NIJMEIJER, J. S., Arias-Vasquez, A., Rommelse, N. N. J., Altink, M. E., Anney, R. J. L., Asherson, P., Banaschewski, T., Buschgens, C. J. M., Fliers, E. A., Gill, M., Minderaa, R. B., Poustka, L., Sergeant, J. A., Buitelaar, J. K., Franke, B., Ebstein, R. P., Miranda, A., Oades, R. D., Roeyers, H., Rothenberger, A., Sonuga-Barke, E. J. S., Steinhausen, H-C., Faraone, S. V., Hartman, C. A., & Hoekstra, P. J. (2010)

Identifying Loci for the Overlap Between Attention-Deficit/Hyperactvity Disorder and Autism Spectrum Disorder Using a Genome-wide QTL Linkage Approach. Journal of the American Academy of Child and Adolescent Psychiatry, 49, 675-685. [Request a copy] - view open access

Introduction: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach.

Methods: In this study from the IMAGE consortium 1143 ADHD probands & 1453 of their siblings were investigated. The total & subscale scores of the Social Communication Questionnaire (SCQ) were used as quantitative traits to run multi-point regression-based linkage analyses on 5407 autosomal SNPs** applying MERLIN-regress software, both without & with inclusion of ADHD symptom scores as covariates. (**Following data cleaning, 5,407 autosomal SNPs with an average-resolution of 1.66 SNP/centimorgan (cM) were entered into the linkage analyses) .

1 - The analyses without ADHD symptom scores as covariates resulted in 3 suggestive linkage signals, -- i.e., on chromosomes 15q24, 16p13, & 18p11.

2 - Inclusion of ADHD symptom scores as covariates resulted in additional suggestive loci on chromosomes 7q36 & 12q24, whereas the LOD score of the locus on chromosome 15q decreased below the threshold for suggestive linkage.

3 - The loci on 7q, 16p, & 18p were found for the SCQ restricted & repetitive subscale, the locus on 15q was found for the SCQ communication subscale, & the locus on 12q for the SCQ total score.

4 - (In more detail) a) 1° analyses (i.e., Conners' scores not included as covariates), the highest LOD score (LOD 3.216) was found for rs1557299 on 18p11.32 for the SCQ restricted & repetitive subscale. b) analyses corrected for Conners inattentive & hyperactive-impulsive scores, suggestive linkage was again found for 18p11.32 and 16p13 for the restricted & repetitive scale.

Our findings suggest that QTL identified in this study are ASD specific, although the 15q QTL potentially has pleiotropic effects for ADHD & ASD.

Discussion: This study confirms that ASD traits lie along a continuum of severity, as loci potentially underlying ASD symptoms in children with ADHD were identified even though autistic cases had been excluded from the IMAGE sample, and also supports the hypothesis that differential genetic factors underlie the 3 ASD dimensions -- 18p11 - a possible locus for ASD (Asperger's disorder). Here, suggestive linkage for marker D18S59, at 0 cM (184 kb from our peak SNP) was reported.

The SNPs that showed the highest LOD scores in our study lie within an intergenic region, but are flanked by an interesting gene c.19 kb upstream, called adenylate cyclase activating polypetide 1 (ADCYAP1). This gene encodes a neuropeptide, and in animal studies has been shown to be associated with hyperactivity, increased exploratory behavior, and abnormal social behavior. -- 7q36. This lies within the most replicated linkage region for autism, namely 7q21.2-36.2 -- In 2 independent samples, suggestive linkage at, respectively, 129 kb & 4Mb from our peak SNP at 12q24 was found.10,65-67 Smalley et al found genome-wide significant linkage for a broad region on 16p13, with the most significant SNP (D16S3114) at 7 Mb from the SNP with the highest LOD score in the present study (rs859302).