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'SLC2A3' Single-Nucleotide Polymorphism and Duplication Influence Cognitive Processing and Population-Specific Risk for Attention-Deficit/Hyperactivity Disorder

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Title: 'SLC2A3' Single-Nucleotide Polymorphism and Duplication Influence Cognitive Processing and Population-Specific Risk for Attention-Deficit/Hyperactivity Disorder
Language: English
Authors: 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
Source: Journal of Child Psychology and Psychiatry. Jul 2017 58(7):798-809.
Availability: Wiley-Blackwell. 350 Main Street, Malden, MA 02148. Tel: 800-835-6770; Tel: 781-388-8598; Fax: 781-388-8232; e-mail: cs-journals@wiley.com; Web site: http://www.wiley.com/WileyCDA
Peer Reviewed: Y
Page Count: 12
Publication Date: 2017
Document Type: Journal Articles
Reports - Research
Descriptors: Attention Deficit Hyperactivity Disorder, Neurological Impairments, Genetic Disorders, Physiology, Metabolism, Children, Adults, Foreign Countries, Correlation, Meta Analysis, At Risk Persons, Cognitive Processes
Geographic Terms: Europe, Germany, Spain
DOI: 10.1111/jcpp.12702
ISSN: 0021-9630
Abstract: 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 EEG recordings 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.
Abstractor: As Provided
Entry Date: 2017
Accession Number: EJ1144957
Database: ERIC
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  Value: <anid>AN0123648582;jyy01jul.17;2024Jun04.08:16;v2.2.500</anid> <title id="AN0123648582-1">SLC2A3 single-nucleotide polymorphism and duplication influence cognitive processing and population-specific risk for attention-deficit/hyperactivity disorder. </title> <p>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 EEG recordings 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.</p> <p>Attention‐deficit/hyperactivity disorder; glucose transporter; SLC2A3; single‐nucleotide polymorphisms; duplication; copy number variants; energy homeostasis; frontostriatal network</p> <p>Investigation of both humans and rodents suggested SLC2A3, encoding the neuronal glucose transporter GLUT3, as a potential risk gene not only for several neuropsychiatric diseases, including dyslexia (Roeske et al., [<reflink idref="bib53" id="ref1">53</reflink>] ), schizophrenia (De Silva, [<reflink idref="bib12" id="ref2">12</reflink>] ; Kuzman, Medved, Terzic, & Krainc, [<reflink idref="bib31" id="ref3">31</reflink>] ), autism (O'Roak et al., [<reflink idref="bib44" id="ref4">44</reflink>] ; Zhao et al., [<reflink idref="bib80" id="ref5">80</reflink>] ), affective disorders (Yang et al., [<reflink idref="bib78" id="ref6">78</reflink>] ), and attention‐deficit/hyperactivity disorder (ADHD; Lesch et al., [<reflink idref="bib35" id="ref7">35</reflink>] ), but also neurodegenerative disorders, such as Huntington's disease (Vittori et al., [<reflink idref="bib66" id="ref8">66</reflink>] ). ADHD is a common, early onset and enduring neurodevelopmental disorder and persistence into adulthood is associated with considerable risk for comorbidity, such as depression, eating, and substance use disorders as well as failure in psychosocial adaptation (Geissler & Lesch, [<reflink idref="bib22" id="ref9">22</reflink>] ). Although substantial heritability of ADHD is documented, with estimates of ~80%, genome‐wide screenings and cross‐disorder approaches have pinpointed only a few ADHD‐related genes (Elia et al., [<reflink idref="bib13" id="ref10">13</reflink>] ; Jarick et al., [<reflink idref="bib27" id="ref11">27</reflink>] ; Lee et al., [<reflink idref="bib33" id="ref12">33</reflink>] ; Neale et al., [<reflink idref="bib42" id="ref13">42</reflink>] ; Sanchez‐Mora et al., [<reflink idref="bib55" id="ref14">55</reflink>] ; The Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, [<reflink idref="bib61" id="ref15">61</reflink>] ; Williams et al., [<reflink idref="bib71" id="ref16">71</reflink>] ). In a recent copy number variant (CNV) association analysis in patients with ADHD, we identified a duplication on chromosome 12p13.31 inherited from an ADHD‐affected mother (Lesch et al., [<reflink idref="bib35" id="ref17">35</reflink>] ). This duplication constitutes a low‐frequency CNV in the general population (Shaikh et al., [<reflink idref="bib58" id="ref18">58</reflink>] ). The duplicated chromosomal region comprises the complete gene locus of SLC2A3 and the initial exons of SLC2A14, a paralog of SLC2A3, which shares substantial identity but is specifically expressed in testis (Wu & Freeze, [<reflink idref="bib77" id="ref19">77</reflink>] ).