A previous study (Willcutt et al., 2002) examining children with reading problems found evidence suggesting that a locus in the chromosome 6p21.3 region, linked to reading disability, may also ...increase risk for ADHD. The current study examined the genetic and environmental contributions to ADHD, inattention (IN), hyperactivity-impulsivity (HI), and sluggish cognitive tempo (SCT), in preparation to replicate genetic linkage to a 20 cM region near 6p21 using two independent samples selected for ADHD. The sample included 167 MZ twins and 275 DZ twins for twin analyses as well as 25–73 probands and their siblings for linkage analyses. Initial analyses showed that SCT was much more highly related to IN than to HI at the phenotypic level, and the substantial phenotypic correlations among IN, HI, and SCT were highly attributable to genes. Although ADHD, IN, HI, and SCT displayed high heritability for both parent and teacher ratings, parent ratings displayed evidence of dominance and/or sibling contrast effects. All of these results are highly consistent with those found in other studies. Linkage analyses were conducted with a marker density of 1 per cM for both samples. Selecting more extreme probands provided greater power to detect linkage. Significant but modest results were detected for DSM-III ADHD in one sample (max t = 1.87, p = .035), for DSM-IV ADHD (max t = 2.07, p = 0.024) and SCT (max t = 2.10, p = .02) in the other sample, and for DSM-IV HI in the combined DSM-IV sample (max t = 1.74, p = .045). Extended linkage analyses did not show differential linkage to any DSM-IV subtype, or that linkage with IN varied with levels of SCT. Bivariate linkage analyses for IN-HI, IN-SCT, and HI-SCT were not significant. Although low power was a limiting factor in all the linkage analyses, the results suggest that a QTL at 6p may increase risk for ADHD in two independent samples. Follow-up with greater numbers of sibling pairs and a denser marker set may yield more power to detect linkage as well as eventually identify the locus or loci that increase risk for ADHD.
The overall goal of this project is to advance our understanding of the multifactorial etiology of Attention Deficit Hyperactivity Disorder (ADHD) by testing a diathesis-stress model of gene x ...environment (g x e) interactions. Although the literature increasingly supports g x e interactions in the manifestation of ADHD, few studies have investigated multiple genetic and environmental risk factors, included direct tests of gene – environment correlations (rG-Es), explored the specificity of interactions to symptom dimensions, or attempted to minimize comparisons. Therefore, utilizing both within-family (FBAT/PBAT) and case-control methodology, this study sought to (1) explore main effects of polymorphisms in the DRD2, DRD4, DRD5, DAT1, 5HTT, ADRA2C and DBH genes on ADHD symptoms in a community sample, (2) explore main effects of environmental risk factors on ADHD symptoms (including direct tests of gene – environment correlation), (3) test for g x e interaction effects between those environmental and genetic risk factors substantiated by main effects, and (4) investigate whether results were specific to particular symptom dimensions of ADHD. Analyses demonstrated a robust main effect of the DRD4 4-repeat allele (DRD4*4R) on ADHD symptoms rather than the DRD4 7-repeat allele (DRD4*7R), that had previously been implicated in ADHD. Analyses also revealed main effects of maternal smoking, prenatal alcohol exposure, season of birth, parental education, and television viewing habits on ADHD symptoms. After considering rG-Es, results demonstrated significant diathesis-stress g x e interactions between DRD4*4R and season of birth, maternal smoking, and parental education that selectively exacerbated hyperactive-impulsive (HI) symptoms. Exploratory analyses demonstrated a main effect of the DAT1 10-repeat allele (DAT1*10R) on ADHD-Combined Type and HI symptoms, and revealed significant interactions between DAT1*10R and parental education and season of birth on HI behaviors. Taken together, these data are consistent with a diathesis-stress model for g x e interactions in ADHD, suggest a possible alternate risk factor in linkage disequilibrium with DRD4*4R and DRD4*7R that may be the true "risk" allele, provide evidence that DAT1*10R may play into a subtype-specific etiology for ADHD-C, and support the idea that polymorphisms in dopaminergic genes interact with parental education and season of birth to selectively exacerbate HI symptoms.
A literature search at the end of 2003 revealed more than 200 published studies that compared groups with and without attention deficit hyperactivity disorder (ADHD) on neuropsychological measures. ...This rapid accumulation of new knowledge illustrates the potential utility of neuropsychological methods as a tool to refine our understanding of the pathophysiology of ADHD. Yet these studies also underscore the complexity of the neuropsychology of ADHD, and clearly demonstrate how much remains to be learned.
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