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101. Retinal Microvascular Calibers Are Associated With Enlarged Perivascular Spaces in the Brain

Author

M. Arfan Ikram, Hieab H.H. Adams, Caroline C W Klaver, Albert Hofman, Unal Mutlu, M. Kamran Ikram, Aad van der Lugt, Meike W. Vernooij, Epidemiology, Radiology & Nuclear Medicine, Ophthalmology, and Neurology

Subjects
Male, Pathology, medicine.medical_specialty, Brain damage, 030204 cardiovascular system & hematology, Fundus (eye), Hippocampus, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Microcirculation, White matter, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Venules, Centrum semiovale, medicine, Humans, Perivascular space, Aged, Advanced and Specialized Nursing, medicine.diagnostic_test, business.industry, Retinal Vessels, Retinal, Magnetic resonance imaging, Anatomy, Middle Aged, White Matter, Arterioles, medicine.anatomical_structure, chemistry, Female, Neurology (clinical), medicine.symptom, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract

Background and Purpose— Perivascular enlargement in the brain is a putative imaging marker for microvascular brain damage, but this link has not yet been confirmed using direct in vivo visualization of small vessels. We investigated the relation between microvascular calibers on retinal imaging and enlarged perivascular spaces (ePVSs) on brain magnetic resonance imaging. Methods— We included 704 participants from the Rotterdam study. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. ePVSs were counted in the centrum semiovale, basal ganglia, hippocampus, and mesencephalon, using a standardized rating method. We determined the association between retinal microvascular calibers and ePVSs with negative binomial regression models, adjusting for age, sex, the other vascular caliber, structural brain magnetic resonance imaging markers, and cardiovascular risk factors. Results— Both narrower arteriolar and wider venular calibers were associated with more ePVSs in the centrum semiovale and hippocampal region. Rate ratios (95% confidence interval) for arterioles in the centrum semiovale and hippocampus were 1.07 (1.01–1.14) and 1.13 (1.04–1.22), respectively, and for venules 1.08 (1.01–1.16) and 1.09 (1.00–1.18), respectively. These associations were independent from other brain magnetic resonance imaging markers and cardiovascular risk factors. Conclusions— Retinal microvascular calibers are related to ePVSs, confirming the putative link between microvascular damage and ePVSs.

Published
2016

102. Genetic loci for serum lipid fractions and intracerebral hemorrhage

Author

Meike W. Vernooij, M. Arfan Ikram, Aad van der Lugt, Cornelia M. van Duijn, Hieab H.H. Adams, Saloua Akoudad, Peter J. Koudstaal, Marileen L.P. Portegies, André G. Uitterlinden, Daniel Bos, Albert Hofman, Epidemiology, Neurology, Radiology & Nuclear Medicine, and Internal Medicine

Subjects
Male, Pathology, Epidemiology, Blood lipids, 030204 cardiovascular system & hematology, Gastroenterology, Rotterdam Study, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Odds Ratio, Prevalence, Medicine, Netherlands, Subclinical infection, education.field_of_study, Middle Aged, Magnetic Resonance Imaging, Lipids, Phenotype, Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, Cerebral microbleeds, medicine.medical_specialty, Population, Risk Assessment, 03 medical and health sciences, Internal medicine, Genetic predisposition, Genetics, Humans, Genetic Predisposition to Disease, cardiovascular diseases, education, Genetic Association Studies, Triglycerides, Aged, Cerebral Hemorrhage, Dyslipidemias, Proportional Hazards Models, Intracerebral hemorrhage, business.industry, Proportional hazards model, Cholesterol, Intracerebral hemorrhages, Cholesterol, HDL, Cholesterol, LDL, medicine.disease, nervous system diseases, Logistic Models, chemistry, Genetic Loci, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

