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.

The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes

“…11 To date, there have been four published genome linkage scans of ADHD; three affected sibling pair studies and one of 16 multiplex pedigrees. [12][13][14][15][16][17][18] These studies have highlighted a number of potential linkage regions for further exploration, although there is as yet no clear consensus across the various data sets and no genes have been identified that account for linkage signals. Several of the linkage regions overlap in two or more of these studies, including regions of chromosomes 5p, 6q, 7p, 11q, 12q and 17p, suggesting that one or more loci of moderately large effect may exist.…”

Quantitative genome scan and Ordered-Subsets Analysis of autism endophenotypes support language QTLs

“…Although Auranen et al 35 also obtained a peak on chromosome 3q, the distance between the peaks is quite large, around 43 cM, suggesting that the peaks are independent. Interestingly, Fisher and colleagues 40 reported a modest linkage peak of ADHD only 22 cM away from the current 3q WORD peak. Moreover, there is evidence for a QTL for phonological memory in families with speech-sound disorder 41 that is about 9 cM from the 3q region linked to WORD in the present autism sample.…”

Association of the dopamine receptor D4 (DRD4) gene 7‐repeat allele with children with attention‐deficit/hyperactivity disorder (ADHD): An update

“…Family, twin and adoption studies, as well as linkage and association studies, have shown strong genetic contributions to the etiology of ADHD [Faraone and Biederman, 1998;Fisher et al, 2002;Ogdie et al, 2003; ArcosBurgos et al, 2004]. The most consistently replicated candidate gene in ADHD genetics is the association with the dopamine receptor D4 gene (DRD4) [LaHoste et al, 1996;Smalley et al, 1998;Swanson et al, 1998;Comings et al, 1999;Faraone et al, 1999;Holmes et al, 2000;Muglia et al, 2000;Tahir et al, 2000;Curran et al, 2001;Mill et al, 2001;Roman et al, 2001;Bhaduri et al, 2006].…”