olle Melander, MD, PHD, PROF, James F. Meschia, MD, Braxton D. Mitchell, PhD, Martina Müller-Nurasyid, PhD, Bo Norrving, MD, PhD, Leema Reddy Peddareddygari, MD, Joanna Pera, MD, PhD, Sara L. Pulit, PhD, Kathryn Rexrode, MD, MPH, Marta Ribasés, PhD, BSc, Jaume Roquer, MD, PhD, Natalia S. Rost, MD, Peter M. Rothwell, FMedSci, Tatjana Rundek, MD PhD, Ralph L. Sacco, MD MS, Reinhold Schmidt, MD, Pankaj Sharma, MD PhD, Agnieszka Slowik, MD, PhD, Carolina Soriano-Tárraga, BSc, PhD, Tara Stanne, PhD, Konstantin Stauch, PhD, O C. Stine, PhD, Cathie LM. Sudlow, BMBCh, MSc, DPhil, FRCP (Ed), Vincent N.S. Thijs, MD, PhD, Sylvia Wasssertheil-Smoller, PhD, David Weir, PhD, Stephen R. Williams, PhD, Quenna Wong, PhD, Daniel Woo, MD, MS, Bradford B. Worrall, MD, MSc, Huichun Xu, MD, PhD, Sudha Seshadri, MD, Hyacinth I Hyacinth, MD, Sandro Marini, MD, Paul Nyquist, MD, PhD, Cathryn Lewis, PhD, Bjorn Hansen, MD, Bo Norrving, MD, PhD, Jonathan Rosand, MD, Alessandro Biffi, MD, Christina Kourkoulis, Bachelor, Chris Anderson, MD, MMSc, Anne-Katrin Giese, MD, Ralph Sacco, MD, MS, Pankaj Sharma, MD, PhD, Jong-Won Chung, MD, MSc, Gyeong-Moon Kim, MD, Steven Lubitz, MD, MPH, Romain Bourcier, MD, Joanna Howson, PhD, Alessandra Granata, PhD, Anna Drazyk, MRCPI, Hugh Markus, MD, Joanna Wardlaw, MD, Braxton Mitchell, MPH, PHD, John Cole, MD, MS, Jemma Hopewell, PhD, FESC, Robin Walters, MA, PhD, PgDip, Iain Turnbull, BA(Hons) MB BChir MRCP(UK) MRCGP, Bradford Worrall, MD, MSc, Josh Bis, PhD, Alex Reiner, MD, MSc, Raj Dhar, MD, Laura Heitsch, MD, Jin-Moo Lee, MD, PhD, Kameshwar Prasad, MD, DM, MMSc, FRCP(Edin), FAMS, Chloé Sarnowski, PhD, Hugo Javier Aparicio, MD, Qiong Yang, PhD, Daniel Chasman, PhD, Kathryn Rexrode, MD, MPH, Chia-Ling Phuah, MD, Guiyou Liu, PhD, Mitchell Elkind, MD, MSc, Leslie Lange, PhD, Natalia Rost, MD, Michael James, MD, Jill Stewart, PhD, Dina Vojinovic, MD, MS, Vincent Thijs, MD, PhD, Eugenio Parati, MD, Giorgio Boncoraglio, MD, Ramin Zand, MD, Philippe Bijlenga, MD, PhD, Magdy Selim, MD, PhD, Caspar Grond-Ginsbach, PhD, Daniel Strbian, MD, PhD, Liisa Tomppo, MD, Hanne Sallinen, MD, Dorothea Pfeiffer, MD, Nuria Torres, MSc, Miguel Barboza, MD, Melanie Laarman, PhD candidate, Roberta Carriero, PhD, Elizabeth Holliday, PhD, Jordi Jimenez-Conde, MD, PhD, Carolina Soriano, BSc, PhD, Dipender Gill, PhD, Stephanie Debette, MD, PhD, Aniket Mishra, PhD, Jer-Yuarn Wu, PhD, Tai-Ming Ko, PhD, Silvia Bione, PhD, Katarina Jood, MD, PhD, Turgut Tatlisumak, MD, PhD, Lukas Holmegaard, PhD, Suo Yue, system engineer, Anna bersano, MD, PhD, Joanna Pera, MD, PhD, Agnieszka Slowik, MD, PhD, Christopher Levi, MBBS B Med Sci FRACP, Kristina Schlicht, Dipl. Biol., Robin Lemmens, MD, PhD, Toshiharu Ninomiya, MD, PhD, Saskia Lesnik Oberstein, PhD, Tsong-Hai Lee, MD, PhD, Rainer Malik, PhD, Martin Dichgans, MD, Arne Lindgren, MD, PhD, Johan Wasselius, MD, PhD, Mattias Drake, student, Olle Melander, MD, PHD, Martin Stenman, MD, Andreea Ilinca, MD, Katherine Crawford, BS, Umme Lena, Bachelors of Arts, Farrah Mateen, MD, PhD, Hakan Ay, MD, Ona Wu, PhD, Markus Schirmer, PhD, Steve Cramer, MD, Polina Golland, PhD, Robert Brown, MD, MPH, James Meschia, MD, Owen A. Ross, PhD, Guillaume Pare, MD, MSc, FRCPC, Mike Chong, MSc, Tatjana Rundek, MD PhD, Katrina Gwinn, MD, Christopher Chen, BMBCh (Oxon), MRCP, FRCP, Jim Koenig, PhD, Eva Giralt, PhD, Danish Saleheen, MBBS, PhD, Frank-Erik de Leeuw, MD, PhD, Karin Klijn, MD, PhD, Yoichiro Kamatani, MD, PhD, Michiaki Kubo, MD, PhD, Yukinori Okada, MD, PhD, Annie Pedersen, MD, Maja Olsson, PhD, Juan José Martín, MD, Huichun Xu, MD, PhD, Eng King Tan, MD, Petrea Frid, MD, Chaeyoung Lee, PhD, David Tregouet, PhD, Thomas Leung, MB, ChB, MRCP, FHKCP, FHKAM, Richard Choy, BSc (Brad.), MSc(Med) (Birm.), PhD (CUHK), Christina Jern, MD, PhD, Keat Wei Loo, BSc, PhD, Gabriel Rinkel, MD, Paulo Franca, PhD, Iscia Cendes, MD, PhD, Caty Carrera, MD, Israel Fernandez-Cadenas, PhD, Joan Montaner, MD, PhD, Helen Kim, PhD, Mayowa Owolabi, MBBS, MSc, DrM, MWACP, FMCP, FAAN, FAS, Reecha Sofat, MD, Mark Bakker, PhD, Ynte Ruigrok, MD, PhD, Allard Hauer, PhD candidate, Sara L. Pulit, PhD, Sander W. van der Laan, PhD, Ryan Irvin, PhD, Murali Sargurupremraj, PhD, Alessandro Pezzini, MD, Foad Abd-Allah, MD, David Liebeskind, MD, Matthew Traylor, PhD, Rhea Tan, BSc (Hons), John Danesh, MD, DPhil, Loes Rutten-Jacobs, PhD, Amanda Donatti, PhD, student, Wagner Avelar, PhD, Joseph