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Genetic Determinants of Cognitive Function and Age-Related Brain Changes

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Genetic Determinants of Cognitive Function and Age-Related Brain Changes Genetic Determinants of Cognitive Function and Age-Related Brain Changes Maaike Schuur Schuur Genetic Determinants of Cognitive Function and Age-Related Brain Changes Genetic Determinants of Cognitive Function and Age-Related Maaike Genetic Determinants of Cognitive Function and Age-Related Brain Changes Maaike Schuur ISBN: 978-90-8559-993-7 Cover & Layout: S. P. Schuur voor CIVIL-X, New York, USA Printed by: Optima Grafische Communicatie, Rotterdam Copyright: M. Schuur, Rotterdam, the Netherlands, 2010 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the holder of the copyright. Titel proefschrift Genetic Determinants of Cognitive Function and Age-Related Brain Changes Vertaling van de titel Genetische determinanten van cognitief functioneren en aan veroudering gerelateerde hersenveranderingen Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 12 mei 2010 om 15:30 uur door Maaike Schuur geboren te Anloo Promotiecommissie Promotoren: Prof.dr.ir. C.M. van Duijn Prof.dr. B.A. Oostra Overige leden: Dr. G.J. Biessels Dr. V. Bonifati Prof.dr. D.I. Boomsma Copromotor: Dr. J.C. van Swieten Table of contents Part I Introduction Chapter 01 General introduction, outline, and scope of the thesis 13 Part II New determants of cognitive function Chapter 02 Insulin-resistance and metabolic syndrome are related to 25 executive function in women in a large family-based study Chapter 03 The apolipoprotein E gene and its age-specific effects on 43 cognitive function Chapter 04 Genome-wide linkage screen of cognitive function identifies 59 susceptible chromosomal regions Chapter 05 Genome-wide association study of cognitive executive 77 functions: Meta-analysis of the CHARGE consortium PART III Genetic determants of Alzheimer’s disease Chapter 06 Cathepsin D gene and the risk of Alzheimer’s disease: 99 A population-based study and meta-analysis Chapter 07 Transferrin and HFE genes interact in Alzheimer’s disease 115 risk: the Epistasis Project PART IV Genetic determinants of age-related brain pathology in hypertensive patients Chapter 08 Genetic risk factors for cerebral small vessel disease in 137 hypertensive patients from a genetically isolated population Chapter 09 The relation of the sortilin-related receptor gene to 147 hippocampal volume and plasma amyloid beta levels in a family-based study of hypertensive patients Chapter 10 Polymorphisms of the renin-angiotensin system and 163 alfa-adducin in associate to circulating amyloid beta levels Part IV General discussion and summary Chapter 11 Findings of this thesis 179 Chapter 12 Grading the credibility of genetic associations in Alzheimer’s 189 disease using the Venice criteria: practical considerations following from the Alzgene database Chapter 13 Future research 205 Chapter 14 Nederlandse samenvatting en conclusies 213 Dankwoord 221 Curriculum Vitae 227 List of Publications 231 Portfolio Summary 235 Publications and manuscripts based on the studies described in this thesis Chapter 02 Schuur M, Henneman P, van Swieten JC , M.C. Zillikens, de Koning I, Janssens ACJW, Witteman JCM, Aulchenko YS, Frants RR, Oostra BA, Willems van Dijk K, van Duijn CM. Insulin-resistance and the metabolic syndrome are related to executive function in women in a large family-based study. European Journal of Epidemiology, In press Chapter 03 ILiu F, Pardo LM, Schuur M, Sanchez-Juan P, Isaacs A, Sleegers K, de Koning I, Zorkoltseva IV, Axenovich TI, Witteman JC, Janssens AC, van Swieten JC, Aulchenko YS, Oostra BA, van Duijn CM The apolipoprotein E gene and its age-specific effects on cognitive function. Neurobiol Aging Epub 2008 Nov 10 Chapter 04 Schuur M, Amin N, Ikram MA, Hommel D, Janssens ACJW, Zorkoltseva IV, Kirichenko A, de Koning I, Axenovich TI, Hofman A, Aulchenko YS, Breteler MMB, Oostra BA, van Swieten JC, van Duijn CM. Genome-wide linkage screen of cognitive function identifies susceptible chromosomal regions. Submitted Chapter 05 Schuur M, Bressler J, Debette S, Fitzpatrick A, Vernon Smith A, Petrovic K, Bish J, Li G, Qiong Yang, Ikram MA, de Koning I, van Swieten JC, Oostra BA, Hofman A, Schmidt R, Seshadri S, Lenore Launer, Breteler MMB, van Duijn CM, Mosley T. Genome-wide association study of cognitive executive functions: Meta-analysis of the CHARGE consortium. In preparation Chapter 06 Schuur M, Ikram MA, van Swieten JC, Isaacs A, Vergeer-Drop JM, Hofman A, Oostra BA, Breteler MMB, van Duijn CM. Cathepsin D gene and the risk of Alzheimer’s disease: A population-based study and meta-analysis. Neurobiol Aging Epub 2009 Nov 17 Chapter 07 Lehmann DJ, Schuur M, Warden DR, Hammond N, Belbin O, Kölsch H, Lehmann MG, Wilcock GK, Brown K, Kehoe PG, Morris CM, Barker R, Coto E, Alvarez V, Deloukas P, Mateo I, Gwilliam R, Combarros O, Arias-Vásquez A, Ikram MA, Aulchenko YS, Breteler MMB, van Duijn