VU Research Portal Common genetic variants underlying cognitive ability Gosso, M.F. 2008 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Gosso, M. F. (2008). Common genetic variants underlying cognitive ability. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 04. Oct. 2021 COMMON GENETIC VARIANTS UNDERLYING COGNITIVE ABILITY María Florencia Gosso Leescommissie: dr. W Crusio prof.dr. NG Martin dr. GJA Ramakers dr. S v/d Sluis prof.dr. CM van Duijn prof.dr. M Verhage This thesis was supported by the Universitair Stimulerings Fonds (grant number 96/22), the Human Frontiers of Science Program (grant number rg0154/1998-B), the Netherlands Organization for Scientific Research (NWO) grants 904-57-94 and NWO/SPI 56-464-14192, and by the Centre for Medical Systems Biology (CMSB), a center of excellence approved by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). The printing of this thesis was supported by, the Center for Neuroscience and Cognitive Research (CNCR), by the “Internationale Stichting Alzheimer Onderzoek” and by Lundbeck B.V. ISBN: 9789086591664 Printed by: PrintPartners Ipskamp Cover Design: María Florencia Gosso Layout: María Florencia Gosso Copyright® María Florencia Gosso, 2007, Amsterdam All rights reserved. No part of this publication may be reproduce, stored in a retrieval system, or transmitted in any form or by any means, without permission of the author or, when appropriate, of the scientific journal in which parts of this book have been published. VRIJE UNIVERSITEIT COMMON GENETIC VARIANTS UNDERLYING COGNITIVE ABILITY ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Psychologie en Pedagogiek op maandag 7 januari 2008 om 15.45 uur in de aula van de universiteit, De Boelelaan 1105 door María Florencia Gosso geboren te Paraná, provincie Entre Ríos, Argentinië promotoren: prof.dr. D.I. Boomsma prof.dr. P. Heutink copromotor: dr. D. Posthuma TABLE OF CONTENTS CHAPTER 1 General Introduction 1 CHAPTER 2 Association between the CHRM2 gene and intelligence 39 CHAPTER 3 Exploring the functional role of the CHRM2 gene and cognition 55 CHAPTER 4 The SNAP-25 gene: synaptic plasticity and cognitive ability 73 CHAPTER 5 The SNAP-25 gene: regulatory variants and cognition 89 CHAPTER 6 A functional polymorphism in the β2 -adrenergic receptors at an amino acid which differs between humans and chimpanzee explains phenotypic differences in intelligence 109 CHAPTER 7 COMT and DRD2 gene variants: evidence of positive heterosis and gene-gene interaction on working memory functioning 129 CHAPTER 8 Summary and Discussion 147 SAMENVATTING 167 RESUMEN 177 APPENDICES I Descriptives and QTDT association results for DBH, DRD2, DRD3, HTR2A, SERT, and TH 188 II Labwork Protocols 194 LIST OF PUBLICATIONS 197 ACKNOWLEDGEMENTS 201 CHAPTER 1 GENERAL INTRODUCTION CHAPTER 1 2 General Introduction INTRODUCTION Cognitive ability Intelligence has been one of the most studied quantitative behavioral traits for more than 100 years. Historically two main, contrasting concepts about the nature of intelligence have been formulated. The first concept, advocated by the so- called “g-theorists”, encompasses the idea of a single general factor called ‘g’, which accounts for the variance in test scores that is shared among subtests (Carrol 1993; Humphreys 1985; Jensen 1998; Spearman 1904). This general factor of intelligence (g), and the specific factors are represented by Spearman’s two-factor theory of abilities (Spearman 1904). Contrary to Spearman’s two-factor theory, Thurstone (1938) advocated his multiple factor analysis theory, from which relatively independent sub-components of intelligence, so-called Primary Mental Abilities (PMA’s), were obtained. However, intelligent behavior can not be explained by just these PMA’s, and also evidence for g was found by Thurstone. Turnstone’s final model therefore takes into account the presence of a general g factor, PMA’s, as well as test-specific factors (Thurstone 1947). Psychometric intelligence tests consist of a number of component subtests that taken together are used to infer a general IQ (intelligence quotient) score. Intelligence tests such as the Revised Amsterdam Child Intelligence Test (RAKIT, (Bleichrodt et al. 1984), the