Dataset Information

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

ABSTRACT: 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.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 single-nucleotide 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.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.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.

SUBMITTER: Markunas CA

PROVIDER: S-EPMC3085270 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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

Markunas Christina A CA Quinn Kaia S KS Collins Ann L AL Garrett Melanie E ME Lachiewicz Ave M AM Sommer Jennifer L JL Morrissey-Kane Erin E Kollins Scott H SH Anastopoulos Arthur D AD Ashley-Koch Allison E AE

Psychiatric genetics 20100401 2

<h4>Objective</h4>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.<h4>Methods</h4>Conners' Parent (CPRS ...[more]

PMID: 20032819

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Project description:BackgroundFor the diagnosis of attention-deficit/hyperactivity disorder (ADHD), the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) proposes that adherence to six symptoms in either group (inattention and hyperactivity/impulsivity) will lead to the diagnosis of one of three presentations of the disorder. Underlying this diagnostic algorithm is the assumption that the 18 symptoms have equal relevance for the diagnosis of ADHD, all are equally severe, and all have the same power to detect the presence of the disorder in all its degrees of severity, without considering the possibility of using marker symptoms. However, several studies have suggested that ADHD symptoms differ in both their power to discriminate the presence of the disorder and the degree of severity they represent. The aim of the present study was to replicate the results of previous research by evaluating the discriminative capacity and relative severity of ADHD symptoms, as well as to extend the investigation of this topic to Spanish-speaking Latin American samples.MethodsThe properties of ADHD symptoms rated by the parents of 474 Chilean children were analyzed. Symptom parameters were estimated using the graded response model.ResultsThe results suggest that symptoms of ADHD differ substantially in both the accuracy with which they reflect the presence of the disorder, and their relative severity. Symptoms "easily distracted by extraneous stimuli" and "have difficulty sustaining attention in tasks" (inattention) and "is on the go, acting as if driven by motor" (hyperactivity/impulsivity) were the most informative, and those with relatively lower severity thresholds.DiscussionThe fact that symptoms differ substantially in the probability of being observed conditionally to the trait level suggests the need to refine the diagnostic process by weighting the severity of the symptom, and even to assess the possibility of defining ADHD marker symptoms, as has been done in other disorders.

Project description:Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p < .05) risk SNPs were classified into independent haplotype blocks. All SNPs, including imputed SNPs within these blocks, and haplotypes across each block, were explored for replication of associations in both samples. The potential biological functions of all risk SNPs were predicted using a series of bioinformatics analyses, their regulatory effects on the putamen volumes were tested, and the KTN1 mRNA expression was examined in three independent human putamen tissue samples. We found that fifteen SNPs were nominally associated with ADHD (p < .05) in the first sample, and three of them remained significant even after correction for multiple testing (1.3 × 10-10 ≤ p ≤ 1.2 × 10-4 ; α = 2.5 × 10-3 ). These 15 risk SNPs were located in five haplotype blocks, and 13 SNPs within four of these blocks were associated with ADHD in the second sample. Six haplotypes within these blocks were also significantly (1.2 × 10-7 ≤ p ≤ .009) associated with ADHD in these samples. These risk variants were located in disease-related transposons and/or transcription-related functional regions. Major alleles of these risk variants significantly increased putamen volumes. Finally, KTN1 mRNA was significantly expressed in putamen across three independent cohorts. We concluded that the KTN1 variants were significantly associated with ADHD. KTN1 may play a functional role in the development of ADHD.

Dataset Information

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

Publications

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

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