Genetic analysis of attention-deficit hyperactivity disorder 'signature' brain markers

Proposal details

Title: Genetic analysis of attention-deficit hyperactivity disorder 'signature' brain markers
Research Area(s): ADHD and Allied Conditions
Background: Family, twin and adoption studies indicate that genes play a strong role in the susceptibility to ADHD, with heritability estimates of 75-91%. However, it is likely to involve multiple genes, each with moderate effect. Some well-supported candidate genes have been established (e.g., the dopamine receptor D4 (DRD4), dopamine transporter (SLC6A3) and serotonin transporter (SLC6A4) genes), but inconsistent results between studies mean that consensus has not been reached for any gene. One problem may lie with the characterisation of ADHD used in most genetic studies. There is growing support for the view that ADHD, like many complex neurological disorders, is not a discrete entity, but is representative of an extreme end of the spectrum of normal brain function. Thus the classification of people into 'ADHD' and 'normal' groups may be too simplistic. BRID test scores from ADHD children and matched controls were used to derive four composite cognitive markers of ADHD. These markers provide a quantitative measure of 'ADHD-ness' that can be assessed in healthy and ADHD children, rather than assigning a 'yes/no' diagnosis of ADHD. The performance measures may also lie closer to the underlying biology of the disorder than diagnosis or clinical symptoms alone, and so may provide stronger statistical associations with predisposing genes.
Aims: We wish to investigate the genetic basis of variation in brain function associated with ADHD, using ADHD 'signature' markers derived from the BRID. We will test the following hypotheses: 1. Genes associated with ADHD diagnosis will associate with ADHD-like marker quantitative traits in the normal population 2. Genes associated with ADHD diagnosis will associate more strongly with marker quantitative traits in ADHD children
Method: We will genotype polymorphisms in candidate genes, concentrating initially on those that have previously been associated with ADHD diagnosis. We will perform statistical analysis of the data to determine if individuals of different genotypes differ significantly in ADHD marker scores. ANOVAs will be performed, with genotype as the independent variable, and the four ADHD composite marker scores as dependent variables. Where multiple polymorphisms are examined within a gene, inferred haplotype will also be used as an independent variable. For ADHD parent-child trios, transmission-disequilibrium tests will provide confirmatory analyses that avoid the potential problems of population stratification.