Background: Serum total cholesterol and its fractions are inversely associated with intracerebral hemorrhages (ICH) and their potential subclinical precursor, cerebral microbleeds. To ascertain whether there is a genetic basis for this inverse association, we studied established genetic loci for serum total, LDL, and HDL cholesterol, and triglycerides in their association with ICH and microbleeds. Methods: Data on 161 genetic variants for serum lipids was collected in 9011 stroke-free participants (mean age 65.8, SD 10.2; 57.9% women) of the population-based Rotterdam Study. Participants were followed from baseline (1997-2005) up to 2013 for the occurrence of ICH. A subset of 4179 participants underwent brain MRI for microbleed assessment between 2005 and 2011. We computed genetic risk scores (GRS) for the joint effect of lipid variants. Cox proportional hazards and logistic regression models were used to investigate the association of GRS of lipid fractions with ICH and microbleeds. Results: After a mean follow-up of 8.7 (SD 4.1) years, 67 (0.7%) participants suffered an ICH. Microbleed prevalence was 19.6%. Higher genetic load for high serum total and LDL cholesterol was associated with an increased risk of ICH. Higher genetic load for high serum LDL cholesterol was borderline associated with a higher prevalence of multiple lobar microbleeds. Conclusions: Genetic susceptibility for high serum total and LDL cholesterol is positively associated with incident ICH and borderline associated with multiple lobar microbleeds. We did not find a genetic basis for the previously reported inverse association between serum lipid levels and ICH. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Published
2016

103. Heritability of the shape of subcortical brain structures in the general population

Author

Wiro J. Niessen, Albert Hofman, Neda Jahanshad, Cornelia M. van Duijn, Katie L. McMahon, Sven J. van der Lee, Nicholas G. Martin, André G. Uitterlinden, Boris A. Gutman, M. Arfan Ikram, Paul M. Thompson, Hieab H.H. Adams, Margaret J. Wright, Meike W. Vernooij, Greig I. de Zubicaray, Gennady V. Roshchupkin, Medical Informatics, Radiology & Nuclear Medicine, Epidemiology, Internal Medicine, and Neurology

Subjects
Adult, Male, 0301 basic medicine, Genotype, Science, Thalamus, Population, General Physics and Astronomy, Hippocampus, Biology, Nucleus accumbens, Globus Pallidus, Amygdala, Brain mapping, Nucleus Accumbens, Article, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Twins, Dizygotic, medicine, Humans, education, Aged, Aged, 80 and over, education.field_of_study, Multidisciplinary, Putamen, Brain, Reproducibility of Results, Organ Size, Twins, Monozygotic, General Chemistry, Middle Aged, Heritability, Magnetic Resonance Imaging, 030104 developmental biology, medicine.anatomical_structure, Female, Caudate Nucleus, Neuroscience, 030217 neurology & neurosurgery
Abstract

The volumes of subcortical brain structures are highly heritable, but genetic underpinnings of their shape remain relatively obscure. Here we determine the relative contribution of genetic factors to individual variation in the shape of seven bilateral subcortical structures: the nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus. In 3,686 unrelated individuals aged between 45 and 98 years, brain magnetic resonance imaging and genotyping was performed. The maximal heritability of shape varies from 32.7 to 53.3% across the subcortical structures. Genetic contributions to shape extend beyond influences on intracranial volume and the gross volume of the respective structure. The regional variance in heritability was related to the reliability of the measurements, but could not be accounted for by technical factors only. These findings could be replicated in an independent sample of 1,040 twins. Differences in genetic contributions within a single region reveal the value of refined brain maps to appreciate the genetic complexity of brain structures., The volume of subcortical brain structures is known to be heritable. Here, Roshchupkin and colleagues studied seven different subcortical brain structures in the general population and show that the genetic contributions go beyond these volumetric measurements, and also extend to their shapes.