Broderick, MD, Daniel Woo, MD, MS, Cathie Sudlow, BMBCh, MSc, DPhil, FRCP, Kristiina Rannikmae, MD, Caitrin Wheeler McDonough, PhD, Tom van Agtmael, PhD, Matthew Walters, MD, MBChB, FRCP, Martin Söderholm, MD, PhD, Erik Lorentzen, Ph.Lic., Sandra Olsson, PhD, MSc, Tara Stanne, PhD, Martina Olsson, MSc, Rufus Akinyemi, PhD, MSc, MWACP, FMCP, Ioana Cotlatciuc, PhD, Patrick McArdle, PhD, Tushar Dave, MSc, Steven Kittner, MD, MPH, John Attia, MD, PhD, James E Faber, PhD, Iona Millwood, DPhil, Elsa Valdés Márquez, PhD, Michelangelo Mancuso, MD, PhD, Riina Vibo, MD, PhD, Janika Korv, MD, PhD, FESO, Jane Maguire, PhD, BN (Hons), BA, RN, Myriam Fornage, PhD, Jennifer Majersik, MD, Adam DeHavenon, MD, Matthew Alexander, MD, Michele Sale, PhD, Andrew Southerland, MD, MSc, Debra Owens, NNP, Bruce Psaty, MD, PhD, W. T. Longstreth, Jr, MD, MPH, Stacey Quintero Wolfe, MD, FAANS, Carl Langefeld, PhD, Carlos Cruchaga, PhD, Jan Konrad, administrative coordinator, Kevin Sheth, MD, Guido Falcone, MD, ScD, MPH, Kathleen Donahue, BS, Alexis N Simpkins, MD, PhD, Tan Wei Liang Byorn, MMBS, student, Bernard Chan, MD, Phil Clatworthy, MD, PhD, Jose Florez, MD, Eric Harshfield, PhD, Atsushi Hozawa, MD, Chung Hsu, MD, PhD, Chaur-Jong Hu, MD, PhD, Laure Ibanez, PhD, Masafumi Ihara, MD, PhD, FACP, Marcos Lange, PhD, Soo Ji Lee, PhD, MPH, I-Hui Lee, MD, PhD, Patricia Musolino, MD, PhD, Hirofumi Nakatomi, MD, PhD, Kwang-Yeol Park, MD, Stephen S Rich, PhD, Chris Riley, MBA, Joohon Sung, MD, PhD, Hideaki Suzuki, MD, PhD, Katie Vo, MD, Kazuo Washida, MD, PhD, Laura Garcia Ibenez, PhD, Agnieszka Slowik, MD, PhD, Albert Hofman, MD, PhD, Ale Algra, MD, MSc, Alex P Reiner, MD, MSc, Alexander S F Doney, PhD, Andreas Gschwendtner, MD, Andreea Ilinca, MD, Anne-Katrin Giese, MD, Arne Lindgren, MD, PhD, Astrid M Vicente, PhD, Bo Norrving, MD, PhD, Børge G Nordestgaard, MD, PhD, DMSc, Braxton D Mitchell, PhD, Bradford B Worrall, MD, MSc, Bruce M Psaty, MD, PhD, Cara L Carty, PhD, Cathie Sudlow, BMBCh, MSc, DPhil, FRCP, Christopher D Anderson, MD, Christopher Levi, MBBS B Med Sci FRACP, Claudia L Satizabal, PhD, Colin N A Palmer, PhD, Dale M Gamble, CCRP, Daniel Woo, MD, MS, Danish Saleheen, MBBS, PhD, E Bernd Ringelstein, MD, FAHA, Einar Valdimarsson, MD, Elizabeth Holliday, PhD, Gail Davies, PhD, Ganesh Chauhan, PhD, Gerard Pasterkamp, MD, PhD, Giorgio Boncoraglio, MD, Gregor Kuhlenbäumer, MD, PhD, Gudmar Thorleifsson, PhD, Guido J Falcone, MD, ScD, MPH, Guillame Pare, MD, MSc, FRCPC, Helena Schmidt, MD, PhD, Hossein Delavaran, MD, PhD, Hugh S Markus, MD, Hugo J Aparicio, MD, Ian Deary, PhD, Ioana Cotlarciuc, PhD, Israel Fernandez-Cadenas, PhD, James Meschia, MD, Jemma C Hopewell, PhD, FESC, Jingmin Liu, MSc, Joan Montaner, MD, PhD, Joanna Pera, MD, PhD, John Cole, MD, MS, John R Attia, MD, PhD, FRACP, FRCPC, Jonathan Rosand, MD, MSc, Jose M Ferro, MD, PhD, Joshua Bis, PhD, Karen Furie, MD, Kari Stefansson, MD, Klaus Berger, MD, PhD, Konstantinos Kostulas, MD, PhD, Kristina Rannikmae, MD, M Arfan Ikram, MD, PhD, Marianne Benn, MD, PhD, Martin Dichgans, MD, Martin Farrall, FRCPath, Massimo Pandolfo, MD, Matthew Traylor, PhD, Matthew Walters, MD, MBChB, FRCP, Michele Sale, PhD, Mike Nalls, PhD, Myriam Fornage, PhD, Natalie R van Zuydam, PhD, Pankaj Sharma, MD, PhD, Patricia Abrantes, PhD, Paul IW de Bakker, PhD, Peter Higgins, FRCP, Peter Lichtner, PhD, Peter M Rothwell, FMedSci, Philippe Amouyel, MD, PhD, Qiong Yang, PhD, Rainer Malik, PhD, Reinhold Schmidt, MD, Robert Clarke, MD, MRCP, FRCP, FFPH, Robin Lemmens, MD, PhD, Sander W van der Laan, PhD, Sara L Pulit, PhD, Sherine Abboud, MD, PhD, Sofia A Oliveira, PhD, Solveig Gretarsdottir, PhD, Stephanie Debette, MD, PhD, Stephen R Williams, PhD, Steve Bevan, BSc, PhD, Steven J Kittner, MD, Sudha Seshadri, MD, Thomas Mosley, PhD, Thomas WK Battey, BS, Turgut Tatlisumak, MD, PhD, Unnur Thorsteinsdottir, PhD, Vincent NS Thijs, MD, PhD, W T Longstreth, MD, Wei Zhao, MD, PhD, Wei-Min Chen, PhD, Yu-Ching Cheng, PhD, Marilyn S. Albert, PhD, Roger L. Albin, MD, Liana G. Apostolova, MD, Steven E. Arnold, MD, Sanjay Asthana, MD, Craig S. Atwood, PhD, Clinton T. Baldwin, PhD, M. Michael Barmada, PhD, Lisa L. Barnes, PhD, Sandra Barral, PhD, Thomas G. Beach, MD, PhD, James T. Becker, PhD, Gary W. Beecham, PhD, Duane Beekly, BS, David A. Bennett, MD, Eileen H. Bigio, MD, Thomas D. Bird, MD, Deborah Blacker, MD, ScD, Bradley F. Boeve, MD, Adam Boxer, MD, PhD, James