SLC2A3 single‐nucleotide polymorphism and duplication influence cognitive processing and population‐specific risk for attention‐deficit/hyperactivity disorder

Medientyp: E-Artikel
Titel: SLC2A3 single‐nucleotide polymorphism and duplication influence cognitive processing and population‐specific risk for attention‐deficit/hyperactivity disorder
Beteiligte: Merker, Sören; Reif, Andreas; Ziegler, Georg C.; Weber, Heike; Mayer, Ute; Ehlis, Ann‐Christine; Conzelmann, Annette; Johansson, Stefan; Müller‐Reible, Clemens; Nanda, Indrajit; Haaf, Thomas; Ullmann, Reinhard; Romanos, Marcel; Fallgatter, Andreas J.; Pauli, Paul; Strekalova, Tatyana; Jansch, Charline; Vasquez, Alejandro Arias; Haavik, Jan; Ribasés, Marta; Ramos‐Quiroga, Josep Antoni; Buitelaar, Jan K.; Franke, Barbara; Lesch, Klaus‐Peter
Erschienen: Wiley, 2017
Erschienen in: Journal of Child Psychology and Psychiatry
Sprache: Englisch
DOI: 10.1111/jcpp.12702
ISSN: 0021-9630; 1469-7610
Schlagwörter: Psychiatry and Mental health ; Developmental and Educational Psychology ; Pediatrics, Perinatology and Child Health
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Beschreibung: <jats:sec><jats:title>Background</jats:title><jats:p>Attention‐deficit/hyperactivity disorder (<jats:styled-content style="fixed-case">ADHD</jats:styled-content>) is a common, highly heritable neurodevelopmental disorder with profound cognitive, behavioral, and psychosocial impairments with persistence across the life cycle. Our initial genome‐wide screening approach for copy number variants (<jats:styled-content style="fixed-case">CNV</jats:styled-content>s) in <jats:styled-content style="fixed-case">ADHD</jats:styled-content> implicated a duplication of <jats:italic><jats:styled-content style="fixed-case">SLC</jats:styled-content>2A3</jats:italic>, encoding glucose transporter‐3 (<jats:styled-content style="fixed-case">GLUT</jats:styled-content>3). <jats:styled-content style="fixed-case">GLUT</jats:styled-content>3 plays a critical role in cerebral glucose metabolism, providing energy for the activity of neurons, which, in turn, moderates the excitatory–inhibitory balance impacting both brain development and activity‐dependent neural plasticity. We therefore aimed to provide additional genetic and functional evidence for <jats:styled-content style="fixed-case">GLUT</jats:styled-content>3 dysfunction in <jats:styled-content style="fixed-case">ADHD</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Case–control association analyses of <jats:italic><jats:styled-content style="fixed-case">SLC</jats:styled-content>2A3</jats:italic> single‐nucleotide polymorphisms (<jats:styled-content style="fixed-case">SNP</jats:styled-content>s) and <jats:styled-content style="fixed-case">CNV</jats:styled-content>s were conducted in several European cohorts of patients with childhood and adult <jats:styled-content style="fixed-case">ADHD</jats:styled-content> (<jats:styled-content style="fixed-case">SNP</jats:styled-content>,<jats:italic> n</jats:italic> = 1,886 vs. 1,988; <jats:styled-content style="fixed-case">CNV</jats:styled-content>,<jats:italic> n</jats:italic> = 1,692 vs. 1,721). These studies were complemented by <jats:italic><jats:styled-content style="fixed-case">SLC</jats:styled-content>2A3</jats:italic> expression analyses in peripheral cells, functional <jats:styled-content style="fixed-case">EEG</jats:styled-content> recordings during neurocognitive tasks, and ratings of food energy content.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Meta‐analysis of all cohorts detected an association of <jats:styled-content style="fixed-case">SNP</jats:styled-content> rs12842 with <jats:styled-content style="fixed-case">ADHD</jats:styled-content>. While <jats:styled-content style="fixed-case">CNV</jats:styled-content> analysis detected a population‐specific enrichment of <jats:italic><jats:styled-content style="fixed-case">SLC</jats:styled-content>2A3</jats:italic> duplications only in German <jats:styled-content style="fixed-case">ADHD</jats:styled-content> patients, the <jats:styled-content style="fixed-case">CNV</jats:styled-content> + rs12842 haplotype influenced <jats:styled-content style="fixed-case">ADHD</jats:styled-content> risk in both the German and Spanish cohorts. Duplication carriers displayed elevated <jats:italic><jats:styled-content style="fixed-case">SLC</jats:styled-content>2A3</jats:italic> m<jats:styled-content style="fixed-case">RNA</jats:styled-content> expression in peripheral blood cells and altered event‐related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of <jats:styled-content style="fixed-case">ADHD</jats:styled-content>, and an underestimation of energy units of high‐caloric food.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Taken together, our results indicate that both common and rare <jats:italic><jats:styled-content style="fixed-case">SLC</jats:styled-content>2A3</jats:italic> variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to <jats:styled-content style="fixed-case">ADHD</jats:styled-content> risk.</jats:p></jats:sec>

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