</p> <p>The monosaccharide glucose is one of the key molecules in energy balance and metabolism. At the cellular level, the transfer of glucose across the plasma membrane is facilitated mainly by the SLC2A family of glucose transporters (GLUTs) comprising 14 members (GLUT1‐14) characterized by 12 transmembrane domains and divided into three classes (class I–III; Fladeby, Skar, & Serck‐Hanssen, [<reflink idref="bib17" id="ref20">17</reflink>] ). In humans, GLUT3, an isoform of class I, is ubiquitously expressed in the brain and represents the principal neuronal GLUT (Nagamatsu et al., [<reflink idref="bib41" id="ref21">41</reflink>] ; Vannucci, Maher, & Simpson, [<reflink idref="bib65" id="ref22">65</reflink>] ), although it is also detected in peripheral tissues including mononuclear blood cells. In comparison with other class I counterparts, GLUT3 displays a relatively low K<subs>m</subs> value for glucose reflecting high affinity, and also transports other substrates, such as galactose (Gould, Thomas, Jess, & Bell, [<reflink idref="bib24" id="ref23">24</reflink>] ). GLUT3 expression is regulated by various factors, for example, insulin (Maratou et al., [<reflink idref="bib38" id="ref24">38</reflink>] ), brain‐derived neurotrophic factor (Burkhalter, Fiumelli, Allaman, Chatton, & Martin, [<reflink idref="bib8" id="ref25">8</reflink>] ), or glucose deprivation (Fladeby et al., [<reflink idref="bib17" id="ref26">17</reflink>] ).</p> <p>GLUT3 protein is primarily located on neuron terminals and dendrites in neocortex and hippocampus providing glucose‐mediated energy for axonal transport and transmitter release (Mantych, James, Chung, & Devaskar, [<reflink idref="bib37" id="ref27">37</reflink>] ). Compromised GLUT3 function may represent a critical factor in the mechanism of energetic insufficiency in neurons. An energy deficit underlying neural network dysfunction, which results in impairments performing various neuropsychological tasks, has been conceptionalized by Killeen, Russell, and Sergeant ([<reflink idref="bib29" id="ref28">29</reflink>] ) as the ‘neuroenergetic model’ of ADHD.</p> <p>Here, we examined both tagging single‐nucleotide polymorphisms (SNPs) and a CNV of SLC2A3 for association with ADHD in several European cohorts. The functional consequences of SLC2A3 duplication were also assessed by analyzing mRNA and protein expression in human cell models. Finally, we tested for a link between allelic variation of SLC2A3 and altered cognitive processing in ADHD‐affected duplication carriers subjected to various neuropsychological tasks.</p> <hd id="AN0123648582-2">Materials and methods</hd> <hd id="AN0123648582-3">Cohorts</hd> <hd id="AN0123648582-4">SNP analysis</hd> <p>The case–control SNP association study was carried out in 536 adult ADHD patients (aADHD; 48% female; mean age 33.2 years, SD: 10.2) and in 195 children with ADHD (cADHD; 21.8% female; mean age 11.9 years, SD: 3.6) of German origin. Controls consisted of 536 healthy volunteers (53% females; mean age 31.5 years, SD: 9.1).</p> <hd id="AN0123648582-5">CNV analysis</hd> <p>In the CNV association study, an extended cohort of 713 patients with aADHD (45.3% female; mean age 33.4 years, SD: 10.3) and 272 cADHD patients (23.4% female; mean age 12.3 years, SD: 3.4) of German origin were enrolled. For controls, 775 healthy volunteers (56% female; mean age 30.3 years, SD: 8.9) originating from Germany participated. Cohorts and ascertainment procedures are described in detail in the Supporting information.