Published
2016

104. Amyloid-β transmission or unexamined bias?

Author

Albert Hofman, Hieab H.H. Adams, Sonja A. Swanson, and M. Arfan Ikram

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Multidisciplinary, Transmission (telecommunications), Amyloid β, business.industry, Biophysics, Medicine, business, 030217 neurology & neurosurgery
Published
2015

105. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Author

Dorret I. Boomsma, Arn M. J. M. van den Maagdenberg, Kai-How Farh, Linda M. Pedersen, Evelin Mihailov, Lydia Quaye, Bertram Müller-Myhsok, Zameel M. Cader, David A. Hinds, Albert Hofman, George McMahon, Lynn Cherkas, Andrea Byrnes, Christopher Sivert Nielsen, Priit Palta, Kauko Heikkilä, Lili Milani, Caleb Webber, Elizabeth Loehrer, Maija Wessman, Stacy Steinberg, Stefan Schreiber, John-Anker Zwart, Nicholas A. Furlotte, Nicholas G. Martin, Paul M. Ridker, Nicholas Eriksson, André G. Uitterlinden, M. Arfan Ikram, Anine H. Stam, Audun Stubhaug, Hieab H.H. Adams, Markus Färkkilä, Verneri Anttila, Antti-Pekka Sarin, Salli Vepsäläinen, Jouke-Jan Hottenga, Pamela A. F. Madden, Andrew C. Heath, Brenda W.J.H. Penninx, Tobias Kurth, Ester Cuenca-León, Kari Stefansson, Veikko Salomaa, Dale R. Nyholt, Jaakko Kaprio, Andrea Carmine Belin, Tune H. Pers, Cynthia Sandor, Eija Hamalainen, Hailiang Huang, Lude Franke, Jie Huang, George Davey Smith, Jes Olesen, Anne Francke Christensen, Juho Wedenoja, Tobias Freilinger, Scott G. Gordon, Mari A. Kaunisto, Hreinn Stefansson, Guntram Borck, Maria Gudlaug Hrafnsdottir, David P. Strachan, Ville Artto, Johan G. Eriksson, Minna Männikkö, Evie Stergiakouli, Thomas Meitinger, Markus Schürks, Olli T. Raitakari, Arpo Aromaa, Mark J. Daly, Marjo-Riitta Järvelin, Andres Ingason, Martin Dichgans, Tim D. Spector, Cornelia M. van Duijn, Mikko Muona, Daniel I. Chasman, Hartmut Göbel, Andres Metspalu, Aarno Palotie, Michel D. Ferrari, Grant W. Montgomery, Susan M. Ring, Caroline Ran, Thomas Werge, Lannie Ligthart, Terho Lehtimäki, Julie E. Buring, Christian Kubisch, Mikko Kallela, Phil Lee, Ann-Louise Esserlind, Bendik S. Winsvold, Markku Koiranen, Benjamin M. Neale, Tõnu Esko, Rainer Malik, Gisela M. Terwindt, Thomas Hansen, and Padhraig Gormley

Subjects
Subset Analysis, Genetics, 0303 health sciences, Aura, Single-nucleotide polymorphism, Locus (genetics), Disease, Biology, medicine.disease, Migraine with aura, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Migraine, Meta-analysis, medicine, medicine.symptom, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Published
2015
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106. White matter lesion progression: A genome-wide search for genetic influences

Author

Sudha Seshadri, Wiro J. Niessen, David J. Stott, Albert V. Smith, Claudia L. Satizabal, Rudi G. J. Westendorp, Cornelia M. van Duijn, Richard Beare, Vilmundur Gudnason, Sigurdur Sigurdsson, Qiong Yang, Christophe Tzourio, Thomas Lumley, M. Arfan Ikram, Carole Dufouil, Brendan M. Buckley, Bernard Mazoyer, Reinhold Schmidt, Michele L. Callisaya, Alexa S. Beiser, Ian Ford, Myriam Fornage, Anton J. M. de Craen, Thanh G. Phan, W. T. Longstreth, Naveed Sattar, Edith Hofer, P. Eline Slagboom, Lenore J. Launer, Stella Trompet, Jing Wang, Gerardo Heiss, Charles DeCarli, Hieab H.H. Adams, B. Gwen Windham, Velandai Srikanth, Kent D. Taylor, Chris Moran, Thomas H. Mosley, Albert Hofman, Margherita Cavalieri, Rebecca F. Gottesman, Christiane Wolf, Alex P. Zijdenbos, Benjamin F.J. Verhaaren, Mark A. van Buchem, Ganesh Chauhan, Oliver Martinez, J. Wouter Jukema, Meike W. Vernooij, Sabrina Schilling, Paul Freudenberger, Stéphanie Debette, Dean Shibata, Helena Schmidt, Anna Maria Töglhofer, Joshua C. Bis, Bruce M. Psaty, Russell Thomson, Philippe Amouyel, Epidemiology, Radiology & Nuclear Medicine, and Medical Informatics