CM, Heun R, Cortina-Borja M, Morgan K, Robson K, Smith AD. Transferrin and HFE genes interact in Alzheimer’s disease risk: the Epistasis Project. Submitted Chapter 08 Schuur M, van Swieten JC, Schol-Gelok S, Ikram MA, Vernooij MW, Liu F, Isaacs A, de Boer R, de Koning I, Niessen WJ, Vrooman H, Oostra BA, van der Lugt A, Breteler MMB, van Duijn CM. Genetic risk factors for cerebral small vessel disease in hypertensive patients from a genetically isolated population. Journal of Neurology, Neurosurgery and Psychiatry, In Press Chapter 09 Schuur M, van der Lijn F, Heijer T, Verbeek M, Aulchenko YS, Vrooman HA, Niessen W, Oostra BA, Breteler MMB, van Duijn CM, van der Lugt A, van Swieten JC. The relation of the sortilin-related receptor gene to hippocampal volume and plasma amyloid beta levels in a family-based study of hypertensive patients. Submitted Chapter 10 Schuur M, Amin N, Coppus T, Breteler MMB, Oostra BA, van Swieten JC, Janssens ACJW, Verbeek M, van Duijn CM. Polymorphisms of the renin-angiotensin system and alfa-adducin in associate to circulating amyloid beta levels. Submitted Chapter 12 Schuur M, Broer L, van Duijn CM, Janssens ACJW. Grading the credibility of genetic associations in Alzheimer’s disease using the Venice criteria: practical considerations following from the Alzgene database. Submitted Part I Introduction 11 01 General introduction, outline, and scope of the thesis 13 The brain is by far the most complicated structure of the human being, and its malfunction is characterized by various degrees and types of morbidity. Several brain functions deteriorate with increasing age during life. Cognitive decline and age-related brain pathology are common in the elderly, but these changes may also become manifest early in life and preceding the onset of clinical symptoms of disease. The detection of early changes may be relevant for therapeutic interventions to prevent disease, and are therefore also increasingly targeted in genetic research as endophenotypes. Endophenotypes are defined as heritable phenotypes that are related to the disease of interest, and are typically approached as quantitative outcomes, i.e., instead of hypertension, the endophenotype of interest is systolic or diastolic blood pressure. In contrast to classical risk factors in epidemiology, an endophenotype is by definition not uniquely associated to a single disease. Blood pressure for example, is consistently associated to various clinically relevant outcomes such as stroke, myocardial infarction and heart failure. There is an increasing interest in the genetic research of endophenotypes, and genome-wide association studies of endophenotypes have been very successful [1,2]. In this thesis I focus on cognitive function and age-related brain changes early in life as endophenotypes for late-life brain disease and as targets for early prevention. Cognitive deterioration can be seen in pre-clinical stages of neurodegenerative and neuropsychiatric disorders like dementia, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder (ADHD) [3-5]. Cognitive function is a broad concept referring to multiple cognitive domains, among which memory, language, executive function and visuospatial ability. Although the domains are highly correlated, it is known that specific domains are related to specific diseases. Cognitive function is in part determined by our genetic make-up. The heritability is estimated to around 40% [6] and there have been various studies that have tried to identify genes explaining the heritability of cognitive functions. These included candidate gene studies [7,8], linkage studies [9-13] and genome-wide association studies [14-17]. The genes and chromosomal regions that have been found so far are partly explained by genes related to neuropsychiatric disease, and partly by genes related to dementia and Alzheimer’s disease (AD) with the Apolipoprotein E gene as genetic factor with one of the strongest effects. In the studies presented here, we will focus on a cognitive test battery targeting AD [18]. Dementia is one of the most common causes of morbidity and mortality in the Western society (prevalence of 25 million cases worldwide), in which Alzheimer disease accounts for over 70% of cases [19,20]. Regarding the high prevalence and major impact of these diseases, early diagnosis and treatment strategies have a high priority in neuroscience. Identifying risk factors for cognitive decline would benefit our increasingly elderly population. At postmortem, AD is characterized by neurofibrillary tangles and amyloid plaques [21]. The major components of the amyloid plaques are amyloid beta (Aβ) proteins, which are formed after 14 01 General Introduction, outline and scope of the thesis proteolytic processing of the amyloid precursor protein (APP). Aβ pathology is also found in brains of cognitively healthy elderly who may develop the disease later. Aβ levels can be measured in plasma probably due to leakage through the blood brain barrier.
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