R. Burke, MD, PhD, Jeffrey M. Burns, MD, MS, Joseph D. Buxbaum, PhD, Goldie S. Byrd, PhD, Guiqing Cai, MD, PhD, Nigel J. Cairns, PhD FRCPath, Laura B. Cantwell, MPH, Chuanhai Cao, PhD, Cynthia M. Carlsson, MD, MS, Regina M. Carney, MD, Minerva M. Carrasquillo, PhD, Steven L. Carroll, MD, PhD, Helena C. Chui, PhD, David G. Clark, MD, David H. Cribbs, PhD, Elizabeth A. Crocco, MD, Carlos Cruchaga, PhD, Philip L. De Jager, MD, PhD, Charles DeCarli, MD, F. Yesim Demirci, MD, Malcolm Dick, Dennis W. Dickson, MD, Ranjan Duara, Md, Nilufer Ertekin-Taner, MD, PhD, Denis A. Evans, MD, Kelley M. Faber, MS, M. Daniele Fallin, PhD, Kenneth B. Fallon, MD, David W. Fardo, PhD, Martin R. Farlow, MD, Lindsay A. Farrer, PhD, Steven Ferris, PhD, Tatiana M. Foroud, PhD, Matthew P. Frosch, MD, PhD, Douglas R. Galasko, MD, Marla Gearing, PhD, Daniel H. Geschwind, MD, PhD, Bernardino Ghetti, MD, John R. Gilbert, PhD, Rodney C.P. Go, PhD, Alison M. Goate, DPhil, Neill R. Graff-Radford, MD, Robert C. Green, MD, MPH, Patrick Griffith, MD, John H. Growdon, MD, Jonathan L. Haines, PhD, Hakon Hakonarson, MD, PhD, Ronald L. Hamilton, MD, Kara L. Hamilton-Nelson, MPH, Vahram Haroutunian, PhD, Lindy E. Harrell, MD, PhD, Lawrence S. Honig, MD, PhD, Ryan M. Huebinger, PhD, Christine M. Hulette, MD, Bradley T. Hyman, MD, PhD, Gregory A. Jicha, MD, PhD, Lee-Way Jin, MD, PhD, Gyungah Jun, PhD, M. Ilyas Kamboh, PhD, Anna Karydas, BA, John S.K. Kauwe, PhD, Jeffrey A. Kaye, MD, Ronald Kim, MD, Neil W. Kowall, MD, Joel H. Kramer, PsyD, Walter A. Kukull, PhD, Brian W. Kunkle, PhD, Frank M. LaFerla, PhD, James J. Lah, MD, PhD, Rosalyn Lang-Walker, PhD, Eric B. Larson, MD, MPH, James B. Leverenz, MD, Allan I. Levey, MD, PhD, Ge Li, MD, PhD, Andrew P. Lieberman, MD, PhD, Mark W. Logue, PhD, Oscar L. Lopez, MD, Kathryn L. Lunetta, PhD, Constantine G. Lyketsos, MD, Wendy J. Mack, PhD, Jennifer J. Manly, PhD, Daniel C. Marson, JD, PhD, Eden R. Martin, PhD, Frank Martiniuk, PhD, Deborah C. Mash, PhD, Eliezer Masliah, MD, Richard Mayeux, MD, Ann C. McKee, MD, Marsel Mesulam, MD, Bruce L. Miller, MD, Carol A. Miller, MD, Joshua W. Miller, PhD, Thomas J. Montine, MD, PhD, John C. Morris, MD, Jill R. Murrell, PhD, Adam C. Naj, PhD, Thomas O. Obisesan, MD, John M. Olichney, MD, Vernon S. Pankratz, PhD, Joseph E. Parisi, MD, Amanda Partch, MS, Henry L. Paulson, MD, PhD, Margaret A. Pericak-Vance, PhD, William Perry, BS, Elaine Peskind, MD, Ronald C. Petersen, MD, PhD, Aimee Pierce, MD, Wayne W. Poon, PhD, Huntington Potter, PhD, Joseph F. Quinn, MD, Ashok Raj, MD, Towfique Raj, PhD, Murray Raskind, MD, Eric M. Reiman, MD, Barry Reisberg, MD, Christiane Reitz, MD, PhD, John M. Ringman, MD, MS, Erik D. Roberson, MD, PhD, Howard J. Rosen, MD, Roger N. Rosenberg, MD, Mark A. Sager, MD, Mary Sano, PhD, Andrew J. Saykin, PsyD, Gerard D. Schellenberg, PhD, Julie A. Schneider, MD, MS, Lon S. Schneider, MD, MS, William W. Seeley, MD, Amanda G. Smith, MD, Joshua A. Sonnen, MD, Salvatore Spina, MD, Robert A. Stern, PhD, Russell H. Swerdlow, MD, Rudolph E. Tanzi, PhD, Tricia A. Thornton-Wells, PhD, John Q. Trojanowski, MD, PhD, Juan C. Troncoso, MD, Debby W. Tsuang, MD, Otto Valladares, MS, Vivianna M. Van Deerlin, MD, PhD, Linda J. Van Eldik, PhD, Badri N. Vardarajan, PhD, MS, Harry V. Vinters, MD, Jean Paul Vonsattel, MD, Li-San Wang, PhD, Sandra Weintraub, PhD, Kathleen A. Welsh-Bohmer, PhD, Jennifer Williamson, MS, MPH, Thomas S. Wingo, MD, Sarah Wishnek, MPH, Randall L. Woltjer, MD, PhD, Clinton B. Wright, MD, MS, Steven G. Younkin, MD, PhD, Chang-En Yu, PhD, Lei Yu, PhD, Ganesh Chauhan, PhD, Audrey Y. Chu, PhD, Myriam Fornage, PhD, Joshua C. Bis, PhD, Aki S. Havulinna, DSc, Muralidharan Sargurupremraj, PhD, Albert Vernon Smith, PhD, Hieab H.H. Adams, MSc, Seung Hoan Choi, MA, Stella Trompet, PhD, Melissa E. Garcia, MPH, Ani Manichaikul, PhD, Alexander Teumer, PhD, Stefan Gustafsson, PhD, Traci M. Bartz, MS, Céline Bellenguez, PhD, Jean Sebastien Vidal, MD, Xueqiu Jian, PhD, Olafur Kjartansson, MD, Kerri L. Wiggins, MS, Claudia L. Satizabal, PhD, Flora Xue, MS, Samuli Ripatti, PhD, Yongmei Liu, PhD, Joris Deelen, PhD, Marcel den Hoed, PhD, Susan R. Heckbert, MD, Kenneth Rice, PhD, Nicholas L. Smith, PhD, Quenna Wong, MS, Hugo J. Aparicio, MD, Julie E. Buring, ScD, Paul M Ridker, MD, Claudine Berr, MD, Jean-François Dartigues, MD, Anders Hamsten, MD, Patrik K. Magnusson, PhD, Nancy L. Pedersen, PhD, Lars Lannfelt, MD, Lars Lind, MD, Cecilia