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Pathology, Genome-wide association study, Article, Cohort Studies, Framingham Heart Study, Leukoencephalopathies, Internal medicine, Epidemiology, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Cognitive decline, Prospective cohort study, Genetic association, Aged, Advanced and Specialized Nursing, business.industry, Middle Aged, White Matter, Hyperintensity, Disease Progression, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, Cohort study, Genome-Wide Association Study
Abstract

Background and Purpose— White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods— Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results— A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance ( P −8 ). Four loci were suggestive ( P −5 ) of an association with WML progression: 10q24.32 (rs10883817, P =1.46×10 −6 ); 12q13.13 (rs4761974, P =8.71×10 −7 ); 20p12.1 (rs6135309, P =3.69×10 −6 ); and 4p15.31 (rs7664442, P =2.26×10 −6 ). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. Conclusions— Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Published
2015

107. O4‐05‐02: Genome‐wide association study of lobar brain volumes

Author

Lisa R. Yanek, Christophe Tzourio, Bernard Mazoyer, Charles DeCarli, Lenore J. Launer, David A. Bennett, M. Arfan Ikram, Najaf Amin, Sven J. van der Lee, Sudha Seshadri, Qiong Yang, Lei Yu, Debra A. Fleischman, Stéphanie Debette, Konstantinos Arfanakis, Ganesh Chauhan, Shuo Li, Cornelia M. van Duijn, Edith Hofer, Hieab H.H. Adams, Albert V. Smith, Claudia L. Satizabal, Philip L. De Jager, and Vincent Chouraki

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology
Published
2015
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108. O4‐05‐03: Whole exome sequence analysis of white matter hyperintensities on cranial MRI

Author

Hieab H.H. Adams, Anita L. DeStefano, Sudha Seshadri, Charles DeCarli, Xueqiu Jian, Myriam Fornage, Vincent Chouraki, Thomas H. Mosley, Cornelia M. van Duijn, Richard A. Gibbs, Eric Boerwinkle, M. Arfan Ikram, Bruce M. Psaty, Jennifer A. Brody, Joshua C. Bis, and W. T. Longstreth

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Whole exome sequence analysis, Neurology (clinical), Anatomy, Geriatrics and Gerontology, business, Hyperintensity
Published
2015
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109. 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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110. Association of Alzheimer's disease GWAS loci with MRI markers of brain aging

Author

Debra A. Fleischman, Helena Schmidt, Wiro J. Niessen, David S. Knopman, Sven J. van der Lee, Clifford R. Jack, Joshua C. Bis, Russell Thomson, James T. Becker, Konstantinos Arfanakis, Charles DeCarli, Christophe Tzourio, Myriam Fornage, Qiong Yang, Meike W. Vernooij, Ganesh Chauhan, Hieab H.H. Adams, Bernard Mazoyer, Oscar L. Lopez, Cornelia M. van Duijn, Philippe Amouyel, William T. Longstreth, Lenore J. Launer, Rebecca F. Gottesman, Albert V. Smith, Thanh G. Phan, Richard Beare, Anna Maria Töglhofer, Stéphanie Debette, Lei Yu, Sudha Seshadri, Albert Hofman, Velandai Srikanth, Galit Weinstein, Thomas H. Mosley, Reinhold Schmidt, Jing Wang, David A. Bennett, M. Arfan Ikram, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), University of Washington [Seattle], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Hangzhou Dianzi University (HDU), Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria, JRC Institute for Transuranium Elements [Karlsruhe] (ITU ), European Commission - Joint Research Centre [Karlsruhe] (JRC), Department of Materials Science and Metallurgy [Cambridge University] (DMSM), University of Cambridge [UK] (CAM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Johns Hopkins University School of Medicine [Baltimore], Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, University of Tasmania [Hobart, Australia] (UTAS), University of Miami [Coral Gables], Delft University of Technology (TU Delft), Estación Experimental de Pastos y Forrajes ‘Indio Hatuey’, Karlsruhe Institute of Technology (KIT), Institut de Mathématiques [Hanoi], Académie des Sciences et Techniques, Murdoch Children's Research Institute (MCRI), Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Monash University [Melbourne], Department of Biomedical Engineering, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], Department of Radiology, Mayo Clinic, 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), Department of Physics [Stockholm], Stockholm University, Mayo Clinic [Rochester], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, 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), University of Mississippi Medical Center (UMMC), Human Genetics Center, The University of Texas Health Science Center at Houston (UTHealth), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], INSERM U897, University of Bordeaux, France, University of Tasmania (UTAS), 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), University of California-University of California, Radboud university [Nijmegen], Epidemiology, and Radiology & Nuclear Medicine

