Anney, R. J. L., Lasky-Su, J., O'Dushlaine, C., Kenny, E., Neale, B. M., Mulligan, A., Franke, B., Zhou, K., Chen, W., Christiansen, H., Arias-Vasquez, A., Banaschewski, T., Buitelaar, J. K., Ebstein, R. P., Miranda, A., Mulas, F., Oades, R. D., Roeyers, H., Rothenberger, A., Sergeant, J. A., Sonuga-Barke, E. J. S., Steinhausen, H-C., Asherson, P., Faraone, S. V.,& Gill, M.P., Conduct Disorder and ADHD: Evaluation of Conduct Problems as a Categorical and Quantitative Trait in the International Multicentre ADHD Genetics Study. (2008) American Journal of Medical Genetics, part B, 147B, 1369-1378, at DOI 10.1002/ajmg.b.30871 (Request a copy) - View Article

Introduction: Attention deficit hyperactivity disorder (ADHD) is characterized by inattention, excessive motor activity, impulsivity, & distractibility. Those with ADHD have significant impairment in family and peer relations, academic functioning and show high co-morbidity with a wide range of psychiatric disorders including oppositional defiant disorder (ODD), conduct disorder (CD), anxiety disorder, depression, substance abuse and pervasive developmental disorder (PDD). -- Family studies suggest that ADHD+CD represents a specific subtype of the ADHD disorder with familial risk factors only partly overlapping with those of ADHD alone. .

Methods: We performed a hypothesis-free analysis of the GAIN-ADHD sample to identify markers and genes important in the development of conduct problems in a European cohort of individuals with ADHD. Using the Family-Based Association Test (FBAT) package we examined three measures of conduct problems in 1,043,963 autosomal markers.

1 - This study is part of a series of exploratory analyses to identify candidate genes that may be important in ADHD and ADHD-related traits, such as conduct problems.

2 - We did not find genome-wide statistical significance (p < 5x10-7) for any of the tested markers and the 3 conduct problem traits.

3 - 54 markers reached strong GWA signals (p < 10-5).

(Across all three phenotypes there were 28 unique modest genome-wide association signals at p = 1x10-5. Following LDE this number increased to 54 markers).

Discussion: We discuss these findings in the context of putative candidate genes and the implications of these findings in the understanding the etiology of ADHD+CD. We aimed to achieve insight into the genetic etiology of a trait using a hypothesis-free study-design and were able to identify a number of biologically interesting markers and genes for follow-up-studies.

Additional background notes

:a) A complete list of serotonin (5-HT)-related genes in this analysis consists of AANAT, ALDH2, AOX1, DDC, HTR1A, HTR1B, HTR1D, HTR1E, HTR1F, HTR2A, HTR2B, HTR3A, HTR3B, HTR4, HTR5A, HTR6, HTR7, INDOL1, INMT, SLC6A4, TPH1 & TPH2. But, ATP7A, ASMT, MAOA, MAOB and HTR2C could not be examined due to their presence on the X-chromosome. None of the genes tagged as "5-HT-related" achieved association signals at p = 1x10-5. But a marker on chromosome 13 in the HT2A Receptor (HTR2A), RS6314 showed the strongest association (RS6314, Categorical Diagnosis of Conduct Problems (Dominant Inheritance) p=.00087).

b) The top 5 association signals were found on chromosomes 13, 21, 11, 4 and 12 - but only that on 12 was within a gene (the PAWR gene a leucine-zipper containing protein that regulates dopamine D2 signal transduction and competes with calmodulin) - the association here was with dominant inheritance of categorical CD (cf. there are hints of association with schizophrenia and Alzheimer's disorder - so a general relationship to mental disorders is conceivable.

c) Genes that are on the periphery of the "psychiatric candidate gene"-literature include YHWAZ (tyrosine 3-monooxygenase/ tryptophan 5-monooxygenase activation protein, zeta polypeptide). This is c.10 kb downstream of RS931812 (Categorical Diagnosis of Conduct Problems [Dominant Inheritance] p=.0000047). The YHWAZ gene product is a binding partner for DA and 5-HT rate-limiting enzymes, TH (tyrosine 3-monoxygenase) and TPH1/TPH2 (tryptophan 3-monooxygenase), again making it a strong candidate gene for disorders associated with DA and 5-HT dysregulation.