M. Lindgren, PhD, Andrew P. Morris, PhD, Albert Hofman, MD, Peter J. Koudstaal, MD, Marileen LP. Portegies, MD, André G. Uitterlinden, PhD, Anton JM de Craen, PhD, Ian Ford, MD, J. Wouter Jukema, MD, David J Stott, MD, Norrina B. Allen, PhD, Michele M. Sale, PhD, Andrew D Johnson, PhD, David A. Bennett, MD, Philip L. De Jager, MD, PhD, Charles C. White, PhD, Hans Jörgen Grabe, MD, Marcello Ricardo Paulista Markus, MD, Oscar L Lopez, MD, Jerome I. Rotter, MD, Michael A. Nalls, PhD, Rebecca F. Gottesman, MD, Michael E. Griswold, PhD, David S. Knopman, MD, B. Gwen Windham, MD, Alexa Beiser, PhD, Erkki Vartiainen, MD, Curtis R. French, PhD, Tobias Kurth, MD, Bruce M. Psaty, MD, Tamara B. Harris, MD, Stephen S Rich, PhD, Anita L. deStefano, PhD, Carsten Oliver Schmidt, PhD, Veikko Salomaa, MD, Thomas H. Mosley, PhD, Erik Ingelsson, MD, PhD, Cornelia M. van Duijn, PhD, Christophe Tzourio, MD, Lenore J Launer, PhD, M. Arfan Ikram, MD, Daniel I. Chasman, PhD, W. T. Longstreth, Jr, MD, MPH, Sudha Seshadri, MD, Stéphanie Debette, MD, Benjamin F.J. Verhaaren, MD, PhD, Stéphanie Debette, MD, PhD, Joshua C. Bis, PhD, Jennifer A. Smith, PhD, MPH, MA, M. Kamran Ikram, MD, PhD, Hieab H. Adams, MSc, Ashley H. Beecham, MSc, Kumar B. Rajan, PhD, Lorna M. Lopez, PhD, Sandra Barral, PhD, Mark A. van Buchem, MD, PhD, Jeroen van der Grond, PhD, Albert V. Smith, PhD, Katrin Hegenscheid, MD, Neelum T. Aggarwal, MD, Mariza de Andrade, PhD, Elizabeth J. Atkinson, PhD, Marian Beekman, PhD, Alexa S. Beiser, PhD, Susan H. Blanton, PhD, Eric Boerwinkle, PhD, Adam M. Brickman, PhD, R. Nick Bryan, MD, PhD, Ganesh Chauhan, PhD, Christopher P.L.H. Chen, FRCP, Vincent Chouraki, MD, PhD, Anton J.M. de Craen, PhD, Fabrice Crivello, PhD, Ian J. Deary, PhD, Joris Deelen, MSc, Philip L. De Jager, MD, PhD, Carole Dufouil, PhD, Mitchell S.V. Elkind, MD, MSc, Denis A. Evans, MD, Paul Freudenberger, MSc, Rebecca F. Gottesman, MD, PhD, Vilmundur Guðnason, MD, PhD, Mohamad Habes, PhD, Susan R. Heckbert, MD, PhD, Gerardo Heiss, MD, Saima Hilal, MBBS, Edith Hofer, PhD, Albert Hofman, MD, PhD, Carla A. Ibrahim-Verbaas, MD, David S. Knopman, MD, Cora E. Lewis, MD, MSPH, Jiemin Liao, MSc, David C.M. Liewald, BSc, Michelle Luciano, PhD, Aad van der Lugt, MD, PhD, Oliver O. Martinez, PhD, Richard Mayeux, MD, MSc, Bernard Mazoyer, MD, PhD, Mike Nalls, PhD, Matthias Nauck, MD, Wiro J. Niessen, PhD, Ben A. Oostra, PhD, Bruce M. Psaty, MD, PhD, Kenneth M. Rice, PhD, Jerome I. Rotter, MD, Bettina von Sarnowski, MD, Helena Schmidt, MD, PhD, Pamela J. Schreiner, PhD, Maaike Schuur, MD, PhD, Stephen S. Sidney, MD, MPH, Sigurdur Sigurdsson, MSc, P. Eline Slagboom, PhD, David J.M. Stott, MD, John C. van Swieten, MD, PhD, Alexander Teumer, PhD, Anna Maria Töglhofer, MSc, Matthew Traylor, PhD, Stella Trompet, PhD, Stephen T. Turner, MD, Christophe Tzourio, MD, PhD, Hae-Won Uh, PhD, André G. Uitterlinden, PhD, Meike W. Vernooij, MD, PhD, Jing J. Wang, PhD, Tien Y. Wong, MD, PhD, Joanna M. Wardlaw, MD, B. Gwen Windham, MD, Katharina Wittfeld, MS, Christiane Wolf, PhD, Clinton B. Wright, MD, Qiong Yang, PhD, Wei Zhao, MD, PhD, Alex Zijdenbos, PhD, J. Wouter Jukema, MD, PhD, Ralph L. Sacco, MD, Sharon L.R. Kardia, PhD, Philippe Amouyel, MD, PhD, Thomas H. Mosley, PhD, W. T. Longstreth, Jr, MD, MPH, Charles C. DeCarli, MD, Cornelia M. van Duijn, PhD, Reinhold Schmidt, MD, Lenore J. Launer, PhD, Hans J. Grabe, MD, Sudha S. Seshadri, MD, M. Arfan Ikram, MD, PhD, Myriam Fornage, PhD, Joshua C. Bis, PhD, Maryam Kavousi, MD, MSc, Nora Franceschini, MD, MPH, Aaron Isaacs, PhD, Gonçalo R Abecasis, PhD, Ulf Schminke, MD, Wendy Post, MD, Albert V. Smith, PhD, L. Adrienne Cupples, PhD, Hugh S Markus, MD, Reinhold Schmidt, MD, Jennifer E. Huffman, MSc, Terho Lehtimäki, MD, PhD, Jens Baumert, PhD, Thomas Münzel, MD, Susan R. Heckbert, MD, PhD, Abbas Dehghan, MD, PhD, Kari North, PhD, Ben Oostra, PhD, Steve Bevan, PhD, Eva-Maria Stoegerer, MD, Caroline Hayward, PhD, Olli Raitakari, MD, PhD, Christa Meisinger, MD, MPH, Arne Schillert, PhD, Serena Sanna, PhD, Henry Völzke, MD, Yu-Ching Cheng, PhD, Bolli Thorsson, MD, Caroline S. Fox, MD, MS, Kenneth Rice, PhD, Fernando Rivadeneira, MD, PhD, Vijay Nambi, MD, Eran Halperin, PhD, Katja E. Petrovic, MSc, Leena Peltonen, MD, PhD, H. Erich Wichmann, MD, PhD, Renate B. Schnabel, MD, MSc, Marcus Dörr, MD, Afshin Parsa, MD, MPH, Thor Aspelund, PhD, Serkalem Demissie, PhD, Sekar Kathiresan, MD, Muredach