</p> <hd id="AN0123648582-6">Replication samples (Dutch, Norwegian, and Spanish aADHD sample)</hd> <p>The SNP association study was replicated in samples from the IMpACT consortium which was described in detail previously (Franke et al., [<reflink idref="bib20" id="ref29">20</reflink>] ; Reif et al., [<reflink idref="bib50" id="ref30">50</reflink>] ). The replication sample included aADHD patients and controls of the following origin: The Netherlands (n<subs>cases</subs> = 403; n<subs>controls</subs> = 646), Norway (n<subs>cases</subs> = 448; n<subs>controls</subs> = 581), and Spain (n<subs>cases</subs> = 304; n<subs>controls</subs> = 225). Replication of the CNV study was carried out in the Dutch (n<subs>cases</subs> = 403; n<subs>controls</subs> = 646) and Spanish (n<subs>cases</subs> = 304; n<subs>controls</subs> = 300) IMpACT sample. For details, see Supporting information.</p> <p>The Ethics Committees of the respective universities approved the study and written informed consent was obtained from all patients and controls after procedures and aims of the study had been fully explained.</p> <hd id="AN0123648582-7">SLC2A3 genotyping</hd> <p>To capture allelic variation in SLC2A3 and its flanking regions (3,500 bp upstream; 1,000 bp downstream), six tag SNPs (rs12842, rs741361, rs2244822, rs7966327, rs933552, and rs7309332) were derived from HapMap CEU data (Frazer et al., [<reflink idref="bib21" id="ref31">21</reflink>] ) using the Tagger function as implemented in Haploview V3.32 (Barrett, Fry, Maller, & Daly, [<reflink idref="bib5" id="ref32">5</reflink>] ) with default settings (Figure [NaN] A,B). SNPs were genotyped as described in Supporting information.</p> <hd id="AN0123648582-8">Copy number analysis</hd> <p>Genotyping of the CNV, containing SLC2A3, was performed using a FAM‐labeled SLC2A3 copy number assay Hs 04406005_cn and the VIC‐labeled RNase P Control Reagent Kit (Applied Biosystems, Foster City, CA). Twelve duplications were confirmed and fine mapped by array comparative genomic hybridization (aCGH) by cohybridizing differentially labeled total genomic sample and reference DNAs onto arrays of custom high‐density oligo microarrays (Agilent Inc., Santa Clara, CA, Figure [NaN] ). For details, see Supporting information.</p> <hd id="AN0123648582-9">Statistical analysis of association</hd> <hd id="AN0123648582-10">SNP and haplotype analysis</hd> <p>For SNP analysis, generalized linear models (GLM) implemented in the R V2.10 (<ulink href="http://www.r-project.org">http://www.r-project.org</ulink>) function glm() were carried out to test for an association between SNP genotype as a independent variable and aADHD as a binary dependent variable. Haplotype associations were calculated by two‐sided chi‐square tests. Both SNPs and haplotypes were adjusted for multiple testing using Bonferroni correction.</p> <hd id="AN0123648582-11">CNV analysis</hd> <p>Analysis of CNV data was also examined with GLM. Furthermore, an additive model was calculated, in which participants were grouped according to their SNP and CNV risk alleles.</p> <hd id="AN0123648582-12">Meta‐analysis</hd> <p>To display common effects of the examined genetic risk factors (SNP, CNV, and SNP + CNV) on the pathogenesis of ADHD, we calculated ORs as a measure for effect size and applied the Q‐statistic to assess heterogeneity (for details, see Supporting information; Fleiss, [<reflink idref="bib18" id="ref33">18</reflink>] ; Lau, Ioannidis, & Schmid, [<reflink idref="bib32" id="ref34">32</reflink>] ).</p> <hd id="AN0123648582-13">Cell culture</hd> <p>Epstein–Barr virus‐transformed lymphoblastoid cell lines (LCLs) with SLC2A3 duplication were generated from blood samples of aADHD patients. Immortalized LCLs were propagated and maintained in standard medium. Native peripheral blood mononuclear cell (PBMC) samples of duplication carriers with ADHD were also collected (for details, see Supporting information).</p> <hd id="AN0123648582-14">SLC2A3 expression analysis</hd> <p>Total RNA was extracted from native mononuclear cell suspensions and LCLs. After reverse transcription of 500 ng RNA per sample, qRT‐PCR was performed in a 384‐well cycler. For Western blotting, cells were lysed, 10 μg of each sample was subjected to a reducing 4–12% SDS‐PAGE, membranes were incubated overnight with anti‐GLUT3 antibody and quantification of GLUT3 protein was performed by densitometry (for details, see Supporting information).