Genetic Basis of Reading Disabilities
Cathy L. Barr, Ph.D., Toronto Western Research Institute/Neurosciences & Mental Health Program, The Hospital for Sick Children and Adrienne Elbert, M.Sc., Toronto Western Research Institute
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Developmental dyslexia, also known as Reading Disabilities (RD), are defined as specific difficulties in reading, despite possession of normal intelligence and access to effective classroom instruction. RD is a complex disorder resulting from a combination of genetic and environmental factors and is estimated to affect 5-12% of school-aged children (Gabel, Gibson, Gruen, & LoTurco, 2010). RD tends to persist across the life span, resulting in significant academic, social, and occupational impairments (Katusic et al., 2001; Shaywitz, Shaywitz, Fletcher & Escobar, 1990; Willis, Kabler-Babbitt, & Zuckerman, 2007). The following section will review the genetic basis of RD, including recent findings and the hypothesized mechanisms by which genetic changes may alter brain structure and function.
Key Research Questions
Currently the main question for our field is what are the gene variations that contribute to reading ability and reading failure?
We have known for many years that RD tends to run in families. Studies comparing identical and fraternal twins have shown that there is a substantial genetic component contributing to reading ability. Multiple genes are thought to be risk factors that contribute to the development of RD. Linkage studies have identified at least 11 chromosomal regions linked to RD or reading skills. These findings indicate the regions of the chromosomes where genes that contribute to risk factors are located. Recent genetic studies have begun to pinpoint the genes within these locations, and the specific genetic variants, that contribute to increasing the risk for RD.
How do some of these genes contribute to both reading disabilities and inattention?
Twin studies support common genetic factors contributing to both RD and Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms, particularly inattention symptoms. How this occurs is unknown.
What is the mechanism by which genetic changes influence reading ability?
RD is a heterogeneous disorder, which means that different etiological factors (i.e., risk factors contributing to the cause of a disorder) may exist in different individuals with similar reading difficulties. Interestingly, many of the genes identified thus far in RD susceptibility are implicated in neuronal migration. Neuronal migration is the process by which a neuron, one of the types of cells found in the brain, migrates and relocates to the appropriate region of the cortex during the development of the brain in the embryo. Therefore, one proposed genetic mechanism for RD is that changes in the function of the genes influence the migration patterns of the cells of the brain.
And finally, how does specific reading training overcome the influence of genetic risks to result in reading acquisition?
Once the genes contributing to RD are identified, we may start to gain an understanding of the networks involved in reading failure that can be targeted for specific reading interventions.
Evidence for the genetic basis of RD from twin studies
Heritability is an estimate of the genetic contribution to the variation of a trait across a group or population. Each individual within that population may have different contributions from genetic and environmental risks. To obtain an estimate of heritability for RD, the co-occurrence of a trait, such as reading difficulty, is compared between monozygotic (identical) and dizygotic (fraternal) twins. Identical twins share virtually all of the same genes, whereas fraternal twins share approximately half of their genes, just as siblings do. The heritability estimates of reading difficulties range from 30-72% (DeFries & Gillis, 1993; Harlaar, Spiath, Dale, & Plomin, 2005; Hawke, Wadsworth, & DeFries, 2006; Wadsworth, Olson, Pennington, & DeFries, 2000; Wadsworth, DeFries, Olson, & Willcutt, 2007). This means that for a given population, approximately 30-72% of the variation in reading difficulties is due to genetic differences. Twin studies also indicate that the genes that contribute to reading impairment also contribute to the normal distribution of reading ability in the population (Harlaar et al., 2005).
Molecular genetic findings
Genetic studies of reading ability have found evidence for linkage to at least 11 chromosomal regions: 1p34-p36, 2p11, 2p15-16, 3p12-q13, 6p21.3-22, 6q11.2-q12, 7q32, 11p15.5, 15q, 18p11.2 and Xq27 (Barr & Couto, 2008; Paracchini, Scerri, & Monaco, 2007).
Scientists have begun to identify risk genes in the linked chromosomal regions above. The candidate genes for RD include Doublecortin domain-containing protein 2 (DCDC2) and KIAA0319 on chromosome 6p (Menget al., 2005; Paracchiniet al., 2006), Dyslexia susceptibility 1 candidate gene 1 protein (DYX1C1/EKN1) and protogenin (PRTG) on chromosome 15q (Taipaleet al., 2003; Wigget al., 2004), roundabout homolog 1 (ROBO1) on chromosome 3 (Hannula-Jouppiet al., 2005), and KIAA0319-Like (KIAA0319L) on chromosome 1p (Coutoet al., 2008). At the present time, it is still not clear if these are the risk genes and further studies are needed.
Genetic relationship of RD and ADHD
Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neuropsychiatric disorder diagnosed in childhood and occurs in 2-18% of the population (Rowland, Lesesne, & Abramowitz, 2002). ADHD and RD co-occur more often than expected by chance. RD occurs in an estimated 20-40% of children who display ADHD symptoms (August & Garfinkel, 1990; Del'Homme, Kim, Loo, Yang, & Smalley, 2007; Dykman & Ackerman, 1991). As for children with RD, 15-26% also have ADHD (Gilger, Pennington, & DeFries, 1992).