P. Reilly, MBBCH, MSCE, Kent Taylor, PhD, Andre Uitterlinden, PhD, David J. Couper, PhD, Matthias Sitzer, MD, Mika Kähönen, MD, PhD, Thomas Illig, PhD, Philipp S. Wild, MD, Marco Orru, MD, Jan Lüdemann, PhD, Alan R. Shuldiner, MD, Gudny Eiriksdottir, MSc, Charles C. White, MPH, Jerome I. Rotter, MD, Albert Hofman, MD, PhD, Jochen Seissler, MD, Tanja Zeller, PhD, Gianluca Usala, PhD, Florian Ernst, PhD, Lenore J. Launer, PhD, Ralph B. D'Agostino, Sr, PhD, Daniel H. O'Leary, MD, Christie Ballantyne, MD, Joachim Thiery, MD, MBA, Andreas Ziegler, Dr. rer. nat. habil., Edward G. Lakatta, MD, Ravi Kumar Chilukoti, MSc, Tamara B. Harris, MD, PhD, Philip A. Wolf, MD, Bruce M. Psaty, MD, PhD, Joseph F Polak, MD, MPH, Xia Li, MD, MPH, Wolfgang Rathmann, MD, MSPH, Manuela Uda, PhD, Eric Boerwinkle, PhD, Norman Klopp, PhD, Helena Schmidt, MD PhD, James F Wilson, DPhil, Jorma Viikari, MD, PhD, Wolfgang Koenig, MD, Stefan Blankenberg, Prof Dr med, Anne B. Newman, MD, MPH, Jacqueline Witteman, PhD, Gerardo Heiss, MD, PhD, Cornelia van Duijn, PhD, Angelo Scuteri, MD, PhD, Georg Homuth, PhD, Braxton D. Mitchell, PhD, Vilmundur Gudnason, MD, PhD, and Christopher J. O’Donnell, MD, MPH, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, and Berr, Claudine

Subjects
Neurology & Neurosurgery, [SDV]Life Sciences [q-bio], Heilaskaði, Clinical Neurology, Stroke Genetics Network (SiGN), the International Stroke Genetics Consortium (ISGC), METASTROKE, Alzheimer's Disease Genetics Consortium (ADGC), and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, R1, Article, [SDV] Life Sciences [q-bio], Taugasjúkdómar, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Meta-analyses, Brain infarcts, GWAS, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, ddc:610, Erfðarannsóknir, MRI
Abstract

Publisher's version (útgefin grein), Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p[BI]= 4.4 × 10-10; p [SSBI] = 1.2 × 10 -4), diabetes (p[BI] = 1.7 × 10 -8; p [SSBI] = 2.8 × 10 -3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI., CHAP: R01-AG-11101, R01-AG-030146, NIRP-14-302587. SMART: This study was supported by a grant from the Netherlands Organization for Scientific Research–Medical Sciences (project no. 904-65–095). LBC: The authors thank the LBC1936 participants and the members of the LBC1936 research team who collected and collated the phenotypic and genotypic data. The LBC1936 is supported by Age UK (Disconnected Mind Programme grant). The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). The brain imaging was performed in the Brain Research Imaging Centre (https://www.ed.ac.uk/clinical-sciences/edinburgh-imaging), a center in the SINAPSE Collaboration (sinapse.ac.uk) supported by the Scottish Funding Council and Chief Scientist Office. Funding from the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the UK Medical Research Council is acknowledged. Genotyping was supported by a grant from the BBSRC (ref. BB/F019394/1). PROSPER: The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J.W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). SCES and SiMES: National Medical Research Council Singapore Centre Grant NMRC/CG/013/2013. C.-Y.C. is supported by the National Medical Research Council, Singapore (CSA/033/2012), Singapore Translational Research Award (STaR) 2013. Dr. Kamran Ikram received additional funding from the Singapore Ministry of Health's National Medical Research Council (NMRC/CSA/038/2013). SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg–West Pomerania, and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. Whole-body MRI was supported by a joint grant from Siemens Healthineers, Erlangen, Germany, and the Federal State of Mecklenburg–West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. OATS (Older Australian Twins Study): OATS was supported by an Australian National Health and Medical Research Council (NHRMC)/Australian Research Council (ARC) Strategic Award (ID401162) and by a NHMRC grant (ID1045325). OATS was facilitated via access to the Australian Twin Registry, which is supported by the NHMRC Enabling Grant 310667. The OATS genotyping was partly supported by a Commonwealth Scientific and Industrial Research Organisation Flagship Collaboration Fund Grant. NOMAS: The Northern Manhattan Study is funded by the NIH grant “Stroke Incidence and Risk Factors in a Tri-Ethnic Region” (NINDS R01NS 29993). TASCOG: NHMRC and Heart Foundation. AGES: The study was funded by the National Institute on Aging (NIA) (N01-AG-12100), Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament), with contributions from the Intramural Research Programs at the NIA, the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Neurological Disorders and Stroke (NINDS) (Z01 HL004607-08 CE). ERF: The ERF study as a part of European Special Populations Research Network (EUROSPAN) was supported by European Commission FP6 STRP grant no. 