</p> <hd id="AN0123648582-15">Neurocognitive tasks</hd> <p>Attention‐deficit/hyperactivity disorder patients (n = 144) and healthy controls (n = 71) participated in functional brain activation studies with EEG performing a Go‐NoGo task (continuous performance test, CPT) and a working memory (n‐back) task. Furthermore, age‐ and sex‐matched subgroups rated the palatability and energy content of food. Details of participants, tasks, and statistical analyses are described in Supporting information.</p> <hd id="AN0123648582-16">Results</hd> <hd id="AN0123648582-17">SNP‐based case–control association studies</hd> <p>To test for association between common SNPs in SLC2A3 and ADHD, six SNPs were genotyped first in the German cohort comprising patients with cADHD and aADHD (Table [NaN] , Figure [NaN] ). Single‐marker analysis of cADHD, aADHD, and of both cohorts combined (comb), revealed that the minor allele (T) of rs12842 was significantly enriched in cases as compared to controls (p<subs>cADHD</subs> = .0016, p<subs>aADHD</subs> = .0038, p<subs>comb</subs> = .0006; Table [NaN] ) remaining significant after Bonferroni correction (p<subs>cADHD</subs> = .008, p<subs>aADHD</subs> = .019, p<subs>comb</subs> = .003; Table [NaN] ). When the three IMpACT replication samples were analyzed individually, no significant effect emerged, neither in the samples alone, nor the combined replication sample (Table [NaN] ). However, in all three samples, the OR > 1 was consistent with the association in the German cohort, with an overlap in the confidence interval of 37–69%. When all samples were subjected to meta‐analysis, rs12842 remained to be significant with a p = .002 corresponding to an OR of 1.27 (95% CI 1.09–1.47; Figure [NaN] A). While none of the other SNPs showed significant association with ADHD (Table [NaN] ; Figure [NaN] ), haplotype analysis revealed a nominal association of haploblock 1 (consisting of rs12842, rs741361, and rs2244822) with aADHD (p<subs>aADHD</subs> = .049, p<subs>comb</subs> = .021; Table [NaN] ) in the German sample.</p> <hd id="AN0123648582-18">CNV‐based case–control association studies</hd> <p>Predicting that rs12842 indicates synthetic association of a functional variant (Kent, [<reflink idref="bib28" id="ref35">28</reflink>] ) and based on the identification of a SLC2A3 duplication segregating with ADHD in our initial CNV screen (Lesch et al., [<reflink idref="bib35" id="ref36">35</reflink>] ), we tested whether there is also an association with ADHD at the population‐based level (Table [NaN] ). We have verified the CNV by array CGH in 12 duplication carriers (Figure [NaN] ) by fluorescence in situ hybridization (Figure [NaN] ). In both, the cADHD (N = 272) and aADHD (N = 713) sample of the German cohort, risk was found to significantly increase with SLC2A3 copy number (OR<subs>cADHD</subs> = 2.247; p = .012; OR<subs>aADHD</subs> = 1.632; p = .048). Combination of the two German samples (985 cases vs. 775 controls) revealed a significant excess of SLC2A3 duplications. In cases, 45 duplications (4.6%) were found, while there were only 20 duplications in the controls (2.6%), resulting in a p = .015 (OR = 1.759). A combined meta‐analysis of the German cohort with the Spanish and Dutch IMpACT aADHD replication samples (1,692 cases vs. 1,721 controls) did not reach significance for an association of the CNV with ADHD [p = .229; OR = 1.26 (95% CI 0.89–1.77)] (Figure [NaN] B).</p> <p>While the analyzed risk factors, rs12842 and the CNV, are not dependent on other variants (p = .99), the probability to develop ADHD was highest in carriers of both risk alleles. Carriers of either the rs12842 T‐allele or the CNV (‘single risk’) and carriers of both variants (‘double risk’) were significantly more enriched in the German cADHD (p = .003) and aADHD (p = .001) samples and revealed an association at p = .0003 upon combination of both samples (Table [NaN] ). Neither the Dutch nor the Spanish sample showed significance in the combined model (p<subs>NL</subs> = .918; p<subs>ES</subs> = .220; Table [NaN] ), although in both samples, the OR > 1 was consistent with the German sample, with a confidence interval overlap of 33–100%. In the meta‐analysis of all samples examined with the combined model (no risk‐allele carrier vs. single and double risk‐allele carrier), the additive effect of both variants was significant [p = .002; OR = 1.36 (95% CI 1.12–1.64)] (Figure [NaN] C).