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Alpha-2A adrenergic receptor gene variants are associated with increased intra-individual variability in response time

Abstract

Intra-individual variability in response time has been proposed as an important endophenotype for attention deficit hyperactivity disorder (ADHD). Here we asked whether intra-individual variability is predicted by common variation in catecholamine genes and whether it mediates the relationship between these gene variants and self-reported ADHD symptoms. A total of 402 non-clinical Australian adults of European descent completed a battery of five cognitive tasks and the Conners’ Adult ADHD Rating Scale. Exclusion criteria included the presence of major psychiatric or neurologic illnesses and substance dependency. A total of 21 subjects were excluded due to incomplete data or poor quality cognitive or genotyping data. The final sample comprised 381 subjects (201 males; mean age=21.2 years, s.d.=5.1 years). Principal components analysis on variability measures yielded two factors (response selection variability vs selective attention variability). Association of these factors with catecholamine gene variants was tested using single-step linear regressions, with multiple comparisons controlled using permutation analysis. The response selection variability factor was associated with two ADRA2A single-nucleotide polymorphisms (SNPs) (rs1800544, rs602618), pcorrected=0.004, 0.012, respectively, whereas the selective attention variability factor was associated with a TH SNP (rs3842727), pcorrected=0.024. A bootstrapping analysis indicated that the response selection variability factor mediated the relationship between the ADRA2A SNP rs1800544 and self-reported ADHD symptoms. Thus this study finds evidence that DNA variation in the ADRA2A gene may be causally related to ADHD-like behaviors, in part through its influence on intra-individual variability. Evidence was also found for a novel association between a TH gene variant and intra-individual variability.

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Acknowledgements

This work was supported by grants from the Australian Research Council (DP0770337) to MAB and CDC, and from the Australian National Health and Medical Research Council (APP1006573) to MAB, ZH and CDC. MAB is supported by Career Development Awards from the NHMRC Australia. We thank Melany Christofidis and Elliot Lambert for assistance with data collection.

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Correspondence to M A Bellgrove.

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MAB and LSN have received remuneration for speaking and travel expenses from Lilly Pharmaceuticals. LSN has also received remuneration for speaking and travel expenses from Janssen-Cilag, Astra-Zeneca, Lundbeck and Bristol Meyers Squibb. MAB, CDC, ZH and LSN report no other conflicts of interest. TDRC, OJ, MAVB, B-NK and JW report no conflicts of interest.

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Cummins, T., Jacoby, O., Hawi, Z. et al. Alpha-2A adrenergic receptor gene variants are associated with increased intra-individual variability in response time. Mol Psychiatry 19, 1031–1036 (2014). https://doi.org/10.1038/mp.2013.140

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