Abstract
BackgroundLow serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. Here we demonstrate the separation of aggressive and cognitive components of impulsivity from symptom ratings and test their association with 5-HT and functionally related genes using a family-based association test (FBAT-PC).MethodsOur sample consisted of 1180 offspring from 607 families from the International Multicenter ADHD Genetics (IMAGE) study. Impulsive symptoms were assessed using the long forms of the Conners and the Strengths and Difficulties parent and teacher questionnaires. Factor analysis showed that the symptoms aggregated into parent- and teacher-rated behavioral and cognitive impulsivity. We then selected 582 single nucleotide polymorphisms (SNPs) from 14 genes directly or indirectly related to 5-HT function. Associations between these SNPs and the behavioral/cognitive groupings of impulsive symptoms were evaluated using the FBAT-PC approach.ResultsIn the FBAT-PC analysis for cognitive impulsivity 2 SNPs from the gene encoding phenylethanolamine N-methyltransferase (PNMT, the rate-limiting enzyme for adrenalin synthesis) attained corrected gene-wide significance. Nominal significance was shown for 12 SNPs from BDNF, DRD1, HTR1E, HTR2A, HTR3B, DAT1/SLC6A3, and TPH2 genes replicating reported associations with ADHD. For overt aggressive impulsivity nominal significance was shown for 6 SNPs from BDNF, DRD4, HTR1E, PNMT, and TPH2 genes that have also been reported to be associated with ADHD. Associations for cognitive impulsivity with a SERT/SLC6A4 variant (STin2: 12 repeats) and aggressive behavioral impulsivity with a DRD4 variant (exon 3: 3 repeats) are also described.DiscussionA genetic influence on monoaminergic involvement in impulsivity shown by children with ADHD was found. There were trends for separate and overlapping influences on impulsive-aggressive behavior and cognitive impulsivity, where an association with PNMT (and arousal mechanisms affected by its activity) was more clearly involved in the latter. Serotonergic and dopaminergic mechanisms were implicated in both forms of impulsivity with a wider range of serotonergic mechanisms (each with a small effect) potentially influencing cognitive impulsivity. These preliminary results should be followed up with an examination of environmental influences and associations with performance on tests of impulsivity in the laboratory.
Highlights
Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness
Having identified the single nucleotide polymorphism (SNP)/model combinations listed in table 4, we examined the associations with attention-deficit/hyperactivity disorder (ADHD) affection status
It has been suggested that one of the key goals for ADHD research should be to parse that heterogeneity, to create more neurobiologically homogeneous sub-groupings so as to provide more refined diagnostic criteria and more specific treatment targets [91]. One manifestation of such a strategy is the search for endophenotypes, for pathophysiologic markers that mediate the pathways from genetic and environmental risk to disorder [92]. From this perspective the current differentiation between two types of impulsiveness on the basis of their associated genes and their behavioral characteristics both highlight these constructs as putative endophenotypes for ADHD and encourage further research to explore the possibility that two 'subtypes' of ADHD might exist marked by different types of impulsiveness
Summary
Low serotonergic (5-HT) activity correlates with increased impulsive-aggressive behavior, while the opposite association may apply to cognitive impulsiveness. Both types of impulsivity are associated with attention-deficit/hyperactivity disorder (ADHD), and genes of functional significance for the 5-HT system are implicated in this disorder. The risky and overly rapid decisions behind these actions demonstrate a cognitive component that is often revealed in gambling and seeking immediate gratification. Impulsivity is a core construct of many mental disorders [1] It is an essential component of the diagnosis of the most prevalent form of attention-deficit/hyperactivity disorder ADHD, namely the 'combined type' (ADHD-ct: [2]). This article focuses on serotonin activity, [4]) and heritable features of ADHD, where a 70–80% heritability has been clearly demonstrated [5]
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