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Genome-Wide Association Scan of Quantitative Traits for Attention Deficit Hyperactivity Disorder Identifies Novel Associations and Confirms Candidate Gene Associations. American Journal of Medical Genetics Part B, 147B, 1345-1354.doi:10.1002/ajmg.b. 30869. [Request a copy] - View Article

Introduction: ADHD is a complex condition with environmental & genetic etiologies. -- Up to this point, research has identified genetic associations with candidate genes from known biological-pathways. In order to identify novel ADHD susceptibility genes, 600,000 SNPs were genotyped in 958 ADHD proband-parent trios.

Methods: After applying data cleaning procedures we examined 430,060 autosomal SNPs in 909 family trios. We generated 6 quantitative phenotypes from 18 ADHD symptoms to be used in genome-wide association analyses.

Results:
1 - With the PBAT screening algorithm, we identified 2 SNPs, rs6565113 & rs552655, that met criteria for genome-wide significance within a specified phenotype.

2 - These SNPs are located in intronic regions of genes CDH13 & GFOD1, respectively.

3 - CDH13 has been implicated previously in substance use disorders. CDH13 acts as a negative regulator of neural cell growth [Takeuchi, 2000] & is expressed in brain regions that structural imaging has also shown to have volumetric reductions in ADHD-diagnosed individuals [Takeuchi, 2000; Valera, 2007]. GFOD1 (UGID:699845), encoding glucose-fructose oxido-reductase domain containing a protein predicted to be involved in electron transport & metabolic processes .

4 - We also evaluated the association of SNPs from a list of 37 ADHD candidate genes that was specified a priori.

Discussion: These findings, along with association p-values with a magnitude less than 10-5, are discussed in this manuscript.

a) The association analyses identified [p-value <10-5] 2 SNPs in IL-16 (associated with the inattentive phenotype), 2 SNPs in LOC390980, and one SNP in or proximal to each of the following genes: CLYBL, FHIT, FOXP1, HAS3, LPL, MEIS2, NAPRT1, OXER1, DMTR2, GRIK1, SLCO3A1, ZNF423, & ZNF544.

b) 17 of these candidate genes had association p-values lower then 0.01: SLC6A1, SLC9A9, HES1, ADRB2, HTR1E, DDC, ADRA1A, DBH, DRD2, BDNF, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, SNAP25, & COMT.

c) Among the candidate genes, SLC9A9 had the strongest overall associations with 58 association test p-values lower than 0.01 & multiple association p-values at a magnitude of 10-5 in this gene. SLC9A9, which codes for a sodium/hydrogen exchanger that is expressed in the brain. Not only did it have 58 association p-values that were less than 0.01, but three associations in this gene had p-values with a magnitude of 10-5. SLC9A9 is located on chromosome 3q24 has been suggested as a strong candidate for ADHD because it is located at a translocation breakpoint in a family having multiple cases of ADHD [deSilva, 2003]

In sum, these findings identify novel genetic associations at viable ADHD candidate genes & provide confirmatory evidence for associations at previous candidate genes. Replication of these results is necessary in order to confirm the proposed disease susceptibility loci

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