Cognitive functioning in affected sibling pairs with ADHD: familial clustering and dopamine genes Sandra K. Loo, 1 Erika Carpenter Rich, 1 Janeen Ishii, 2 James McGough, 1 James McCracken, 1 Stanley Nelson, 2 and Susan L. Smalley 1 1 UCLA Department of Psychiatry and Biobehavioral Sciences, Los Angeles, USA; 2 Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, USA Background: This paper examines familiality and candidate gene associations of cognitive measures as potential endophenotypes in attention-deficit/hyperactivity disorder (ADHD). Methods: The sample consists of 540 participants, aged 6 to 18, who were diagnosed with ADHD from 251 families recruited for a larger genetic study of ADHD. All members of the family underwent psychiatric interviews and children were administered a large battery of cognitive tasks. Subjects were genotyped for several dopaminergic candidate genes (DAT1, DRD4, and DRD5). Results: Performance on measures of intel- ligence, working memory, and set-shifting had the highest sibling correlations and exhibited significant familial clustering. The 7-repeat allele of the dopamine receptor D4 (DRD4) gene was associated with poor performance on measures of intelligence, color naming, interference control, and working memory. There were no significant associations with DAT1 and DRD5. Conclusions: Sibling correlations, familial clustering and candidate gene associations provide strong support for verbal working memory as a candidate endophenotype for ADHD. More complex models of, and larger sample sizes for, genetic association with cognitive functions are encouraged for future study. Keywords: Endophenotype, working memory, DRD4, genetics, executive function, neuropsychology, parent psychopathology. Attention-deficit/hyperactivity disorder (ADHD; American Psychiatric Association (APA), 1994) is a prevalent childhood psychiatric disorder that often continues into adulthood. The etiology is unknown; however, a large body of literature strongly supports the influence of genes in conferring risk for the dis- order. Family and twin studies have demonstrated that ADHD is a highly heritable disorder, with 76% of the variance attributable to genetic influences (Faraone et al., 2005). Among the four genome scans conducted to date, the results are largely mixed; however, three have identified overlapping regions of linkage (of varying magnitude) on chromosomes 5p and 17p (Arcos-Burgos et al., 2004; Bakker et al., 2003; Hebebrand et al., 2006; Ogdie et al., 2003). Association studies have focused on the dopamin- ergic genes due to the hypothesized role of dopamine in the pathophysiology of ADHD (Swanson et al., 2007) as well as the efficacy of psychostimulants in treating ADHD. Recent meta-analyses suggest sta- tistically significant yet small effect sizes for several genes and ADHD, including the dopamine trans- porter (DAT1), dopamine receptors D4 (DRD4) and D5 (DRD5) (1.13, 1.45 and 1.24 respectively; Fara- one et al., 2005). Current evidence suggests that ADHD is a polygenic disorder, probably the result of several genes of small to moderate effect. Taken together, these results support genetic influences, complex inheritance, and likely genetic heterogeneity across ADHD populations. Investiga- tions of intermediate phenotypes or endophenotypes in ADHD may help reduce sources of etiological heterogeneity and increase linkage or association signals. Endophenotypes have been increasingly used in psychiatric genetics as they are thought to be closer to gene action than diagnoses (Gottesman & Gould, 2003). Endophenotypes for ADHD such as inhibition, working memory, delay aversion, and temporal processing have been suggested based on the extant neuroscience literature (Castellanos & Tannock, 2002). A step in this direction has been to test the associ- ation between dopaminergic candidate genes and cognitive processes implicated in ADHD, of which there have been a handful of studies. Of these, DRD4 has been most frequently studied; however, the results are mixed. Two groups have found that the DRD4-7-repeat allele of the 48-bp VNTR, the variant that has been shown to be a risk factor for ADHD, is associated with better cognitive functioning when compared to children who do not have the 7-repeat allele (Manor et al., 2002; Swanson et al., 2000). Specifically, the 7-absent group had a longer reaction time, more commission errors, and a more variable reaction time than children carrying the 7-repeat allele. In contrast, other studies (Kieling, Roman, Doyle, Hutz, & Rohde, 2006; Langley et al., 2004) have found that ADHD children who had at least one copy of the 7-repeat allele exhibited a fast and impulsive response style and higher rates of commission errors than 7-absent and normal control children. One longitudinal study (Barkley, Smith, Fischer, & Navia, Conflict of interest statement: No conflicts declared. Journal of Child Psychology and Psychiatry 49:9 (2008), pp 950–957 doi:10.1111/j.1469-7610.2008.01928.x Ó 2008 The Authors Journal compilation Ó 2008 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main Street, Malden, MA 02148, USA