Testing Genetic Modifiers of Behavior and Response to Atomoxetine in Autism Spectrum Disorder with ADHD

Abstract

Background Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (TPH2), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT, SLC6A3). Method We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites. Results There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score (p=0.03). DBH rs1611115 genotype was associated with ADI-R Social score (p=0.002) and Restrictive/Repetitive Behavior score (p=0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p=0.01 and SNAP ADHD p=0.03), replicating a previous finding. Conclusions We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD.

Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder

“…Candidate TPH2 variants including the ones in our study have long been well replicated in case of MDD (Mandelli et al, 2012;Van der Auwera et al, 2014;Han et al, 2017). Further, associations between TPH2 polymorphisms and ASD susceptibility particularly repetitive and stereotyped behaviors suggesting that they might affect the ASD phenotypes and augment ASD susceptibility have been reported (Coon et al, 2005;Yang et al, 2012;Barrie et al, 2018). However, in our treatment group the rs11178997 with AT genotype demonstrated significantly higher expression language raw scores than the TT genotype.…”

“…In addition, case-control and family-based investigations with molecular approaches unveiled serotonin-associated candidate genes in ASD including tryptophan hydroxylase 2 (TPH2), Brain-Derived Neurotrophic Factor (BDNF) and Matrix metallopeptidase 9 (MMP-9) (Noroozi et al, 2016;Meng et al, 2017;Barrie et al, 2018). TPH2 is a gene located on chromosome 12 encoding for a rate-limiting enzyme for brain serotonin synthesis playing a role in ASD susceptibility associated phenotypic impairments and repetitive behavior (Coon et al, 2005;McKinney et al, 2005;Zafeiriou et al, 2009).…”

Catecholaminergic and Cholinergic Neuromodulation in Autism Spectrum Disorder: A Comparison to Attention-Deficit Hyperactivity Disorder

“…Furthermore, in an ASD sample, DBH was associated with both ASD and ADHD behaviors (Barrie et al 2018).…”

Presence of recombination hotspots throughout SLC6A3

“…In this targeted deep-sequencing study, we uncover unique and common polymorphisms and haplotypes, and recombination hotspots for two major U.S. populations, African Americans (AAs) and European Americans (EAs), for finding generalization. The findings may help explain the mixed association findings[25, 70, 71] and instruct our future strategy for identifying disease loci in SLC6A3 [29, 72, 73].…”