Lasky-Su, J., Anney, R. J .L., Neale; B.M. Franke, B., Zhou, K., Maller, J. B., Vasquez, A. A., Chen, W., Asherson, P., Buitelaar, J. K., Banaschewski, T., Ebstein, R. P., Gill, M., Miranda, A., Mulas, F., Oades, R. D., Roeyers, H., Rothenberger, A., Sergeant, J. A., Sonuga-Barke, E. J. S., Steinhausen, H-C., Taylor, E. A., Daly, M., Laird, N., Lange, C. & Faraone, S. V.

Genome-wide association scan of the time to onset of Attention Deficit Hyperactivity Disorder.

American Journal of Medical Genetics Part B, 147B, 1355-1358. [Request a copy] [view whole article]

Introduction: A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for ADHD to determine if associations exist with the age at onset of ADHD.

Methods: The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs & 930 parent-offspring trios were used found suitable for use & a family-based log-rank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest**. We could not analyse for D5 (Lasky-Su ea 2007) as the array had no SNPs in this region. We pre-specified analysis for ADRA1A, ADRA1B, ADRA2A, ADRA2C, ADRB1, ADRB2, ADRBK1, ADRBK2, ARRB1, ARRB2, BDNF, CHRNA4, COMT, CSNK1E, DBH, DDC, DRD1, DRD2, DRD3, DRD4, FADS1, FADS2, HES1, HTR1B, HTR1E, HTR2A, HTR3B, NFIL3, NR4A2, PER1, PER2, PNMT, SLC18A2, SLC6A1, SLC6A2, SLC6A3 (DAT1), SLC6A4, SLC9A9, SNAP25, STX1A, STY1, TPH1, & TPH2.

1 - No SNP achieved genome-wide significance. The lowest p-values had a magnitude of 10-7.

2 - Several SNPs among a pre-specified list of candidate genes had nominal associations including SLC9A9, DRD1, ADRB2 (NA b2), SLC6A3, NFIL3 (IL-3), ADRB1 (NA b1), SYT1 (synaptotagmin), HTR2A, ARRB2 (arrestin), & CHRNA4 (ACh nicotine a4). [human IL-3 gene is located on chromosome 5, is pro-inflammatory, and neurotrophic on ACh neurons]

3 - Of these findings SLC9A9 (sodium/hydrogen exchanger) stood out as a promising candidate, with nominally significant SNPs in six distinct regions of the gene. (caveat 180 SNPs in this gene so some significance by chance is to be expected) (HTR2A had associations with in 2 distinct regions).

4 - Note: age at onset had an inverse correlation with the number of hyperactive-impulsive symptoms (r = -0.11, p = 0.0005) [inattentive symptoms were inversely but non-significantly related]

Background: we estimated the heritability of this phenotype** (age of manifesting the first symptoms) using a separate sample of 481 related ADHD individuals -- heritability of the trait was found to be 0.19 (p-value = 0.02), suggesting that this trait is genetically relevant (Lasky-Su ea 2007).