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Meta-analysis of genome-wide association studies of attention deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 49, 884- 897 (2010). [Request a copy] - view open access

Introduction: Although twin-&-family studies have shown ADHD to be highly heritable, genetic variants influencing the trait at a genome wide significant level have yet to be identified. -- As prior genomewide association scans (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies. .

Methods: We used data from 4 projects: a) the Children's Hospital of Philadelphia (CHOP), b) phase-I of the International Multisite ADHD Genetics Project (IMAGE), c) phase-II of IMAGE (IMAGE II), & d) the Pfizer funded study from the University of California, Los Angeles, Washington University & the Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases & 2,455 Cs. For each study, we imputed HapMap SNPs, computed & association Z-score & then combined weighted Z-scores in a meta-analysis. .

1 - No genome-wide significant associations were found,

2 - although an analysis of candidate genes suggests that some of them may be involved in the disorder.

3 - The top 50 SNPs - included Cadherin 13, GABA-T (transporter SLC6A1) [p=5-7 x 10-5], FIGNL1 (fidgetin-like 1, an ATPase), ADRA1A (alpha-1a, NA), DDC (dopa decarboxylase), TPH2 (p<0.0068), [rs11179003 chromosome 12] & ADRBK2 (NA beta receptor kinase 2) .......... (note no SNPs relating to DA).

4 - [best hit: chromosome 7 (8 SNPs) - SHFM1 (proteolysis), chromosome 20 (4 SNPs) - no known genes, chromosome 8 (5 SNPs) - CHMP7 (endosomal sorting vescular transport), chromosome 11 (8 SNPs) - DHCR7 & NADSYN1 (NAD synthase: coenzyme in metabolic redox reactions) ..... n.b. effect sizes extremely small for any individual gene - 0.5% of variance explained].

Discussion: Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of ADHD risk variants must, individually, be very small.