</p> <hd id="AN0123648582-19">SLC2A3 expression analysis</hd> <p>Quantitative RT‐PCR revealed a strong impact of SLC2A3 duplication on SLC2A3 mRNA expression both in PBMCs and LCLs with mean normalized relative expression values (mean Q<subs>n</subs>) being significantly higher in duplication carriers (Figure [NaN] A,B). In PBMCs, this group difference was ~220% (U = 6.0, p < .001), whereas it was 73.1% in LCLs (U = 37.0, p = .001). While differences in GLUT3 protein concentration and cellular glucose uptake did not reach significance between groups, GLUT3 was nominally increased by 37% in PBMCs of duplication carriers (Figure [NaN] ).</p> <hd id="AN0123648582-20">Neurocognitive tasks</hd> <p>In the continuous performance task (CPT), ADHD patients carrying the SLC2A3 duplication showed reduced NoGo‐anteriorization (NGA) as a marker of altered medial prefrontal brain activity with a large effect size (0.31 ± 0.57 vs. 0.85 ± 0.37; t<subs>16</subs> = 2.36, p = .031, d = 1.12; Figure [NaN] A). This effect was based on the centroid of the Go‐condition which was located more anterior (3.33 ± 0.52 vs. 3.91 ± 0.25; t<subs>12</subs> = 3.008, p = .011, d = 1.42). No difference was observed in the sample of healthy individuals and between the two groups in the NoGo topography (t<subs>16</subs> = 0.302, p = .767, d = 0.13). Regarding rs12842, ANOVA of between‐subject variables ‘genotype’ (T‐ vs. C‐allele carriers) and ‘diagnosis’ (ADHD vs. healthy controls) revealed an interaction between factors (F<subs>1,211</subs> = 4.16, p < .05, ηp2 = .019), with the subgroup of ADHD C‐allele carriers showing reduced NGA values compared to controls (t<subs>161</subs> = 2.99, p = .003, d = 0.49; Figure [NaN] B).</p> <p>In the working memory task (n‐back), analysis of the amplitude of the P300, repeated‐measures ANOVA showed a main effect of genotype (SLC2A3 duplication noncarriers vs. carriers) within the group of ADHD patients (F<subs>1,16</subs> = 11.91, p = .003, ηp2 = .43) with overall higher values in noncarriers. Significant interactions between copy number status and ‘condition’ (1‐back vs. 2‐back; F<subs>1,16</subs> = 5.74, p = .029, ηp2 = .26) as well as ‘trial type’ (target vs. nontarget; F<subs>1,16</subs> = 4.70, p = .046, ηp2 = .23) prompted post hoc tests showing that this effect was particularly prominent for 1‐back (t<subs>16</subs> = 3.94, p = .001, d = 1.85) as well as target trials (t<subs>14</subs> = 3.44, p = .004, d = 1.62; Figure [NaN] A). Moreover, a decrease in P300 amplitudes from 1‐back to 2‐back blocks as well as from target to nontarget trials was only observable within the ADHD group of noncarriers (t<subs>8</subs> = 5.38, p = .01, d = 1.79 and t<subs>8</subs> = 3.08, p = .015, d = 1.03, respectively) indicating modulation in information processing that did not occur in carriers of the duplication; in this group of carriers, no significant difference in P300 amplitudes was observed between the 1‐back and 2‐back condition as well as between target and nontarget trials, which was confirmed by effect size measures indicating only very small effects for these two contrasts (t<subs>8</subs> = 0.15, p = .89, d = 0.05 and t<subs>8</subs> = 0.38, p = .72, d = 0.13, respectively). While the P300 component for rs12842 was not altered, for the N200, an event‐related potential (ERP) component primarily associated with inhibition and conflict processing during cognitively demanding tasks, a trend for a main effect ‘genotype’ with a tendency for overall reduced latencies in T‐allele carriers was detected (F<subs>1,173</subs> = 2.87, p < .1, ηp2 = .016). This effect was further qualified by the n‐back trial type (target vs. nontarget) as indicated by a significant interaction between both factors (F<subs>1,173</subs> = 8.37, p = .004, ηp2 = .046). Post hoc analyses confirmed that across groups C‐allele carriers showed a significant increase in N200 latencies for nontarget (214.2 ± 19.3 ms) as compared to target trials (199.7 ± 24.2 ms; t<subs>134</subs> = 8.13, p < .001; Wilcoxon Z = 8.0, p < .001, d = 0.70), an effect that did not occur in T‐allele carriers at a significant level (t<subs>41</subs> = 1.15, Z = 1.90, n.s.; also note the small effect size: d = 0.18; Figure [NaN] B). Moreover, rs12842 C‐allele carriers showed increased N200 latencies compared to T‐allele carriers for nontarget 2‐back trials in ADHD patients (t<subs>34</subs> = 2.80, p = .008, d = 0.68; Figure [NaN] B).