Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies

Abstract

A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing approximately 500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.

Genome-wide linkage analysis in a Dutch multigenerational family with attention deficit hyperactivity disorder

“…42 They reported the locus on 14q11.2-12, which overlaps with the region found in our family. With the GWA analysis, two genes from the area were highlighted: SLC7A8 and NOVA1.…”

“…With the GWA analysis, two genes from the area were highlighted: SLC7A8 and NOVA1. 42 It is remarkable that in a clinically and genetically heterogeneous disorder such as ADHD, overlapping genomic regions are reported by studies conducted in different populations, using different assessment, genotyping and analysis strategies. Hopefully, the ongoing GWA studies [18][19][20] will help to highlight specific SNPs and genes within the broad areas detected by our, as well as other, linkage studies.…”

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

“…60,63,64 Although several genes affected by CNVs identified in this study contain SNPs that yield significant signals in GWA studies, there is presently no obvious relationship between the heritability of ADHD and the number or strength of the observed effects. Unlike rare CNVs, common variants for ADHD may be of very small effect and thus require very large samples to be reliably detected.…”

“…5 It is noteworthy that the 5q12.1 deletion in patient 241 (also see preceding section) is only B250 kb upstream of a linkage interval flanked by markers D5S1968-D5S629 in an extended pedigree (Lin et al, unpublished results) and nominally significant association of several SNPs (highest ranking SNP rs17780175, P = 3.41 Â 10 À9 ) in PDE4D, was also revealed by a pooling-based genome-wide association (GWA) study in adult ADHD. 60 Of related interest, PDE4D variants that distinguish dependent versus non-dependent individuals abusing methamphetamine, alcohol, nicotine and other substances have been previously identified in several GWA studies of addiction vulnerability. 61 Given the high comorbididty of ADHD with substance use disorders, the convergence with genes identified in GWA studies of addiction vulnerability and related phenotypes provides further confidence in our data.…”

Hunters in a Farmer’s World: ADHD and Hunter Gatherers

“…Some work has examined the genetics of ADHD [23][24][25]. There is a large heritable component in ADHD, around 70%, suggesting that genes play a role in its aetiology.…”