Understanding “the whirling ball of comorbidity”: Reading Disability and ADHD Erik Willcutt, Ph.D. University of Colorad

1. Understanding “the whirling ball of comorbidity”: Reading Disability and ADHD Erik Willcutt, Ph.D. University of Colorado, Boulder

3. Anxious “That’s it! Just me, alone at home, trying to be a good parent for my little whirling ball of comorbidity” Too active Aggressive Learning Comorbidity

4. Questions we will answer today

5. Why should we care about comorbidity?

6. Comorbidity is the rule, not the exception

7. Comorbidity is associated with greater initial impairment and more extensive and severe negative outcomes RD RD+ADHD Control ADHD

8. Comorbidity has important implications for treatment RD  ADHD ADHD  RD Shared risk factor  RD + ADHD

9. Our ongoing studies most relevant to comorbiditybetween RD and ADHD • Colorado Learning Disabilities Research Center (Director: Olson) • 8 - 18 year old twins screened through schools • RD only (N = 400), ADHD only (N = 275), RD + ADHD (N = 125) • Comparison group without RD or ADHD (N = 1,000) • extensive initial testing and five-year follow-up assessment • International Twin Study of Early Reading Development(PI: Olson) • unselected sample of approximately 2,000 twins in US, Australia, Scand. • Tested yearly from preschool until 4th grade • Validity of ADHD in adults(PI: Willcutt, Banich) • screening: 4,000 undergraduates • individual testing: 200 students with ADHD, 100 without ADHD

10. Defining RD and ADHD • Reading Disability • unexpected difficulty learning to read. • not explained by environmental deprivation, inadequate education, or low cognitive ability. • 1.5 SD below the estimated population mean on a test of single-word decoding (PIAT or WJ-III). • ADHD • inattentive and / or hyperactivity-impulsive behaviors that are inconsistent with an individual’s developmental level. • Parent interview (DICA-IV) and teacher ratings (DSM-IV) • Similar results for DSM-IV subtypes, so pooled for this presentation.

11. What causes comorbidity?more than 25 different explanations have been proposed(at last count)

12. Competing Explanations for Comorbidity(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995) Clinical Sample Bias: Comorbidity is only present in clinical samples.

13. Comorbidity is present in our community samples 8% 5% 3%

14. Artifactual Hypothesis Clinical Sample Bias Results Not supported Tests of the Competing Hypotheses

15. Competing Explanations for Comorbidity(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995) Clinical Sample Bias: Comorbidity is only present in clinical samples. Method bias: Comorbidity occurs because both disorders are assessed with the same measure.

16. Artifactual Hypothesis Clinical Sample Bias Method Bias Results Not supported Not supported Tests of the Competing Hypotheses

17. Competing Explanations for Comorbidity(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995) Artifactual Hypotheses Clinical Sample Bias: Comorbidity is only present in clinical samples. Method bias: Comorbidity occurs because both disorders are assessed with the same measure. Rater bias: raters are more likely to endorse symptoms of a second disorder if the child has the first disorder. Secondary symptom (phenocopy) hypothesis: Disorder #1 causes an individual to exhibit the symptoms of disorder #2 when they do not actually have the disorder.

18. Attention Problems in Individuals With and Without RD(Willcutt, Chhabildas, & Pennington, 1998; Willcutt et al., under review) 8 - 18 year old twins Undergraduates

19. Artifactual Hypothesis Clinical Sample Bias Method Bias Rater Bias Secondary Symptom Results Not supported Not supported Not supported Not supported Tests of the Competing Hypotheses

20. Competing Explanations for Comorbidity(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995) Clinical Sample Bias: Comorbidity is only present in clinical samples. Method bias: Comorbidity occurs only because both disorders are assessed with the same measure. Rater bias: raters are more likely to endorse symptoms of a second disorder if the child has the first disorder. Secondary symptom (phenocopy) hypothesis: Disorder #1 causes an individual to exhibit the symptoms of disorder #2 when they do not actually have the disorder. Causal Hypothesis: Disorder #1 directly causes disorder #2.

21. A plausible causal model Poor attention to instruction Weak phonological development RD ADHD

22. Artifactual Hypothesis Clinical Sample Bias Method Bias Rater Bias Secondary Symptom “True Comorbidity” Models Causal Hypothesis Result Not supported Not supported Not supported Not supported More work is needed Tests of the Competing Hypotheses

23. Competing Explanations for Comorbidity(e.g., Caron & Rutter, 1991; Neale & Kendler, 1995) Clinical Sample Bias: Comorbidity is only present in clinical samples. Method bias: Comorbidity occurs only because both disorders are assessed with the same measure. Rater bias: raters are more likely to endorse symptoms of a second disorder if the child has the first disorder. Secondary symptom (phenocopy) hypothesis: Disorder #1 causes an individual to exhibit the symptoms of disorder #2 when they do not actually have the disorder. Causal Hypothesis: Disorder #1 directly causes disorder #2. Common Etiology Hypothesis: The two disorders co-occur due to shared risk factors.

