Genetic variants in SLC9A9 are associated with measures of Attention-deficit/hyperactivity disorder symptoms in families

Abstract

Objective A family was previously identified that cosegregates a pericentric inversion, inv(3)(p14 : q21), with an early-onset developmental condition, characterized by impulsive behavior and intellectual deficit. The inversion breakpoints lie within DOCK3 and SLC9A9 at the p-arm and q-arm, respectively. Based on this report, these genes were selected to be evaluated in a family-based attention-deficit/hyperactivity disorder (AD/HD) association study. Methods Conners’ Parent (CPRS) and Teacher (CTRS) Rating Scales of AD/HD symptoms and Conners’ Continuous Performance Test (CPT) measures were collected and a minimal number of tagging singlenucleotide polymorphisms (SNPs) in each gene were selected for analysis. Analyses were performed on families who met research criteria for AD/HD. Using the program, QTDT, each tagging SNP was tested for association with T-scores from the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) subscales according to the CTRS and CPRS, and five CPT measures. Results After adjusting for multiple testing, a SNP in the 3′ UTR of SLC9A9, rs1046706, remained significantly associated (false discovery rate, q value < 0.05) with scores on the DSM-IV hyperactive-impulsive and total symptom subscales according to the CTRS and errors of commission on the CPT. In addition, an intronic SLC9A9 SNP, rs2360867, remained significantly associated with errors of commission. Conclusion Our results suggest that SLC9A9 may be related to hyperactive-impulsive symptoms in AD/HD and the disruption of SLC9A9 may be responsible for the behavioral phenotype observed in the inversion family. The association with SLC9A9 is particularly interesting as it was recently implicated in a genome-wide association study for AD/HD. Further investigation of the role of SLC9A9 in AD/HD and other behavioral disorders is warranted.

Effects of Npas4 deficiency on anxiety, depression-like, cognition and sociability behaviour

“…We had hypothesised that we would see differences in social behaviour between phenotypes in this test, as Npas4 has been linked to neurodevelopmental disorders such as schizophrenia and autism in animal models of social, cognition and sensorimotor gating impairments [15] and of rearing in social isolation [37,38]. Npas4 has also been linked to attention-deficit hyperactivity disorder [39][40][41] and autism comorbid with epilepsy [42] in patient populations, through mutations affecting the SLC9A9 gene, a putative target of Npas4 [42]. However, the social behaviour of all genotypes was found to be normal, with all mice preferring to socialise in the first phase of the sociability test, and spend more time with the novel stranger mouse in the preference for social novelty stage.…”

Emerging roles of Na+/H+ exchangers in epilepsy and developmental brain disorders

“…It is not classified as an X-linked intellectual disability, but it does affect more males than females, with ratios ranging from 1:3 to 1:16, depending on country (Novik et al, 2006). Several genome wide association studies have suggested correlations between SLC9A9 and ADHD (Brookes et al, 2006; Lasky-Su et al, 2008; Markunas et al, 2010). NHE9 interacts with regulatory proteins at the intracellular C-terminal juxtamembrane domain (Zhang-James et al, 2011).…”

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…By genetic approaches, NHE9 was linked to attention-deficit hyperactivity disorder (ADHD), addiction and mental retardation [37,102,153,109]. Several rare nonsense and missense mutations not found otherwise in asymptomatic individuals were described in affected patients.…”