Genetic Linkage of Attention-Deficit/Hyperactivity Disorder on Chromosome 16p13, in a Region Implicated in Autism

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder in childhood and likely represents an extreme of normal behavior. ADHD significantly impacts learning in school-age children and leads to impaired functioning throughout the life span. There is strong evidence for a genetic etiology of the disorder, although putative alleles, principally in dopamine-related pathways suggested by candidate-gene studies, have very small effect sizes. We use affected-sib-pair analysis in 203 families to localize the first major susceptibility locus for ADHD to a 12-cM region on chromosome 16p13 (maximum LOD score 4.2; P=.000005), building upon an earlier genomewide scan of this disorder. The region overlaps that highlighted in three genome scans for autism, a disorder in which inattention and hyperactivity are common, and physically maps to a 7-Mb region on 16p13. These findings suggest that variations in a gene on 16p13 may contribute to common deficits found in both ADHD and autism.

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.…”

European clinical guidelines for hyperkinetic disorder ? first upgrade

“…Some genes involved may have pleiotropic effects. Thus, it has been suggested that AD/HD and reading disability [6,147,185], and AD/HD and autism [6,147] share genetic susceptibility factors.…”

High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder

“…6 Despite the high heritability of ADHD, initial genome scan studies have failed to identify genes of major effect, 7 although a region on chromosome 16p13 has been implicated in subsequent studies by the same group. 8 Such negative results are not unexpected for a complex genetic disorder like ADHD, where phenotypic heterogeneity is likely, and the practical but (to date) restricted sample sizes limit statistical power. [9][10][11][12][13] Candidate gene studies, on the other hand, require much smaller sample sizes to achieve the same statistical power.…”