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007–2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). Exome sequencing analysis in ERF was supported by the ZonMw grant (project 91111025). Najaf Amin is supported by the Netherlands Brain Foundation (project no. F2013[1]-28). ARIC: The Atherosclerosis Risk in Communities study was performed as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HSN268201100006C, HSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL70825, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant no. UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. This project was also supported by NIH R01 grant NS087541 to M.F. FHS: This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contracts no. N01-HC-25195 and no. HHSN268201500001I), and its contract with Affymetrix, Inc. for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This study was also supported by grants from the NIA (R01s AG033040, AG033193, AG054076, AG049607, AG008122, and U01-AG049505) and the NINDS (R01-NS017950, UH2 NS100605). Dr. DeCarli is supported by the Alzheimer's Disease Center (P30 AG 010129). ASPS: The research reported in this article was funded by the Austrian Science Fund (FWF) grant nos. P20545-P05, P13180, and P20545-B05, by the Austrian National Bank Anniversary Fund, P15435, and the Austrian Ministry of Science under the aegis of the EU Joint Programme–Neurodegenerative Disease Research (JPND) (jpnd.eu). LLS: The Leiden Longevity Study has received funding from the European Union's Seventh Framework Programme (FP7/2007–2011) under grant agreement no. 259679. This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (grant 050-060-810), all in the framework of the Netherlands Genomics Initiative, Netherlands Organization for Scientific Research (NWO), UnileverColworth, and by BBMRI-NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007). CHS: This CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC15103, and HHSN268200960009C and grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL085251, and R01HL130114 from the NHLBI with additional contribution from NINDS. Additional support was provided through R01AG023629 from the NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research (NWO) Investments (no. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/NWO project no. 050-060-810. The Rotterdam Study is funded by Erasmus MC Medical Center and Erasmus MC University, Rotterdam, Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. M.A.I. is supported by an NWO Veni grant (916.13.054). The 3-City Study: The 3-City Study is conducted under a partnership agreement among the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Bordeaux, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme “Cohortes et collections de données biologiques.” C.T. and S.D. have received investigator-initiated research funding from the French National Research Agency (ANR) and from the Fondation Leducq. S.D. is supported by a starting grant from the European Research Council (SEGWAY), a grant from the Joint Programme of Neurodegenerative Disease research (BRIDGET), from the European Union's Horizon 2020 research and innovation programme under grant agreements No 643417 & No 640643, and by the Initiative of Excellence of Bordeaux University. Part of the computations were performed at the Bordeaux Bioinformatics Center (CBiB), University of Bordeaux. This work was supported by the National Foundation for Alzheimer's Disease and Related Disorders, the Institut Pasteur de Lille, the Labex DISTALZ, and the Centre National de Génotypage. ADGC: The Alzheimer Disease Genetics Consortium is supported by NIH. NIH-NIA supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; NACC, U01 AG016976; NCRAD, U24 AG021886; NIA LOAD, U24 AG026395, U24 AG026390; Banner Sun Health Research Institute, P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01AG33193; Columbia University, P50 AG008702, R37 