Wechsler Intelligence Scale for Children Revised (WISC-R, Dutch version, (Van Haassen et al. 1986) and the Wechsler Adult Intelligence Scale (WAIS, (Wechsler 1997)) are theoretically based on Thurstone’s factor analysis theory (Thurstone 1938) and provide an index of general IQ and primary abilities such as word fluency, verbal comprehension, spatial visualization, number facility, associative memory, reasoning, and perceptual speed. The Wechsler IQ tests have been broadly used for measuring intelligence quotient. First published in 1939 as the Wechsler-Bellevue Scale, Wechsler IQ tests have become among the most widely used tests to assess psychometric intelligence. Both the WISC and WAIS are standardized and frequently revised among different age strata and populations, making them a particularly useful psychometric tool to be used when comparing intellectual abilities among different age and population cohorts. Standardized IQ scores typically have a mean of 100 and a standard deviation of 15 IQ points. The Wechsler Adult Intelligence Scale (WAIS) and Wechsler Intelligent Scale for Children (WISC) consist of several sub-tests, each comprising a number of different items. Three main scores, namely Verbal IQ (VIQ), Performance IQ (PIQ) and Full IQ (FIQ) can be generated; as well as 3 CHAPTER 1 different IQ dimensions (verbal comprehension, perceptual organization, processing speed, working memory). Previous twin studies have established that general IQ is influenced by genetic factors at all ages. Heritability estimates increase from around 30% in preschool children to 80% in early adolescence and adulthood (Ando et al. 2001; Bartels et al. 2002; Boomsma & van Baal 1998; Bouchard & McGue 1981; Luciano et al. 2001; Petrill et al. 2004; Plomin 1999; Posthuma et al. 2001a). The stability of IQ performance during childhood is mainly driven by genetic influences. Bartels et al. (2002) and Petrill et al. (2004) showed in longitudinal designs that one common factor influenced IQ performance from early childhood to adolescence, and that the influence of this genetic factor is amplified when children grow older. If a trait is heritable, then the next step is to identify what causes this heritability. I will first provide a general introduction into how genetic variation in the human genome can lead to individual differences in trait values, and will then continue with summarizing the current efforts for identifying genetic variants for cognitive ability. How does genetic variation lead to individual trait differences: From DNA to phenotype The classical dogma of molecular biology is that RNA is transcribed from DNA and subsequently translated into proteins. DNA is made of a long sequence of smaller units strung together (nucleotides). The genetic code consists of 64 triplets of nucleotides (codons). With three exceptions, each codon encodes for one of the 20 amino acids used in the synthesis of proteins (Crick 1968). The human genome is the term used to describe the total genetic information in human cells. DNA located in the nucleus (genomic DNA – gDNA) accounts for the vast majority of the total genetic material (>99.99%); while the remaining genetic fraction is localized at the mitochondrial level (mitochondrial DNA - mDNA). The nuclear genome encompasses about 3,300 Mb (Lander et al. 2001). Genomic variation in the human genome Back in the early 1980s, functional as well as positional cloning were the only approaches available to link simple Mendelian traits to genes. Positional cloning, however, was a difficult and time-consuming approach and more systematic coverage of the human genome was required. The idea of having free access to an accurate human genome map was in its early developmental stage. 4 General Introduction The mesmerizing idea of being able to obtain a global and more systematic view of genomes was the next goal for the scientific community; not only for the purpose of identifying all human genes and their mutations responsible for causing monogenic diseases, but more importantly: investigating genomic variation underlying complex (common) traits as well as obtaining a better understanding of complex regulatory networks. With an exhaustive scientific