Subjects
Oncology, Apolipoprotein E, Male, Aging, Sialic Acid Binding Ig-like Lectin 3, Genome-wide association study, Neurodegenerative, Alzheimer's Disease, Bioinformatics, Hippocampus, [SCCO]Cognitive science, 0302 clinical medicine, GWAS, 2.1 Biological and endogenous factors, Aetiology, screening and diagnosis, 0303 health sciences, education.field_of_study, General Neuroscience, Brain, Single Nucleotide, Organ Size, Magnetic Resonance Imaging, Genetic risk score, 3. Good health, Detection, Neurological, Brain size, Female, MRI-Markers, Alzheimer's disease, Psychology, Risk, medicine.medical_specialty, Clinical Sciences, Population, Locus (genetics), Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Apolipoproteins E, Clinical Research, Alzheimer Disease, Internal medicine, Acquired Cognitive Impairment, Genetics, medicine, Humans, Polymorphism, Allele, education, Alleles, 030304 developmental biology, Genetic association, Neurology & Neurosurgery, Prevention, [SCCO.NEUR]Cognitive science/Neuroscience, Human Genome, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, Hippocampal volume, Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, Alzheimer, Dementia, Neurology (clinical), Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta +/- SE = -0.047 +/- 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons. (C) 2015 Elsevier Inc. All rights reserved.

Published
2015
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111. A priori collaboration in population imaging: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium

Author

Petra Katschnig-Winter, Meike W. Vernooij, Sven J. van der Lee, Reinhold Schmidt, Petra Schwingenschuh, M. Kamran Ikram, Charles DeCarli, Hieab H.H. Adams, Katharina Wittfeld, Mohamad Habes, M. Arfan Ikram, Hans J. Grabe, Christopher Chen, Sudha Seshadri, Saima Hilal, Cornelia M. van Duijn, Radiology & Nuclear Medicine, and Epidemiology

Subjects
Pathology, medicine.medical_specialty, Population imaging, Quantification methods, Population, Neuroimaging, Virchow robin spaces, Virchow-Robin spaces, Magnetic resonance imaging, medicine, ddc:610, Perivascular space, education, Cerebrovascular disease, education.field_of_study, Population based, medicine.diagnostic_test, business.industry, Small sample, Anatomy, Brain pathologies, Stroke, Psychiatry and Mental health, medicine.anatomical_structure, Risk factors, Dementia, Neurology (clinical), business
Abstract

