Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test

Lasky-Su, Jessica; Banaschewski, Tobias; Buitelaar, Jan K; Franke, Barbara; Brookes, Keeley Joane; Sonuga-Barke, Edmund J.S.; Ebstein, Richard; Eisenberg, Jacques; Gill, Michael; Manor, Iris; Miranda, Ana; Mulas, Fernando; Oades, Robert D. LSF; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph A; Steinhausen, Hans-Christoph; Taylor, Eric A; Zhou, Kaixin; Thompson, Margaret; Asherson, Philip; Faraone, Stephen V.

ABSTRACT Background: Previous research found an association between SNPs in the promoter region of DRD4 and statistically-derived phenotypes generated from ADHD symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. Methods: Four SNPs were genotyped in and around DRD4 in 2,631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs / genetic model combinations with the greatest power to detect an association within each candidate gene. Results: One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = 0.02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result. Conclusions: This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. Rs7124601 is LD with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association.

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Lasky-Su, J., Banaschewski, T., Buitelaar, J.K., Franke, B., Brookes, K.J., Sonuga-Barke, E.J.S., Ebstein, R., Eisenberg, J., Gill, M., Manor, I., Miranda, A., Mulas, F., Oades, R.D., Roeyers, H., Rothenberger, A., Sergeant, J.A., Steinhausen, H.-C., Taylor, E.A., Zhou, K., Thompson, M., Asherson, P., Faraone, S.V., 2011. Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test. https://doi.org/10.1016/j.biopsych.2007.03.006
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