Abstract
Attention deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, with genetic factors accounting for 75–80% of the phenotypic variance. Recent studies have suggested that ADHD patients might present with atypical central myelination that can persist into adulthood. Given the essential role of sphingolipids in myelin formation and maintenance, we explored genetic variation in sphingolipid metabolism genes for association with ADHD risk. Whole-exome genotyping was performed in three independent cohorts from disparate regions of the world, for a total of 1520 genotyped subjects. Cohort 1 (MTA (Multimodal Treatment study of children with ADHD) sample, 371 subjects) was analyzed as the discovery cohort, while cohorts 2 (Paisa sample, 298 subjects) and 3 (US sample, 851 subjects) were used for replication. A set of 58 genes was manually curated based on their roles in sphingolipid metabolism. A targeted exploration for association between ADHD and 137 markers encoding for common and rare potentially functional allelic variants in this set of genes was performed in the screening cohort. Single- and multi-locus additive, dominant and recessive linear mixed-effect models were used. During discovery, we found statistically significant associations between ADHD and variants in eight genes (GALC, CERS6, SMPD1, SMPDL3B, CERS2, FADS3, ELOVL5, and CERK). Successful local replication for associations with variants in GALC, SMPD1, and CERS6 was demonstrated in both replication cohorts. Variants rs35785620, rs143078230, rs398607, and rs1805078, associated with ADHD in the discovery or replication cohorts, correspond to missense mutations with predicted deleterious effects. Expression quantitative trait loci analysis revealed an association between rs398607 and increased GALC expression in the cerebellum.
Highlights
Attention deficit hyperactivity disorder (ADHD) is defined as a neurodevelopmental condition characterized by persistent, cross-situational and developmentally inappropriate levels of inattention, hyperactivity, and impulsiveness that leads to various degrees of functional impairment[1]
Interesting results have emerged from studies of candidate genes involved in the monoamine neurotransmitter systems, which had been implicated in the pathophysiology of ADHD by the mechanisms of action of drugs used in clinical management
Using the singlelocus linear mixed-effect models (LMEMs), we identified seven markers significantly associated with persistent ADHD (Table 2a)
Summary
Attention deficit hyperactivity disorder (ADHD) is defined as a neurodevelopmental condition characterized by persistent, cross-situational and developmentally inappropriate levels of inattention, hyperactivity, and impulsiveness that leads to various degrees of functional impairment[1]. It is the most common neuro-behavioral disorder in childhood, affecting 5.29–7.1% of children and adolescents[2]. Interesting results have emerged from studies of candidate genes involved in the monoamine neurotransmitter systems, which had been implicated in the pathophysiology of ADHD by the mechanisms of action of drugs used in clinical management. Family-based and case–control studies of candidate genes have replicated significant linkage and/or association between ADHD and variants
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