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Analysis of 51 candidate genes in DSM-IV combined subtype attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Molecular Psychiatry, 11, 934 - 953, (2006) (request a copy) [View whole article]

Introduction: ADHD is a common neurodevelopmental disorder. It starts in early childhood & can persist into adulthood in many cases. Family & twin studies have demonstrated the importance of genetic factors & candidate gene association studies have identified several loci that exert small but significant effects on ADHD. Four genome linkage scans-have pointed to moderately large effects of loci on 5p, 6q, 7p, 11q, 12q & 17p chromosomal regions.

To provide further clarification of reported associations & identify novel-associated genes, we examined 915 SNPs spanning 52 candidate genes involved in the regulation of neurotransmitter pathways, particularly DA, NA & 5HT pathways, in addition to circadian rhythm (& clock) genes.

Methods: -- Analysis used within family tests of association in a sample of 674 families with 776 DSM-IV combined type cases ascertained for the International Multi-centre Genetics project (IMAGE) -- 93.5% were male, mean age was 11.2y, (5-17y) for cases & siblings (n=808). Association tests were the transmission disequilibrium test implemented by UNPHASED & WHAP programmes ((www.hgmp.mrc.ac.uk/Registered/Options/unphased.html). SNP genotyping (1536 SNPs in original-array) used the Illumina high-throughput "Bead Array" technology.
Results: 1 ) We found nominal significance with one or more SNPs in 18 genes, -- these included the 2 most replicated findings in the literature: -- for the dopamine D4 receptor (DRD4), and the dopamine transporter (DAT1).
Results: 2 ) Gene-wide tests, adjusted for the number of SNPs analysed in each gene, identified associations with TPH2, ARRB2, SYP, DAT1, ADRB2, HES1, MAOA & PNMT. i.e. loci where the products affect synthesis or breakdown or a receptor for DA, NA, 5HT & adrenalin - & membrane fluidity / responsiveness (fatty acid desaturases) & circadian rhythm / oscillator / clocks

Yet, we must conclude that -- Further studies will be needed to confirm or refute the observed associations & their generalizability to other samples.