Single Gene Studies of ADHD

Alan Zametkin, Monique Ernst, and Robert Cohen

Introduction

Over the past 25 years, it has become apparent that neuropsychiatric syndromes as diverse as Huntington’s disease, Fragile-X syndrome, and Lesch Nyhan disorder, are caused by single genes. On the other hand, to date no single gene has been identified for complex behavioural conditions such as schizophrenia, bipolar illness, Tourette syndrome or Attention Deficit Hyperactivity Disorder (ADHD), despite concerted efforts by international research programmes.

This chapter presents an overview of the strategies for single gene studies of ADHD. We then review proposed modes of inheritance for the disorder, and describe current knowledge of the association between several diseases that present with attentional difficulties, and are caused by single gene abnormalities. These disorders are Generalised Resistance to Thyroid Hormone (GRTH), and Fragile-X syndrome. Finally, we will discuss the potential implications, for research and therapy, of single gene studies.

Genetics

Perhaps the strongest support for a neurobiological basis for ADHD are the many studies supporting the concept that the disorder runs in families. Dating back to the early 1970s, studies of adoption, twins, families, and. most recently, molecular investigations point toward genetic influences as one mechanism underlying symptoms of ADHD. This has been discussed in some of the earlier chapters of this book.

Many models for the inheritance of ADHD have been proposed, including single gene, polygenic, and multifactorial models. Amongst the earliest models was that of Deutsch. Matthysse, Swanson & Farkas (1990), in which a genetic latent structure analysis of dysmorphology was performed. They reported that the autosomal dominant model best fit the data.

Family studies with 140 ADHD probands and 368 first-degree relatives, were consistent with a model of highly penetrant autosomal dominant gene transmission (Faraone et al., 1992). An important point from this study was that female members of the family seemed to be linked to an increased familial risk of the disorder. Additionally, if a parent had ADHD, the risk was 6.6 times greater for sisters, and 1.5 times greater for brothers. The authors rejected the hypothesis of a more severe genetic disorder in girls. Their model speculated that in the males, a proportion of the cases was caused by environmental rather than genetic factors.

More recent data from the Colorado Reading Project (Stevenson, Pennington, Gilger. DeFries. & Gillis, 1993), suggested that ADHD in these reading disabled families, and in the controls, followed the pattern of either a single dominant gene, or a single major gene. Finally, more recent family studies report a higher risk for ADHD in siblings of ADHD probands (20.8%), than in siblings of normal probands (5.6%) (Biederman et al., 1992).

 
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