Research Article From: NCBI – PubLMed.gov US National Library of Medicine National Institutes of Health. Published in final edited form as: Cortex. 2010 Nov–Dec; 46(10): 1345–1361. Published online 2010 Jul 1. doi: 10.1016/j.cortex.2010.06.009
By: Willcutt EG1, Betjemann RS, McGrath LM, Chhabildas NA, Olson RK, DeFries JC, Pennington BF.
Introduction
Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are complex childhood disorders that frequently co-occur, but the etiology of this comorbidity remains unknown.
Method
Participants were 457 twin pairs from the Colorado Learning Disabilities Research Center (CLDRC) twin study, an ongoing study of the etiology of RD, ADHD, and related disorders. Phenotypic analyses compared groups with and without RD and ADHD on composite measures of six cognitive domains. Twin analyses were then used to test the etiology of the relations between the disorders and any cognitive weaknesses.
Results
Phenotypic analyses supported the hypothesis that both RD and ADHD arise from multiple cognitive deficits rather than a single primary cognitive deficit. RD was associated independently with weaknesses on measures of phoneme awareness, verbal reasoning, and working memory, whereas ADHD was independently associated with a heritable weakness in inhibitory control. RD and ADHD share a common cognitive deficit in processing speed, and twin analyses indicated that this shared weakness is primarily due to common genetic influences that increase susceptibility to both disorders.
Conclusions
Individual differences in processing speed are influenced by genes that also increase risk for RD, ADHD, and their comorbidity. These results suggest that processing speed measures may be useful for future molecular genetic studies of the etiology of comorbidity between RD and ADHD.
Keywords: ADHD, reading disability, executive functions, comorbidity, genetics
During the latter half of the twentieth century, conceptual models of complex disorders such as reading disability (RD) and attention-deficit / hyperactivity disorder (ADHD) typically implicated linear causal pathways in which a single genetic or environmental risk factor led to a single neurocognitive deficit that provided a necessary and sufficient explanation of all of the symptoms of the disorder. Models that proposed a 1:1 relation between a specific etiology, a specific neuropsychological dysfunction, and a categorical disorder worked well for conditions that were caused by a single gene, such as Huntington’s Disease and phenylketonuria (although even in these examples the etiology is far more complex than was initially understood). In contrast, an increasing literature suggests that these models do not provide a satisfactory explanation for most complex disorders.
Pennington (2006) recently summarized the arguments against single-deficit models for complex disorders. Molecular genetic risk factors first identified for RD or ADHD have replicated in some studies but not others, and the observed effect sizes of these risk factors are too small to be a single risk factor that is sufficient to account for all cases of the disorder by itself (e.g., Bates, Luciano, Castles, Coltheart, Wright, and Martin 2007; Cardon, Smith, Fulker, Kimberling, Pennington, and DeFries 1994; Cardon, Smith, Fulker, Kimberling, Pennington, and DeFries 1995; Curran et al. 2001; Fisher and DeFries 2002; McGrath, Smith, and Pennington 2006). In addition, subsequent studies also identified several other genetic and neuropsychological risk factors for each disorder (e.g., Fisher and DeFries 2002; Gizer, Ficks, and Waldman 2009; Willcutt 2008; Zhou et al. 2008), providing additional evidence against single-deficit models for RD or ADHD.
Another important criticism of single-deficit models is especially germane to the current paper. Models that propose a single cognitive dysfunction that is unique to each disorder cannot easily account for the pervasive comorbidity between different disorders. For example, although RD and ADHD each occur in approximately 5% of children in the population, 25-40% of children with either RD or ADHD also meet criteria for the other disorder (e.g., August and Garfinkel 1990; Semrud-Clikeman, Biederman, Sprich-Buckminster, Lehman, Faraone, and Norman 1992; Willcutt and Pennington 2000). Similarly, studies of dimensional measures of reading and ADHD symptoms report significant correlations that are low to moderate in magnitude (r = .2 – .5; Bauermeister et al. 2005; Nigg, Hinshaw, Carte, and Treuting 1998; Willcutt et al. 2001; Willcutt, Pennington, Olson, Chhabildas, and Hulslander 2005).
Taken together, these converging results have precipitated a major reconceptualization of theoretical models of RD, ADHD, and other complex disorders. Rather than attempting to identify a single necessary and sufficient cause that is specific to each disorder, more recent theoretical models explicitly hypothesize that complex disorders are heterogeneous conditions that arise from the additive and interactive effects of multiple genetic and environmental risk factors to lead to weaknesses in multiple cognitive domains (Pennington 2006; Sonuga-Barke, Sergeant, Nigg, and Willcutt 2008; Willcutt, Sonuga-Barke, Nigg, and Sergeant 2008). In this paper we use neuropsychological and behavior genetic methods to test multiple-deficit models of RD and ADHD, then test if a subset of cognitive weaknesses may increase susceptibility to both disorders, leading to comorbidity.
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