AG015473; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG06781, UO1 HG004610; Indiana University, P30 AG10133; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, MO1RR00096, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG30146; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582, UL1RR02777; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573, P50, P50 AG016575, P50 AG016576, P50 AG016577; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant NS39764, NIMH MH60451, and by GlaxoSmithKline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232, the Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council [MRC], local NHS trusts, and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England [HEFCE], Alzheimer's Research Trust [ART], BRACE, as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, and Universitat de Barcelona). ADNI: Funding for ADNI is through the Northern California Institute for Research and Education by grants from Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly and Co., Medpace, Inc., Merck and Co., Inc., Novartis AG, Pfizer Inc, F. Hoffman-La Roche, Schering-Plough, Synarc, Inc., Alzheimer's Association, Alzheimer's Drug Discovery Foundation, the Dana Foundation, and the National Institute of Biomedical Imaging and Bioengineering and NIA grants U01 AG024904, RC2 AG036535, and K01 AG030514. Support was also provided by the Alzheimer's Association (LAF, IIRG-08-89720; MAP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. SiGN: Stroke Genetic Network (SiGN) was supported in part by award nos. U01NS069208 and R01NS100178 from NINDS. Genetics of Early-Onset Stroke (GEOS) Study was supported by the NIH Genes, Environment and Health Initiative (GEI) grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to Johns Hopkins University (contract no. HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S. Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from NINDS and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). METASTROKE: ASGC: Australian population control data were derived from the Hunter Community Study. This research was funded by grants from the Australian National and Medical Health Research Council (NHMRC Project Grant ID: 569257), the Australian National Heart Foundation (NHF Project Grant ID: G 04S 1623), the University of Newcastle, the Gladys M Brawn Fellowship scheme, and the Vincent Fairfax Family Foundation in Australia. E.G.H. was supported by a Fellowship from the NHF and National Stroke Foundation of Australia (ID: 100071). J.M. was supported by an Australian Postgraduate Award. BRAINS: Bio-Repository of DNA in Stroke (BRAINS) is partly funded by a Senior Fellowship from the Department of Health (UK) to P.S., the Henry Smith Charity, and the UK-India Education Research Institutive (UKIERI) from the British Council. GEOS: Genetics of Early Onset Stroke (GEOS) Study, Baltimore, was supported by GEI Grant U01 HG004436, as part of the GENEVA consortium under GEI, with additional support provided by the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488), and the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs. Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to the Johns Hopkins University (contract no. HHSN268200782096C). Assistance with data cleaning was provided by the GENEVA Coordinating Center (U01 HG 004446; PI Bruce S. Weir). Study recruitment and assembly of datasets were supported by a Cooperative Agreement with the Division of Adult and Community Health, Centers for Disease Control and Prevention, and by grants from NINDS and the NIH Office of Research on Women's Health (R01 NS45012, U01 NS069208-01). HPS: Heart Protection Study (HPS) (ISRCTN48489393) was supported by the UK MRC, British Heart Foundation, Merck and Co. (manufacturers of simvastatin), and Roche Vitamins Ltd. (manufacturers of vitamins). Genotyping was supported by a grant to Oxford University and CNG from Merck and Co. J.C.H. acknowledges support from the British Heart Foundation (FS/14/55/30806). ISGS: Ischemic Stroke Genetics Study (ISGS)/Siblings With Ischemic Stroke Study (SWISS) was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000954-06. ISGS/SWISS used samples and clinical data from the NIH-NINDS Human Genetics Resource Center DNA and Cell Line Repository (ccr.coriell.org/ninds), human subjects protocol nos. 2003-081 and 2004-147. ISGS/SWISS used stroke-free participants from the Baltimore Longitudinal Study of Aging (BLSA) as controls. The inclusion of BLSA samples was supported in part by the Intramural Research Program of the NIA, NIH project Z01 AG-000015-50, human subjects protocol no. 2003-078. The ISGS study was funded by NIH-NINDS Grant R01 NS-42733 (J.F.M.). The SWISS study was funded by NIH-NINDS Grant R01 NS-39987 (J.F.M.). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (biowulf.nih.gov). MGH-GASROS: MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS) was supported by NINDS (U01 NS069208), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research 0775010N, the NIH and NHLBI's STAMPEED genomics research program (R01 HL087676), and a grant from the National Center for Research Resources. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. Milan: Milano–Besta Stroke Register Collection and genotyping of the Milan cases within CEDIR were supported by the Italian Ministry of Health (grant nos.: RC 2007/LR6, RC 2008/LR6; RC 2009/LR8; RC 2010/LR8; GR-2011-02347041), FP6 LSHM-CT-2007-037273 for the PROCARDIS control samples. WTCCC2: Wellcome Trust Case-Control Consortium 2 (WTCCC2) was principally funded by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z and WT084724MA). The Stroke Association provided additional support for collection of some of the St George's, London cases. The Oxford cases were collected as part of the Oxford Vascular Study, which is funded by the MRC, Stroke Association, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Biomedical Research Centre, Oxford. The Edinburgh Stroke Study was supported by the Wellcome Trust (clinician scientist award to C.L.M.S.) and the Binks Trust. Sample processing occurred in the Genetics Core Laboratory of the Wellcome Trust Clinical Research Facility, Western General Hospital, Edinburgh. Much of the neuroimaging occurred in the Scottish Funding Council Brain Imaging Research Centre (https://www.ed.ac.uk/clinical-sciences/edinburgh-imaging), Division of Clinical Neurosciences, University of Edinburgh, a core area of the Wellcome Trust Clinical Research Facility, and part of the SINAPSE (Scottish Imaging Network: A Platform for Scientific Excellence) collaboration (sinapse.ac.uk), funded by the Scottish Funding Council and the Chief Scientist Office. Collection of the Munich cases and data analysis was supported by the Vascular Dementia Research Foundation. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreements no. 666881, SVDs@target (to M.D.) and no. 667375, CoSTREAM (to M.D.); the DFG as part of the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) and the CRC 1123 (B3) (to M.D.); the Corona Foundation (to M.D.); the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain) (to M.D.); the e:Med program (e:AtheroSysMed) (to M.D.) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement no. Health-F2-2013-601456) (to M.D.). M.F. and A.H. acknowledge support from the BHF Centre of Research Excellence in Oxford and the Wellcome Trust core award (090532/Z/09/Z). VISP: The GWAS component of the Vitamin Intervention for Stroke Prevention (VISP) study was supported by the US National Human Genome Research Institute (NHGRI), grant U01 HG005160 (PI Michèle Sale and Bradford Worrall), as part of the Genomics and Randomized Trials Network (GARNET). Genotyping services were provided by the Johns Hopkins University Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the NIH to Johns Hopkins University. Assistance with data cleaning was provided by the GARNET Coordinating Center (U01 HG005157; PI Bruce S. Weir). Study recruitment and collection of datasets for the VISP clinical trial were supported by an investigator-initiated research grant (R01 NS34447; PI James Toole) from the US Public Health Service, NINDS, Bethesda, MD. Control data obtained through the database of genotypes and phenotypes (dbGAP) maintained and supported by the United States National Center for Biotechnology Information, US National Library of Medicine. WHI: Funding support for WHI-GARNET was provided through the NHGRI GARNET (grant no. U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157). Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the GEI (U01 HG004424). R.L. is a senior clinical investigator of FWO Flanders. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre.

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2019
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