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

Chen, Wai and Zhou, Kaixin and Sham, Pak and Franke, Barbara and Kuntsi, Jonna and Campbell, Desmond and Fleischman, Karin and Knight, Jo and Andreou, Penny and Arnold, Renée and Altink, Marieke and Boer, Frits and Boholst, Mary Jane and Buschgens, Cathelijne and Butler, Louise and Christiansen, Hanna and Fliers, Ellen and Howe-Forbes, Raoul and Gabriëls, Isabel and Heise, Alexander and Korn-Lubetzki, Isabelle and Marco, Rafaela and Medad, She'era and Minderaa, Ruud and Müller, Ueli C and Mulligan, Aisling and Psychogiou, Lamprini and Rommelse, Nanda and Sethna, Vaheshta and Uebel, Henrik and McGuffin, Peter and Plomin, Robert and Banaschewski, Tobias and Buitelaar, Jan and Ebstein, Richard and Eisenberg, Jacques and Gill, Michael and Manor, Iris and Miranda, Ana and Mulas, Fernando and Oades, Robert D. and Roeyers, Herbert and Rothenberger, Aribert and Sergeant, Joseph and Sonuga-Barke, Edmund and Steinhausen, Hans-Christoph and Taylor, Eric and Thompson, Margaret and Faraone, Stephen V. and Asherson, Philip (2008) DSM-IV combined type ADHD shows familial association with sibling trait scores : a sampling strategy for QTL linkage. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 147B (8). pp. 1450-1460. ISSN 1552-4841

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 (lambda(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.