INTRODUCTION: Virchow-Robin spaces (VRS), or perivascular spaces, are compartments of interstitial fluid enclosing cerebral blood vessels and are potential imaging markers of various underlying brain pathologies. Despite a growing interest in the study of enlarged VRS, the heterogeneity in rating and quantification methods combined with small sample sizes have so far hampered advancement in the field.METHODS: The Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement (UNIVRSE) consortium was established with primary aims to harmonize rating and analysis (www.uconsortium.org). The UNIVRSE consortium brings together 13 (sub)cohorts from five countries, totaling 16,000 subjects and over 25,000 scans. Eight different magnetic resonance imaging protocols were used in the consortium.RESULTS: VRS rating was harmonized using a validated protocol that was developed by the two founding members, with high reliability independent of scanner type, rater experience, or concomitant brain pathology. Initial analyses revealed risk factors for enlarged VRS including increased age, sex, high blood pressure, brain infarcts, and white matter lesions, but this varied by brain region.DISCUSSION: Early collaborative efforts between cohort studies with respect to data harmonization and joint analyses can advance the field of population (neuro)imaging. The UNIVRSE consortium will focus efforts on other potential correlates of enlarged VRS, including genetics, cognition, stroke, and dementia.

Published
2015
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112. P3‐071: A GENOME‐WIDE META‐ANALYSIS OF PLASMA CLUSTERIN LEVELS IN THE CHARGE CONSORTIUM

Author

Vilmundur Gudnason, Sudha Seshadri, Daniel Levy, Veer Bala Gupta, Henry Brodaty, Lenore J. Launer, Richard Dobson, Jennifer Mollon, Gudny Eiriksdottir, Fei Song, Vincent Chouraki, Karen A. Mather, Mohammad Arfan Ikram, Madhav Thambisetty, Anbupalam Thalamuthu, John Attia, Liz Holliday, Perminder S. Sachdev, Toshiko Tanaka, Ralph N. Martins, Christopher Oldmeadow, Rodney J. Scott, Johanna Jakobsdottir, Hieab H.H. Adams, Simon Lovestone, and Anne Poljak

Subjects
Clusterin, biology, Epidemiology, Chemistry, Health Policy, Charge (physics), Plasma, Computational biology, Genome, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, biology.protein, Neurology (clinical), Geriatrics and Gerontology
Published
2014
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113. O4‐08‐03: GENETIC RISK OF NEURODEGENERATIVE DISEASES IS ASSOCIATED WITH MILD COGNITIVE IMPAIRMENT AND CONVERSION TO DEMENTIA: THE ROTTERDAM STUDY

Author

Meike W. Vernooij, Hieab H.H. Adams, Mohammad Arfan Ikram, Cornelia M. van Duijn, Peter J. Koudstaal, Albert Hofman, André G. Uitterlinden, and Renée F.A.G. de Bruijn

Subjects
medicine.medical_specialty, Epidemiology, business.industry, Health Policy, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Rotterdam Study, Developmental Neuroscience, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, Genetic risk, business, Psychiatry, Cognitive impairment
Published
2014
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114. P1‐270: DETERMINANTS OF ENLARGED VIRCHOW‐ROBIN SPACES: THE UNIVRSE CONSORTIUM

Author

Reinhold Schmidt, Mohammad Arfan Ikram, Petra Schwingenschuh, Meike W. Vernooij, Hieab H.H. Adams, Gabriel P. Krestin, Petra Katschnig-Winter, Albert Hofman, and Aad van der Lugt

Subjects
Epidemiology, Health Policy, media_common.quotation_subject, Art history, Virchow robin spaces, Art, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Center (algebra and category theory), Neurology (clinical), Geriatrics and Gerontology, Erasmus+, media_common
Abstract

ROBIN SPACES: THE UNIVRSE CONSORTIUM Hieab H.H. Adams, Petra Schwingenschuh, Aad van der Lugt, Petra Katschnig-Winter, Albert Hofman, Gabriel Krestin, Meike Vernooij, Reinhold Schmidt, Mohammad Arfan Ikram, Erasmus MC, Rotterdam, Netherlands; Medical University Graz, Graz, Austria; Erasmus Medical Center, Rotterdam, Netherlands; Medical University Graz, Graz, Austria. Contact e-mail: h.adams@erasmusmc.nl

Published
2014
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115. O4‐04‐05: ASSOCIATION OF ALZHEIMER DISEASE GWAS LOCI WITH MRI‐MARKERS OF BRAIN AGING

