TY - JOUR
T1 - SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder
AU - Merker, Soeren
AU - Reif, Andreas
AU - Ziegler, Georg C.
AU - Weber, Heike
AU - Mayer, Ute
AU - Ehlis, Ann-Christine
AU - Conzelmann, Annette
AU - Johansson, Stefan
AU - Mueller-Reible, Clemens
AU - Nanda, Indrajit
AU - Haaf, Thomas
AU - Ullmann, Reinhard
AU - Romanos, Marcel
AU - Fallgatter, Andreas J.
AU - Pauli, Paul
AU - Strekalova, Tatyana
AU - Jansch, Charline
AU - Vasquez, Alejandro Arias
AU - Haavik, Jan
AU - Ribases, Marta
AU - Antoni Ramos-Quiroga, Josep
AU - Buitelaar, Jan K.
AU - Franke, Barbara
AU - Lesch, Klaus-Peter
PY - 2017/7
Y1 - 2017/7
N2 - Background: Attention-deficit/hyperactivity disorder (ADHD) 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 (CNVs) in ADHD implicated a duplication of SLC2A3, encoding glucose transporter-3 (GLUT3). GLUT3 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 GLUT3 dysfunction in ADHD. Methods: Case-control association analyses of SLC2A3 single-nucleotide polymorphisms (SNPs) and CNVs were conducted in several European cohorts of patients with childhood and adult ADHD (SNP, n = 1,886 vs. 1,988; CNV, n = 1,692 vs. 1,721). These studies were complemented by SLC2A3 expression analyses in peripheral cells, functional EE Grecordings during neurocognitive tasks, and ratings of food energy content. Results: Meta-analysis of all cohorts detected an association of SNP rs12842 with ADHD. While CNV analysis detected a population-specific enrichment of SLC2A3 duplications only in German ADHD patients, the CNV + rs12842 haplotype influenced ADHD risk in both the German and Spanish cohorts. Duplication carriers displayed elevated SLC2A3 mRNA expression in peripheral blood cells and altered event-related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of ADHD, and an underestimation of energy units of high-caloric food. Conclusions: Taken together, our results indicate that both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to ADHD risk.
AB - Background: Attention-deficit/hyperactivity disorder (ADHD) 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 (CNVs) in ADHD implicated a duplication of SLC2A3, encoding glucose transporter-3 (GLUT3). GLUT3 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 GLUT3 dysfunction in ADHD. Methods: Case-control association analyses of SLC2A3 single-nucleotide polymorphisms (SNPs) and CNVs were conducted in several European cohorts of patients with childhood and adult ADHD (SNP, n = 1,886 vs. 1,988; CNV, n = 1,692 vs. 1,721). These studies were complemented by SLC2A3 expression analyses in peripheral cells, functional EE Grecordings during neurocognitive tasks, and ratings of food energy content. Results: Meta-analysis of all cohorts detected an association of SNP rs12842 with ADHD. While CNV analysis detected a population-specific enrichment of SLC2A3 duplications only in German ADHD patients, the CNV + rs12842 haplotype influenced ADHD risk in both the German and Spanish cohorts. Duplication carriers displayed elevated SLC2A3 mRNA expression in peripheral blood cells and altered event-related potentials reflecting deficits in working memory and cognitive response control, both endophenotypic traits of ADHD, and an underestimation of energy units of high-caloric food. Conclusions: Taken together, our results indicate that both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in neurocognitive deficits known to contribute to ADHD risk.
KW - Attention-deficit/hyperactivity disorder
KW - glucose transporter
KW - SLC2A3
KW - single-nucleotide polymorphisms
KW - duplication
KW - copy number variants
KW - energy homeostasis
KW - frontostriatal network
KW - DEFICIT HYPERACTIVITY DISORDER
KW - GLUCOSE-TRANSPORTER EXPRESSION
KW - GENOME-WIDE ASSOCIATION
KW - NEUROTRANSMITTER HOMEOSTASIS
KW - SUSCEPTIBILITY GENE
KW - WORKING-MEMORY
KW - RARE VARIANTS
KW - IGF-I
KW - BRAIN
KW - BEHAVIOR
U2 - 10.1111/jcpp.12702
DO - 10.1111/jcpp.12702
M3 - Article
C2 - 28224622
SN - 0021-9630
VL - 58
SP - 798
EP - 809
JO - Journal of Child Psychology and Psychiatry
JF - Journal of Child Psychology and Psychiatry
IS - 7
ER -