Evaluating the External Validity of DSM-IV ADHD Subtypes and an Alternative Diagnostic Subtyping System Public

Abstract

Heterogeneity within the attention-deficit/hyperactivity disorder (ADHD) diagnosis likely accounts for some inconsistent findings in molecular genetic studies of ADHD. The present dissertation evaluated whether an alternative comorbid ADHD phenotype increases the external validity over and above the extant DSM-IV diagnostic subtypes by identifying more homogeneous conditions genetically and with regard to sex, age, and overlapping disorders. The sample included 372 children (ages 5 - 18) who were recruited as part of an ongoing study on the genetics of ADHD. Probands, their siblings, and parents were genotyped for a variable number of tandem repeats (VNTR) in exon 3 of the dopamine D4 receptor gene (DRD4) and an insertion / deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR). Planned comparisons revealed that the Combined subtype is characterized by a higher proportion of males, lower mean age, and higher symptom levels of oppositional defiant and conduct disorders, depression, and anxiety disorders compared with the Inattentive or Hyperactive-Impulsive subtypes. Genetic association analyses suggested that the DRD4 7-repeat allele is more strongly related to the Combined and Inattentive subtypes than the Hyperactive-Impulsive subtype, whereas the 5-HTTLPR long allele is more strongly related to the Inattentive subtype compared with the other two subtypes. Furthermore, there was evidence suggesting that co-occurring symptoms of conduct disorder (CD) moderated the ADHD-DRD4 relation, such that the association between ADHD and DRD4 was stronger in children with both ADHD and elevated CD symptoms. There was also evidence of a moderating influence of co-occurring symptoms of anxiety, whereby the association between ADHD and 5-HTTLPR was stronger in children with higher levels of anxiety. In contrast, there was no significant evidence of association between the overall ADHD diagnosis and the DRD4 7-repeat allele or the 5-HTTLPR long allele. These findings suggest that when testing a phenotypically heterogeneous condition such as ADHD, undertaking subgroup analyses (i.e., examining either diagnostic subtypes or comorbid subgroups of ADHD) or incorporating continuous measures of overlapping psychopathology as moderators can be a useful strategy for enhancing external validity and our ability to detect genetic associations that might be otherwise obscured.

Table of Contents

General Introduction...................................................................................................................... 1

Paper 1: Evaluating the External Validity and Distinctiveness of DSM-IV

Attention-Deficit/Hyperactivity Disorder Subtypes.................................................................... 14

Abstract............................................................................................................................................ 15

Introduction...................................................................................................................................... 16

Method.............................................................................................................................................. 26

Results............................................................................................................................................. 33

Discussion...................................................................................................................................... 38

References...................................................................................................................................... 46

Tables............................................................................................................................................... 59

Paper 2: Reexamining the Associations of DRD4 and 5-HTT with ADHD Using

an Alternative Comorbid ADHD Phenotype............................................................................... 64

Abstract............................................................................................................................................. 65

Introduction....................................................................................................................................... 66

Method............................................................................................................................................... 81

Results.............................................................................................................................................. 89

Discussion....................................................................................................................................... 96

References...................................................................................................................................... 107

Tables............................................................................................................................................... 123

General Discussion....................................................................................................................... 130

References........................................................................................................................................147

Appendix.............................................................................................................................................164

About this Dissertation

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School	Laney Graduate School
Department	Psychology
Subfield / Discipline	Clinical Psychology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Psychology, Clinical
Mot-clé	candidate genes ADHD phenotype refinement DSM-IV classification subtypes validity
Committee Chair / Thesis Advisor	Waldman, Irwin, Emory University
Committee Members	Walker, Elaine, Emory University Lilienfeld, Scott O, Emory University Maney, Donna, Emory University Hamann, Stephan, Emory University

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