Author

Mohammad Arfan Ikram, Myriam Fornage, Joshua C. Bis, Lei Yu, James T. Becker, Meike W. Vernooij, Albert V. Smith, David S. Knopman, Hieab H.H. Adams, Philippe Amouyel, Velandai Srikanth, Thomas H. Mosley, Stéphanie Debette, Lenore J. Launer, Christophe Tzourio, Oscar L. Lopez, Sudha Seshadri, Cornelia M. van Duijn, Sven J. van der Lee, William T. Longstreth, Reinhold Schmidt, Galit Weinstein, Ganesh Chauhan, David A. Bennett, Charlie S. DeCarli, and Helena Schmidt

Subjects
Epidemiology, business.industry, Health Policy, Genome-wide association study, medicine.disease, Bioinformatics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business, Association (psychology), Brain aging
Published
2014
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116. TMEM106B Influences Volume of Left-Sided Temporal Lobe and Interhemispheric Structures in the General Population

Author

M. Arfan Ikram, André G. Uitterlinden, Albert Hofman, Henri A. Vrooman, Meike W. Vernooij, Aad van der Lugt, Cornelia M. van Duijn, Hieab H.H. Adams, Wiro J. Niessen, Benjamin F.J. Verhaaren, Radiology & Nuclear Medicine, Internal Medicine, and Epidemiology

Subjects
Male, Pathology, medicine.medical_specialty, Population, Anterior commissure, Nerve Tissue Proteins, Corpus callosum, Functional Laterality, Temporal lobe, Superior temporal gyrus, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Gray Matter, education, Biological Psychiatry, Aged, education.field_of_study, Polymorphism, Genetic, Brain, Membrane Proteins, Frontotemporal lobar degeneration, Commissure, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Temporal Lobe, Frontotemporal Dementia, Female, Psychology, Frontotemporal dementia
Abstract

Background Frontotemporal lobar degeneration is a neurodegenerative disease characterized by brain atrophy of the frontal and anterior temporal lobes. The associated frontotemporal dementia syndromes are clinically heterogeneous, and the pattern of affected cortical regions varies among subtypes. The TMEM106B rs1990622 polymorphism is associated with frontotemporal lobar degeneration, but little is known about how it affects the brain. Methods We investigated the rs1990622 polymorphism in relation to regional brain volumes to identify potential structures through which TMEM106B confers risk for frontotemporal lobar degeneration. In 4413 nondemented and stroke-free participants from the population-based Rotterdam Study, 150 cortical brain structures and 6 commissural regions were segmented from magnetic resonance imaging. Results A distinct pattern of association was found between rs1990622 and gray matter volume of left-sided temporal brain regions important for language processing, including the superior temporal gyrus (β = −88.8 μL per risk allele, p = 7.64 × 10 −5 ), which contains Wernicke's area. The risk allele was also associated with a smaller anterior commissure cross-sectional area (β = −.167 mm 2 per risk allele, p = 4.90 × 10 −5 ) and posterior part of the corpus callosum (β = −15.3 μL per risk allele, p = 1.23 × 10 −5 ), both of which contain temporal lobe commissural tracts. Conclusions The asymmetric, predominantly left-sided involvement suggests an effect of TMEM106B on functions lateralized to the dominant hemisphere, such as language. These results show that, in nondemented persons, TMEM106B influences the volume of temporal brain regions that are important for language processing.

