Investigating the Genetic Basis of Reading and Language Skills
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Investigating the genetic basis of reading and language skills Proefschrift ter verkrijging van de graad van doctor aan de Radboud Universiteit Nijmegen op gezag van de rector magnificus prof. dr. Th.L.M. Engelen, volgens besluit van het college van decanen in het openbaar te verdedigen op vrijdag 11 september 2015 om 10.30 uur precies door Alessandro Gialluisi geboren op 26 augustus 1984 te Castellana Grotte (Italië) Promotor Prof. dr. Simon E. Fisher Copromotor Dr. Clyde Francks (MPI) Manuscriptcommissie Prof. dr. Barbara Franke Prof. dr. Ben A. M. Maassen (Rijksuniversiteit Groningen) Prof. dr. Thomas Bourgeron (Université Paris Diderot et Institut Pasteur, Frankrijk) Investigating the genetic basis of reading and language skills Doctoral Thesis to obtain the degree of doctor from Radboud University Nijmegen on the authority of the Rector Magnificus prof. dr. Th.L.M. Engelen, according to the decision of the Council of Deans to be defended in public on Friday, September 11, 2015 at 10.30 hours by Alessandro Gialluisi born on August 26, 1984 in Castellana Grotte (Italy) Supervisor Prof. dr. Simon E. Fisher Co-supervisor Dr. Clyde Francks (MPI) Doctoral Thesis Committee Prof. dr. Barbara Franke Prof. dr. Ben A. M. Maassen (University of Groningen) Prof. dr. Thomas Bourgeron (Université Paris Diderot et Institut Pasteur, France) "There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved." Charles Robert Darwin, On the Origin of Species by Means of Natural Selection © 2015 Alessandro Gialluisi All rights reserved. No part of this thesis may be reproduced or printed in any form, by any electronic or mechanical means, without written permission of the author. Cover design: Mauro Giannoccaro Printed by: Ipskamp Drukkers, Enschede Contents Chapter 1: General introduction ..................................................................................................2 Chapter 2: Phenotypic analysis of reading and language traits .................................. 33 Chapter 3: Genome-wide screening for DNA variants associated with reading and language traits .................................................................................................. 62 Chapter 4: Testing associations of candidate SNPs and genes previously implicated in reading and language: the consistency issue ............... 112 Chapter 5: Investigating the effect of Copy Number Variants on reading and language traits ........................................................................................................ 153 Chapter 6: Assessing two novel candidate genes associated with reading and language in relation to cerebral cortical structure ................................. 210 Chapter 7: Summary and General discussion .................................................................. 235 Nederlandse samenvatting ............................................................................................ 251 Curriculum Vitae ................................................................................................................ 255 Research contributions ................................................................................................... 256 Acknowledgements ........................................................................................................... 259 MPI Series in Psycholinguistics.................................................................................... 260 1 Chapter 1. General introduction Chapter 1: General introduction 2 Chapter 1. General introduction General introduction Reading and language capacities represent fundamental keystones in the developmental route of a child, and impairment of these abilities can have long-lasting effects, resulting in relatively reduced educational and professional achievements and low socioeconomic status in adulthood (Bishop & Snowling, 2004; Pennington & Bishop, 2009). In this chapter I provide an overview of the most frequently studied reading and language skills along with two of the most prevalent and investigated language-related disorders, namely Reading Disability and Specific Language Impairment. A complete view of these disorders will allow us to understand more of the neuropsychology, neurobiology and genetics supporting reading and language skills, which represent the main object of investigation of the present thesis. How is reading/language performance assessed? The use of continuous traits Although the concept of reading and language performance may appear quite simple to understand, defining in an objective way how "well" an individual can read or speak is far from easy. Indeed, assessing reading and language skills not only means testing the actual capacity of a subject to read (usually represented by word reading, spelling and reading comprehension) and to speak/understand oral language (usually assessed through expressive/receptive language scores). It also means assessing various cognitive skills underlying written and oral language capacities, such as phoneme awareness and phonological short term memory (see Table 1 for a complete list and definition of these traits), which are often handicapped in subjects with poor reading/language performance and represent part of their core cognitive deficits. Several psychometric tests, each measuring a specific reading-/language-related trait, have been developed for this purpose. These continuous traits tap into diverse cognitive domains underlying reading and language, generally show strong intercorrelations -underpinned by common environmental and genetic influences (Harlaar et al., 2008; Logan et al., 2011)- and tend to have a normal distribution in the general population (Figure 1). In this view, Reading Disability (RD, also known as developmental dyslexia) and Specific Language Impairment (SLI, sometimes referred to as Language Impairment, LI) represent the lower tails of these distributions, and can therefore help us to understand more of the neuropsychological, neurobiological and genetic basis of reading and language (reviewed below). 3 Chapter 1. General introduction Trait Description (ability assessed) Word Readinga Reading real words Word Spellinga Spelling real words Reading Comprehensiona Ability to read text, process it and understand its meaning Ability to convert letter strings into sounds, Phonological Decoding according to given phonetic rules Phoneme Awareness Ability to recognize and manipulate speech sounds (phonemes) Ability to recognize a word as an orthographic unit and to retrieve the Orthographic Coding corresponding phonological form Ability to rapidly produce verbal labels for visual stimuli Rapid Automatized Naming (colors, numbers, letters, pictures) Ability to automatically and fluently perform Processing Speed relatively easy or over-learned cognitive tasks Ability to repeat nonsense words orally presented Nonword repetitionb (phonological short term memory) Expressive Languageb Sentence recalling and production (expressive domain of language) Receptive Languageb Listening and auditory comprehension (receptive domain of language) Table 1. Cognitive traits routinely used to assess reading and language performance. a Commonly used to diagnose RD. b Commonly used to diagnose SLI. Reading Disability (RD) and Specific Language Impairment (SLI): a brief overview Definition and Diagnosis RD is defined as a difficulty/delay in the acquisition of written language ability that cannot be explained by obvious causes, such as low IQ, sensory impairments or lack of educational opportunity; while SLI is defined as an unexpected difficulty/delay in acquiring oral language abilities, despite normal hearing and intelligence, and in the absence of overt neurological deficits or other syndromes (American Psychiatric Association, 2013). These disorders are usually diagnosed when a subject shows typical reading or language scores at least 1.5 standard deviations (SDs) below the normative mean of the general population, matched for age and IQ (Peterson and Pennington, 2012; Reader et al., 2014). Nonetheless, this cutoff threshold is somewhat arbitrary (Pennington & Bishop, 2009; Peterson and Pennington, 2012; Raskind et al., 2013) and may vary across studies, usually ranging between -2.0 and -1.0 SDs (Bishop & Snowling, 2004; Newbury et al., 2014; Newbury et al., 2010; Willcutt et al., 2005; Willcutt et al., 2010). This partly explains the variation in the epidemiological estimates of these disorders (see paragraph below and Table 2). Traits routinely assessed to diagnose RD include word reading, spelling and reading 4 Chapter 1. General introduction comprehension, while expressive and receptive language and nonword repetition are commonly tested to diagnose SLI. Another matter of debate in RD and SLI definition is the role of general cognitive abilities in reading and language capacities. The diagnosis of RD and SLI has been customarily based on the discrepancy between poor reading/language performance and normal general intelligence, and low IQ was unanimously considered an exclusion criterion for the diagnosis of these disorders (Bishop & Snowling, 2004; Pennington & Bishop, 2009). More recently this approach has been criticized, as poor readers/speakers with normal nonverbal IQ often show the same underlying deficits