</p> <p>In a test measuring reactivity toward food cues the stimulus effect for the rating of energy units revealed higher ratings of calories for high‐ as compared to low‐caloric food (F<subs>1,39</subs> = 60.0, p < .001). While there was a trend for a group effect (F<subs>2,39</subs> = 2.6, p = .088), a significant interaction group × stimulus (F<subs>3,39</subs> = 3.4, p = .044) was revealed (Figure [NaN] ). The ADHD duplication carriers rated the amount of calories of high‐caloric food to be lower in comparison to controls (p = .050). For further details on the results, see Supporting information.</p> <hd id="AN0123648582-21">Discussion</hd> <p>We report evidence for an association of both common and low‐frequency SLC2A3 variants with ADHD. While SNP rs12842, which tags almost the entire SLC2A3 region, was replicably associated with ADHD across several European samples, the SLC2A3 duplication reached significance only in the German cohort, suggesting population‐specificity of the SLC2A3 CNV‐linked disease risk (Choudhury et al., [<reflink idref="bib10" id="ref37">10</reflink>] ). This is further supported by the notion that rs12842 tags synthetic association with a functional CNV (Kent, [<reflink idref="bib28" id="ref38">28</reflink>] ), and also confers risk independently. A maturing view of the role of genetic variation in pathogenesis of neurodevelopmental disorders suggests that, in addition to a large number of common variants with very modest effect size, rare mutations of severe effect are responsible for a substantial portion of disease, but are specific for a subgroup of affected patients (Lesch, [<reflink idref="bib34" id="ref39">34</reflink>] ). It is biologically plausible that evolutionary forces generate this vast genetic heterogeneity in disease, specifically ADHD, which may have been under positive selective pressure in ancient hunter‐gatherer societies, by introducing many new variants in each generation, each individually rare and specific to one population, single families, or even one person (Bevilacqua et al., [<reflink idref="bib6" id="ref40">6</reflink>] ; Lesch et al., [<reflink idref="bib35" id="ref41">35</reflink>] ; McClellan & King, [<reflink idref="bib39" id="ref42">39</reflink>] ; Palmer et al., [<reflink idref="bib46" id="ref43">46</reflink>] ; Piton et al., [<reflink idref="bib47" id="ref44">47</reflink>] ).</p> <p>The SLC2A3 duplication resulted in a gene dose‐dependent increase of mRNA expression in PBMCs which validates previously reported findings in fibroblast lines (Yang et al., [<reflink idref="bib78" id="ref45">78</reflink>] ). In contrast to the reported SLC2A3 copy number‐dependent changes in GLUT3 protein levels (Vittori et al., [<reflink idref="bib66" id="ref46">66</reflink>] ) and despite the striking impact of SLC2A3 CN on mRNA level, corresponding protein amounts, as assessed via semiquantitative analysis of whole‐cell GLUT3 protein, differences between carriers of SLC2A3 duplication and controls did not reach significance, neither in LCLs nor in PBMCs, although the direction of effect was similar. Inconsistencies between mRNA and protein levels of glucose transporters have been described in other expression studies in both PBMCs and muscle cells (Bourey, Koranyi, James, Mueckler, & Permutt, [<reflink idref="bib7" id="ref47">7</reflink>] ; Estrada et al., [<reflink idref="bib14" id="ref48">14</reflink>] ), which may be attributed to pretranslational mechanisms delimiting the quantity of GLUT protein as reported in rat brain (Nehlig et al., [<reflink idref="bib43" id="ref49">43</reflink>] ). On the other hand, it is also possible that posttranslational modifications are involved, as cells are capable of adapting to situations of altered energy demand via trafficking