Published
2014

117. Erratum: Corrigendum: Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Author

Daniel I. Chasman, Stefan Schreiber, Paul M. Ridker, Salli Vepsäläinen, Antti-Pekka Sarin, Veikko Salomaa, Christopher Sivert Nielsen, Tobias Freilinger, Markus Schürks, John-Anker Zwart, Hartmut Göbel, Lydia Quaye, Cynthia Sandor, Nicholas Eriksson, Tõnu Esko, Hieab H.H. Adams, Thomas Meitinger, Andres Ingason, Lude Franke, Rainer Malik, Brenda W.J.H. Penninx, Verneri Anttila, Julie E. Buring, Thomas Hansen, Tobias Kurth, Tim D. Spector, Padhraig Gormley, Mikko Muona, Maija Wessman, Arpo Aromaa, E. Cuenca-Leon, Marjo-Riitta Järvelin, Mikko Kallela, Nicholas A. Furlotte, Linda M. Pedersen, George Davey Smith, Mitja I. Kurki, Aarno Palotie, Reedik Mägi, David P. Strachan, Hailiang Huang, Eija Hämäläinen, Caleb Webber, Nicholas G. Martin, Arn M. J. M. van den Maagdenberg, Zameel M. Cader, Mart Kals, Stacy Steinberg, Markus Färkkilä, Pamela A. F. Madden, Michel D. Ferrari, Grant W. Montgomery, Caroline Ran, Thomas Werge, Lannie Ligthart, Jouke-Jan Hottenga, Kari Stefansson, Tune H. Pers, Bertram Müller-Myhsok, Anine H. Stam, Susan M. Ring, Andres Metspalu, Terho Lehtimäki, Jes Olesen, Andrea Byrnes, Evelin Mihailov, Andrew Heath, Kauko Heikkilä, Jaakko Kaprio, David A. Hinds, Ville Artto, Jie Huang, Maria Gudlaug Hrafnsdottir, Dale R. Nyholt, Evie Stergiakouli, Benjamin M. Neale, Dorret I. Boomsma, Martin Dichgans, Guntram Borck, Kai-How Farh, Christian Kubisch, Cornelia M. van Duijn, André G. Uitterlinden, Albert Hofman, George McMahon, Audun Stubhaug, Kalle Pärn, Priit Palta, Lynn Cherkas, Mark J. Daly, Mari A. Kaunisto, Phil Lee, Ann-Louise Esserlind, Gisela M. Terwindt, Andrea Carmine Belin, Bendik S. Winsvold, Markku Koiranen, Johan G. Eriksson, Minna Männikkö, Olli T. Raitakari, Hreinn Stefansson, Anne Francke Christensen, Juho Wedenoja, Scott G. Gordon, M. Arfan Ikram, Elizabeth Loehrer, and Lili Milani

Subjects
0301 basic medicine, Genetics, Published Erratum, MEDLINE, Biology, medicine.disease, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Migraine, Meta-analysis, medicine, Susceptibility locus, 030217 neurology & neurosurgery
Abstract

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 44 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Published
2016
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118. HASE: Framework for efficient high-dimensional association analyses

Author

C M van Duijn, Wiro J. Niessen, Arfan Ikram, Hieab H.H. Adams, Gennady V. Roshchupkin, Albert Hofman, Meike W. Vernooij, Medical Informatics, Radiology & Nuclear Medicine, Epidemiology, and Neurology

Subjects
0301 basic medicine, Computer science, Association (object-oriented programming), Genomics, High dimensional, Terabyte, computer.software_genre, Health outcomes, Proteomics, Genome-wide association studies, Article, Reduction (complexity), 03 medical and health sciences, 0302 clinical medicine, 030304 developmental biology, Genetic association, 0303 health sciences, Data collection, Multidisciplinary, Individual participant data, Data science, 030104 developmental biology, Data mining, computer, Software, 030217 neurology & neurosurgery
Abstract

High-throughput technology can now provide rich information on a person’s biological makeup and environmental surroundings. Important discoveries have been made by relating these data to various health outcomes in fields such as genomics, proteomics, and medical imaging. However, cross-investigations between several high-throughput technologies remain impractical due to demanding computational requirements (hundreds of years of computing resources) and unsuitability for collaborative settings (terabytes of data to share). Here we introduce the HASE framework that overcomes both of these issues. Our approach dramatically reduces computational time from years to only hours and also requires several gigabytes to be exchanged between collaborators. We implemented a novel meta-analytical method that yields identical power as pooled analyses without the need of sharing individual participant data. The efficiency of the framework is illustrated by associating 9 million genetic variants with 1.5 million brain imaging voxels in three cohorts (total N = 4,034) followed by meta-analysis, on a standard computational infrastructure. These experiments indicate that HASE facilitates high-dimensional association studies enabling large multicenter association studies for future discoveries.

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