ORIGINAL ARTICLE A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs J Hebebrand 1 , A Dempfle 2 , K Saar 3 , H Thiele 4 , B Herpertz-Dahlmann 5 , M Linder 6 , H Kiefl 6 , H Remschmidt 7 , U Hemminger 8 , A Warnke 8 , U Kno ¨ lker 9 , P Heiser 10 , S Friedel 1 , A Hinney 1 , H Scha ¨fer 2 , P Nu ¨ rnberg 4 and K Konrad 5 1 Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany; 2 Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany; 3 Molecular Genetics and Gene Mapping Center, Max Delbru ¨ ck Center Berlin-Buch, Berlin, Germany; 4 Cologne Center for Genomics, University of Cologne, Cologne, Germany; 5 Department of Child and Adolescent Psychiatry, RWTH Aachen, Aachen, Germany; 6 Psychiatric Clinic for Children and Adolescents, Regensburg, Germany; 7 Department of Child and Adolescent Psychiatry, University of Marburg, Marburg, Germany; 8 Department of Child and Adolescent Psychiatry, University of Wu ¨ rzburg, Wu ¨ rzburg, Germany; 9 Department of Child and Adolescent Psychiatry, University of Lu ¨beck, Lu ¨ beck, Germany and 10 Department of Psychiatry, University of Marburg, Marburg, Germany Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent. Molecular Psychiatry (2006) 11, 196–205. doi:10.1038/sj.mp.4001761; published online 11 October 2005 Keywords: ADHD; 5p13; dopamine transporter Introduction Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable disorders in child and adolescent psychiatry; heritability is estimated at approximately 0.8 1 and the recurrence risk in siblings is in the magnitude of 5. 2 A number of candidate genes have been investigated using both case–control and family-based studies in order to identify genetic variation underlying the disorder. 3 The most fre- quently analyzed genes include the dopamine D4 receptor gene (DRD4) and the gene for the dopamine transporter (DAT1, SLC6A3); meta-analyses have yielded significant (Po0.02) results for DRD4 4,5 and negative results (P ¼ 0.06 and 0.21) for the DAT1 VNTR. 5,6 The first whole-genome scan was performed in a US sample encompassing 126 affected sib-pairs from 104 families, 7 which was subsequently extended to 204 families with a total of 270 sib-pairs. 8,9 An independent genome scan based on 164 sib-pairs from 106 families was performed in a Dutch sample. 10 A third group performed a genome-wide scan of 16 extended and multigenerational families with ADHD from a genetic isolate located in Columbia. 11 These genome scans and subsequent fine mapping studies of peak regions have yielded significant evidence of linkage 12 on 4q13.2, 5q33.3, 11 6q12, 9 11q22, 11 16p13, 13 and 17p11. 9,11 Chromosomal regions that yielded at least nominal evidence of linkage in two of the three genome scans include 11q22, 17p11, 20q13, 8,9,11 3q13 and 9q33. 10,11 Nominal evidence of linkage was Received 17 May 2005; revised 9 August 2005; accepted 1 September 2005; published online 11 October 2005 Correspondence: Professor J Hebebrand, Department of Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg- Essen, Virchowstr. 174, D-45147 Essen, Germany. E-mail: Johannes.Hebebrand@uni-duisburg-essen.de Molecular Psychiatry (2006) 11, 196–205 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp