A genomewide scan for loci involved in attention-deficit/hyperactivity disorder

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common heritable disorder with a childhood onset. Molecular genetic studies of ADHD have previously focused on examining the roles of specific candidate genes, primarily those involved in dopaminergic pathways. We have performed the first systematic genomewide linkage scan for loci influencing ADHD in 126 affected sib pairs, using a approximately 10-cM grid of microsatellite markers. Allele-sharing linkage methods enabled us to exclude any loci with a lambda(s) of > or =3 from 96% of the genome and those with a lambda(s) of > or =2.5 from 91%, indicating that there is unlikely to be a major gene involved in ADHD susceptibility in our sample. Under a strict diagnostic scheme we could exclude all screened regions of the X chromosome for a locus-specific lambda(s) of >/=2 in brother-brother pairs, demonstrating that the excess of affected males with ADHD is probably not attributable to a major X-linked effect. Qualitative trait maximum LOD score analyses pointed to a number of chromosomal sites that may contain genetic risk factors of moderate effect. None exceeded genomewide significance thresholds, but LOD scores were >1.5 for regions on 5p12, 10q26, 12q23, and 16p13. Quantitative-trait analysis of ADHD symptom counts implicated a region on 12p13 (maximum LOD 2.6) that also yielded a LOD >1 when qualitative methods were used. A survey of regions containing 36 genes that have been proposed as candidates for ADHD indicated that 29 of these genes, including DRD4 and DAT1, could be excluded for a lambda(s) of 2. Only three of the candidates-DRD5, 5HTT, and CALCYON-coincided with sites of positive linkage identified by our screen. Two of the regions highlighted in the present study, 2q24 and 16p13, coincided with the top linkage peaks reported by a recent genome-scan study of autistic sib pairs.

Figure 1

LOD score plots from multipoint analyses of the whole genome in ASPs with ADHD. A, MLS analyses for “narrow” and “broad” diagnostic schemes. B, QTL analyses for total symptom count derived from clinical interview. Cumulative distance in Haldane centimorgans is displayed along the bottom, with chromosome numbers at the top. Peak LOD scores >1 are summarized in table 4.

Figure 2

Exclusion mapping of the whole genome in ADHD ASPs for a λ_s of 2. LOD score plots are shown under narrow and broad diagnostic schemes. Regions are excluded if they produce a LOD of <−2. See tables 5 and 6 for more details. Cumulative distance in Haldane centimorgans is displayed along the bottom, with chromosome numbers at the top.