DSM‐IV combined type ADHD shows familial association with sibling trait scores: A sampling strategy for QTL linkage

Abstract

Attention deficit hyperactivity disorder (ADHD) is a discrete clinical syndrome characterized by the triad of inattention, hyperactivity, and impulsivity in the context of marked impairments. Molecular genetic studies have been successful in identifying genetic variants associated with ADHD, particularly with DSM-IV inattentive and combined subtypes. Quantitative trait locus (QTL) approaches to linkage and association mapping have yet to be widely used in ADHD research, although twin studies investigating individual differences suggest that genetic liability for ADHD is continuously distributed throughout the population, underscoring the applicability of quantitative dimensional approaches. To investigate the appropriateness of QTL approaches, we tested the familial association between 894 probands with a research diagnosis of DSM-IV ADHD combined type and continuous trait measures among 1,135 of their siblings unselected for phenotype. The sibling recurrence rate for ADHD combined subtype was 12.7%, yielding a sibling recurrence risk ratio (l sib ) of 9.0. Estimated sibling correlations around 0.2-0.3 are similar to those estimated from the analysis of fraternal twins in population twin samples. We further show that there are no threshold effects on the sibling risk for ADHD among the ADHD probands; and that both affected and unaffected siblings contributed to the association with ADHD trait scores. In conclusion, these data confirm the main requirement for QTL mapping of ADHD by demonstrating that narrowly defined DSM-IV combined type probands show familial association with dimensional ADHD symptom scores amongst their siblings. INTRODUCTIONAttention deficit hyperactivity disorder (ADHD) is a common and heritable disorder that starts in early childhood and is characterized by developmentally inappropriate levels of hyperactive, impulsive, and inattentive behaviors accompanied by psychosocial impairments. The disorder is known to aggregate in families, with recent estimates suggesting a fourto sixfold increase in the risk for ADHD among first-degree relatives of ADHD probands [Faraone et al., 2000;Brookes et al., 2006a]. Twin studies using parent and teacher rated ADHD symptom scales demonstrate the predominant role of genetic factors with heritability estimates in the range 60-90% [Thapar et al., 1999;Faraone et al., 2005]. Molecular genetic studies using candidate gene association approaches have yielded positive findings with dopamine and related monoamine neurotransmitter genes, in particular with genetic variants of the dopamine transporter, dopamine D4 and D5 receptor genes [reviewed in Asherson and The Image Consortium, 2004;Faraone et al., 2005;Brookes et al., 2006b;Li et al., 2006;Asherson et al., 2007]. Linkage studies using affected sib-pair or extended pedigree approaches have identified chromosomal regions containing putative risk alleles for ADHD [Fisher et al., 2002a;Bakker et al., 2003;Ogdie et al., 2003Ogdie et al., , 2004Ogdie et al., , 2006Arcos-Burgos et al., 2004;Hebebrand et al., 2006].I...

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