24. Causes of RD and ADHD • Family studies • RD and ADHD are each significantly familial (e.g., Wadsworth et al., 2000; Willcutt et al., 2000) • RD and ADHD run in the same families (Friedman et al., 2003)

25. Causes of RD and ADHD • Family studies • RD and ADHD are each significantly familial (e.g., Wadsworth et al., 2000; Willcutt et al., 2000) • RD and ADHD run in the same families (Friedman et al., 2003) • Twin Studies: disentangle three causes of individual differences in reading or ADHD • Heritability: genetic influences • Shared environment: environmental factors that affect both twins in a similar way. • Nonshared environment: environmental factors that are specific to the child with the disorder.

26. Twin studies of individual differences in ADHD symptoms (N > 15,000 twin pairs)

27. Twin studies of individual differences in reading

28. Comorbidity of RD and ADHD is explained by shared genes(Trszenlewski et al., 2006; Willcutt et al., 2000, 2003, in press a and b) Shared Genes Genetic and environmental risk factors specific to RD Genetic and environmental risk factors specific to ADHD RD ADHD

29. Causes of RD and ADHD • Family studies • RD and ADHD are each significantly familial (e.g., Wadsworth et al., 2000; Willcutt et al., 2000) • RD and ADHD run in the same families (Friedman et al., 2003) • Twin Studies • ADHD: highly heritable, minimal shared environment • RD: highly heritable + shared environment • The association between reading deficits and inattention is due primarily to common genetic influences (e.g., Willcutt et al., 2007) • other genetic and environmental influences are unique to each disorder (Willcutt et al., 2007a, 2007b)

30. Artifactual Hypothesis Clinical Sample Bias Method Bias Rater Bias Secondary Symptom “True Comorbidity” Models Causal Hypothesis Common Etiology Result Not supported Not supported Not supported Not supported More work is needed Supported: Shared genetic risk factors Tests of the Competing Hypotheses

31. Sounds good, but one final detail... Where are these shared genes and what do they do?

32. The “old school” model: One Gene, One Deficit, One Disorder G2 G1 G3 G4 Cog 2 Cog 1 Cog 3 Cog 4 RD ADHD Autism Schiz.

33. A Subset of the Genes Associated with ADHD • Dopamine genes • Dopamine transporter • Dopamine D2, D3, D4, D5 receptors • Dopamine-beta-hydroxylase • Serotonin genes • Serotonin Transporter • Serotonin receptor 1A, 2B • Other neurotransmitters • Monoamine oxidase A (Jiang et al., 2000) • Genes whose exact location and function is still unknown • Chromosomes 2, 3, 4, 5, 11, 15, 16, 17 (send me an email if you would like the full list)

34. Causes of RD and ADHD • Family studies • RD and ADHD are each significantly familial (e.g., Wadsworth et al., 2000; Willcutt et al., 2000) • RD and ADHD run in the same families (Friedman et al., 2003) • Twin Studies • ADHD: highly heritable, minimal shared environment • RD: highly heritable + shared environment • The association between reading deficits and inattention is due primarily to common genetic influences (e.g., Willcutt et al., 2007) • other genetic and environmental influences are unique to each disorder (Willcutt et al., 2007a, 2007b) • Molecular genetics • RD and ADHD are each influenced by multiple genetic and environmental risk factors • Each of these risk factors accounts for a small amount of the variance in reading and/or ADHD symptoms

35. A simplified hypothetical model of the genetic and environmental etiology of RD and ADHD (see Shanahan et al., 2006; Willcutt et al., 2005b) RD ADHD

36. A large pool of genetic and environmental risk factors influence RD and ADHD G E E G G G G G E G E G ... RD ADHD

37. Shared genetic influences increase risk for both disorders, sometimes leading to comorbidity G G G G RD ADHD

38. Additional genetic and environmental risk factors are specific to RD or specific to ADHD G E E G G G G G E G E G RD ADHD

39. How do these causal factors influence brain functioning?

40. What cognitive weaknesses are intermediate between the genes and the behavioral symptoms? (see Shanahan et al., 2006; Willcutt et al., 2005b) G G E G G G G G E G E E Cognitive Deficit 1 Cognitive Deficit 2 Cognitive Deficit 3 Cognitive Deficit 4 RD ADHD

41. Four Key Cognitive Processes Phonological processing: recognize and manipulate the phonemic constituents in speech. - say “plig” without the “l”

42. Four Key Cognitive Processes Phonological processing: recognize and manipulate the phonemic constituents in speech. - say “plig” without the “l” Working memory: retain information in short-term memory and manipulate that information. - repeat a series of digits in reverse order.

43. Four Key Cognitive Processes Phonological processing: recognize and manipulate the phonemic constituents in speech. - say “plig” without the “l” Working memory: retain information in short-term memory and manipulate that information. - repeat a series of digits in reverse order. Response inhibition: suppress a response when it is not correct / appropriate.

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