of different GLUT isoforms from intracellular vesicular pools to the cellular surface, thus changing the ratio of active to inactive GLUTs (Malide, Davies‐Hill, Levine, & Simpson, [<reflink idref="bib36" id="ref50">36</reflink>] ; Wilson, Mitsumoto, Maher, & Klip, [<reflink idref="bib74" id="ref51">74</reflink>] ). Therefore, the subcellular distribution of GLUT3 protein may differ between individuals with SLC2A3 copy number variation. Whether such regulatory mechanisms constitute a unique feature of peripheral blood cells or also occur in the brain, thus impacting neural plasticity/function and disease risk, remains to be elucidated.</p> <p>At the level of systems function, we showed that ADHD‐associated SLC2A3 variants influence ERPs during a CPT and an n‐back test which reliably assesses cognitive traits of response control and working memory representing endophenotypes for ADHD (Castellanos & Tannock, [<reflink idref="bib9" id="ref52">9</reflink>] ; Fallgatter et al., [<reflink idref="bib15" id="ref53">15</reflink>] ). In the CPT, ADHD patients carrying the SLC2A3 duplication displayed reduced NGA as a function of the Go‐condition centroid being located more anterior in ADHD duplication carriers, while NoGo‐related centroids did not exhibit a group difference. A similar Go‐condition pattern has been previously reported for ADHD risk alleles of the gene encoding tryptophan hydroxylase‐2 (TPH2), a candidate consistently linked to ADHD risk (Baehne et al., [<reflink idref="bib2" id="ref54">2</reflink>] ). Thus, the effects of SLC2A3 variation may be interpreted as an indicator of altered brain activity during a cognitive response control task rather than impaired response inhibition itself.</p> <p>In the n‐back task, P300 amplitudes were considerably lower in ADHD patients carrying the SLC2A3 duplication. As the P300 component is considered sensitive to the attentional and working memory demands of a task (Gevins et al., [<reflink idref="bib23" id="ref55">23</reflink>] ), the effect was particularly marked during target trials that is when participants were supposed to react, as well as under 1‐back conditions that is when participants required memory for stimuli in the antecedent trial. The increased late positive ERP to nonmatching stimuli indicates a higher amount of resources being required for updating of working memory (McEvoy, Smith, & Gevins, [<reflink idref="bib40" id="ref56">40</reflink>] ) and it emphasizes the relevance of nominal task difficulty and required memory load. Reduced P300 amplitudes of SLC2A3 duplication carriers with ADHD may be counterbalanced when cognitive effort drives the participant's attention to the task. Moreover, rs12842 C‐allele carriers displayed increased N200 latencies in nontarget trials, across diagnostic groups and n‐back test conditions, whereas this was not observed in T‐allele carriers exhibiting steady N200 latencies, independent of trial type, n‐back test condition or ADHD diagnosis. N200 is known as a negative‐directed EEG wave that is evoked 200–350 ms after the onset of a specific visual or auditory stimulus, and is suggested to be associated with executive control and conflict processing (Folstein & Van Petten, [<reflink idref="bib19" id="ref57">19</reflink>] ). Notably, the latency of N200 was described to be changeable as a function of discrimination difficulty, which implies increased N200 latencies in situations when decision‐making is demanding (Towey, Rist, Hakerem, Ruchkin, & Sutton, [<reflink idref="bib63" id="ref58">63</reflink>] ). Overall, our findings indicate a negative influence of the rs12842 C‐allele compared to the T‐allele, given that increased (i.e. delayed) N200 latencies following nontarget stimuli have been discussed as markers for slowed automatic cognitive processing and impaired cognitive inhibition (Wang et al., [<reflink idref="bib68" id="ref59">68</reflink>] ; Williams, Gordon, Wright, & Bahramali, [<reflink idref="bib72" id="ref60">72</reflink>] ). The findings thus indicate that processes of cognition are not necessarily following a linear trajectory and may be counterbalanced by other mechanisms, such as increased impulsivity. Of note, altered cognitive