The use of quantitative trait measures for ADHD genetic research is based on findings from numerous population-based twin studies that show high heritability for parent and teacher ratings of ADHD symptoms (Thapar et al., 1999). We know, for example, that correlations for parent- and teacher-rated ADHD symptoms are 70% to 75% for identical (monozygotic [MZ]) twins (who share 100% of their genes) and 30% to 35% for nonidentical (dizygotic [DZ]) twins (who share 50% of their genes).
In order to examine the genetic correlation between ADHD diagnosis and continuous rating scale measures, a method called DF analysis estimates group heritability from the differential regression of identical and nonidentical co-twin trait scores to the population trait mean where twin probands are selected for extreme scores (DeFries and Fulker, 1988). In one study of 6,000 preschool twins, the group heritability for twins where probands were selected for extreme scores ranged from 0.83 to 0.93 (Price et al., 2001).
Using the IMAGE dataset, we estimated the familial correlation between combined-type ADHD probands and continuous measures of ADHD symptoms among siblings. As expected, both inattentive and hyperactive-impulsive symptoms show familial associations to combined-type ADHD of around 0.2 to 0.3, which is similar to sibling correlations for DZ twins estimated from population samples (Table 3).
There are several potential advantages to our study design. The collection of DNA from a large sample of ADHD probands allows us to perform powerful tests of association that can identify small genetic effects, such as those seen for candidate genes listed in Table 2. At the same time, we can investigate whether alleles associated with ADHD correlate with quantitative ratings in siblings and we can increase the power of our analysis by combining within- and between-pair tests of association.
We previously tested the utility of this approach by investigating whether some of the genes associated with ADHD showed QTL associations in a population twin sample with parent ratings of ADHD behavior (Mill et al., 2005). We found significant correlations with previously identified risk alleles from SLC6A3 and DRD5 and a protective allele from SNAP-25. Our analyses found positive correlations using within-pair tests of association that are independent of genetic stratification and are robust to potential stratification effects generated by parent raters who may scale similar behaviors differently. In other words, within-pair differences for behavioral scores are more reliable than across-pair comparisons. This was reflected in the strength of the genetic associations we observed. The QTL linkage also takes advantage of the reliable nature of within-pair differences by looking for correlations between the similarity between siblings and the number of parental chromosomes they share at a particular genetic locus.
The IMAGE dataset contains a subset of affected sibling pairs that can be used for more traditional tests of association and linkage using diagnostic status alone. In our initial set of 608 ADHD combined-type probands, we found a sibling concordance rate for combined-subtype ADHD of 22.1% for males and 5.2% for females. This gives rise to similar sibling risk ratios for the combined subtype for males (9.2%) and females (11.5%) when expressed as a ratio against recent prevalence rates in a European population (2.4% males, 0.4% females).
As we discover more genes, the goal of ADHD genetic research will shift from gene discovery toward gene functionality. Quantitative genetic findings have shifted perception of ADHD toward that of a quantitative trait sharing etiological influences with other developmental, behavioral and cognitive traits. Molecular genetics has confirmed a priori hypotheses of dopamine system dysregulation and promises to identify additional genes in the coming decade. Combining genetic, environmental and neurobiological research has the potential to delineate causal links between ADHD and the developmental course of the disorder, including persistence of ADHD symptoms into adulthood and comorbidity with associated psychiatric disorders/traits.
Acknowledgements