The causal relationship of this overlap has been the subject of some debate, with the literature previously dominated by two ideas: 1) learning difficulties are secondary to problems of attention and 2) ADHD is the consequence of learning difficulties (McGee & Share, 1988). Only recently have genetic studies provided support for common neurobiological origins (Greven, Harlaar, Dale, & Plomin, 2011; Willcutt, Pennington, & DeFries, 2000; Willcutt, Pennington, Olson, & DeFries, 2007). Twin and linkage studies support the genetic overlap between ADHD and reading, particularly for the inattentive symptoms (Greven et al., 2011; Willcutt et al., 2000). These findings suggest that there are some shared genes for ADHD and RD.Interestingly, variations in PRTG and DCDC2 (RD candidate risk genes mentioned above) have been associated with risk for ADHD (Coutoet al., 2009; Wigget al., 2008).
Neuronal migration deficits as a contributing mechanism to RD
There are many theories about the causes of RD. One theorized biological cause of RD is atypical neuronal migration within specific brain regions during brain development. During brain development, the neurons are born deep within the brain and then crawl along specific pathways to their correct location. Anything that disrupts this process will influence the final placement of the neurons in the brain and possibly their connections to other neurons.
The autopsy examination of four brains from individuals with RD revealed ectopias and dysplasias in the cortex, which are subtle cortical neuronal abnormalities (Galaburda, Sherman, Rosen, Aboitiz, & Geschwind, 1985; Humphreys, Kaufmann, & Galaburda, 1990). Ectopias refer to cells that are in an inappropriate cortical layer. In all four brains examined, there were groups of neurons in layer I of the cortex, where there are normally no neurons in adults (Shipp, 2007). These abnormalities tended to affect the left cortex more severely. The ectopias were often adjacent to dysplasias, which refer to distortions of the normally developed organization of cells. Both ectopias and dysplasias can be caused when early neuronal cells fail to migrate to their predetermined cortical position during development.
Neuronal migration abnormalities can help explain some of the theories, which were based on observation and study of individuals with RD. For instance, the cerebellar theory of RD suggests that dysfunction of the cerebellum (a part of the brain involved in sensory integration, motor control and coordination) leads to problems with automatization of the reading process. It is thought that this dysfunction can originate from abnormal neuronal connections due to migration abnormalities (Nicolson & Fawcett, 1990). The phonological deficit theory, where the deficit lies in the storage and retrieval of phonemes, can also be explained in a similar fashion. A neuronal migration disorder called Periventricular Nodular Heterotopia provides more evidence for the role of neuronal migration abnormalities in RD. Eight out of ten individuals with this disorder displayed reading impairment despite normal intelligence (Changet al., 2005).
The identification of RD genes is still in progress and many genes are yet to be identified. In the genes identified thus far, we have not yet determined the specific DNA changes that alter gene function contributing to risk for RD. This crucial piece of information is necessary to understand how the genes are working differently in the brain. As we continue to identify risk genes, networks of genes that influence brain development and connectivity may become evident, allowing for specific hypotheses of the relationship of genetic predisposition to reading failure.
The identification of genes that play a role in increasing risks for RD will provide new insight into the neurobiological risk for difficulties in reading with the possibility of providing a biological framework for intervention. For example, there is substantial controversy concerning the role of deficits in temporal-auditory processing of speech sounds and complex non-speech sounds in RD (Ramus, 2006; Schulte-Korne, Deimel, Bartling, & Remschmidt, 1999), as well as the efficacy of specific training for temporal sound processing (Kujalaet al., 2001; Strehlowet al., 2006; Tallalet al., 1996). Current estimates suggest that possibly one third of individuals with RD may have this deficit; however, it is not clear if these deficits are the source of the phonological deficits (Paul, Bott, Heim, Wienbruch, & Elbert, 2006; Ramus, 2006). The studies of RD risk gene DXY1C1 in rats indicate deficits in discriminating complex auditory stimuli (Threlkeldet al., 2007). Thus, the genetic findings reopen the relationship of auditory processing as a primary deficit in a subset of children with particular genetic risks. Tailored interventions may be more effective in children with these risks.
One difficulty in genetic studies is disassociating genetic and environmental risks because they are often correlated. For instance, print exposure (reading and being read to) is one of the most important influences on early reading ability. A child who has difficulty reading will be less likely to read for pleasure, thus exacerbating their reading problems. Further, because RD is familial, family members may also have difficulty reading and may be less likely to read to the child or have reading materials in the home. These types of genetic and environmental interactions are difficult to separate, and point to the need to study the interrelationship of multiple risk factors.
Over the past few years, studies to identify genes contributing to RD have progressed rapidly. A number of candidates have been identified, most of which are involved in neuronal migration. While this work is promising, it is important to note that the genes require more study before they can be confirmed as risk genes. The risk variants in these genes identified thus far are common in the population, and many individuals without reading impairment carry these variants. Thus, they cannot be used for diagnostic purposes. Also, the scientific community is not in agreement about which variants confer risk as different groups’ data support different variants. Genetic studies rely on association with DNA markers that point to the location of the risk variant but can provide different associations in different populations. As studies continue and the DNA changes that alter the function of the genes are identified, association findings between studies will become consistent. Given the current discrepant findings, it is concerning that some personal genome companies are reporting to their clients some of the associated variants as RD risk variants. Clearly further studies are required to identify risk variants and resolve the inconsistent findings between studies before they should be used to indicate someone is at risk.
Identifying genetic risks and determining their contribution to the RD may explain the heterogeneity seen in cognitive deficits in individuals with RD. With the understanding of how genetic variation influences reading component skills and related processes, more specific remediation may be tailored for a child’s specific deficits (Eden & Moats, 2002). Such early intervention would be in keeping with a preventative approach to RD that has the potential to significantly reduce the morbidity, both academic and social-emotional, associated with reading failure.
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