processing in the n‐back task and differences in brain activity during a cognitive response control task is also consistent with findings in Slc2a3 mutant mice, a model of Glut3 loss‐of‐function. While heterozygous Slc2a3‐deficient mice display no alterations in food intake, body weight, blood glucose, and insulin levels as well as emotion regulation, they are characterized by generally increased electrical activity in EEG, reduced ultrasonic vocalization, increased sensitivity for acoustic startle, as well as deficits in working memory and spatial learning (Schmidt et al., [<reflink idref="bib56" id="ref61">56</reflink>] ; Stuart et al., [<reflink idref="bib59" id="ref62">59</reflink>] ; Zhao et al., [<reflink idref="bib80" id="ref63">80</reflink>] ).</p> <p>Our analyses indicated that SLC2A3 impacts ratings of energy units of high‐ or low‐caloric food stimuli when responses of duplication carriers with ADHD are compared to responses of ADHD and control subjects with two copies of the gene. In line with the assumption that SLC2A3 influences reactivity toward food stimuli, we observed that ADHD patients carrying the SLC2A3 duplication underestimated the energy units specifically of high‐caloric food stimuli. While knowledge about the role of GLUT3‐regulated glucose metabolism and energy balance in the pathophysiology of ADHD is remarkably sparse, several reports indicated a relationship between ADHD and central glucose utilization. Zametkin et al. ([<reflink idref="bib79" id="ref64">79</reflink>] ) reported that cerebral glucose metabolism is reduced in ADHD‐implicated brain regions, supporting the view of ADHD as an ‘energy deficiency syndrome’ mediated by dysregulation of astrocytal glucose and glycogen metabolism (Russell et al., [<reflink idref="bib54" id="ref65">54</reflink>] ; Todd & Botteron, [<reflink idref="bib62" id="ref66">62</reflink>] ). Narratives from relatives of affected children also suggest that ADHD symptom severity is influenced by carbohydrate intake, although there are no controlled studies clarifying this phenomenon (Hoover & Milich, [<reflink idref="bib25" id="ref67">25</reflink>] ; Kinsbourne, [<reflink idref="bib30" id="ref68">30</reflink>] ; Wender & Solanto, [<reflink idref="bib70" id="ref69">70</reflink>] ; Wolraich et al., [<reflink idref="bib75" id="ref70">75</reflink>] ). At the mechanistic level, compromised GLUT3 function may represent a critical factor in the mechanism of energetic insufficiency in neurons, specifically in those mediating GABAergic signaling. An energy deficit underlying for example corticostriatal dysfunction, which results in cognitive impairment comprising various dimensions of the ADHD‐associated phenotype, such as inhibition, inattention, working memory, and executive function, has been conceptionalized by Killeen et al. ([<reflink idref="bib29" id="ref71">29</reflink>] ) as the ‘neuroenergetic model’ of ADHD. While meta‐analysis argues against a general role of sugar intake in behavior or cognitive functioning (Wolraich, Wilson, & White, [<reflink idref="bib76" id="ref72">76</reflink>] ), adaptive alterations in the mesolimbic dopamine system moderating the excitatory/inhibitory balance in frontostriatal networks following chronic glucose consumption may link ADHD pathophysiology to highly comorbid eating disorders.</p> <p>Furthermore, with dysregulation of dopamine‐modulated signaling appearing central to ADHD pathophysiology, evidence suggests that dopaminergic transmission (and its reciprocal regulation by glutamate/GABA circuits) is influenced by glucose utilization, insulin sensitivity, and GLUT function (Bak, Schousboe, Sonnewald, & Waagepetersen, [<reflink idref="bib3" id="ref73">3</reflink>] ; Bak, Schousboe, & Waagepetersen, [<reflink idref="bib4" id="ref74">4</reflink>] ; Schoffelmeer et al., [<reflink idref="bib57" id="ref75">57</reflink>] ). Methylphenidate, methamphetamine, and cocaine, which all increase synaptic availability of dopamine (Abdul Muneer, Alikunju, Szlachetka, & Haorah, [<reflink idref="bib1" id="ref76">1</reflink>] ; Huang, Tsai, Su, & Sim, [<reflink idref="bib26" id="ref77">26</reflink>] ; Thanos, Michaelides, Benveniste, Wang, & Volkow, [<reflink idref="bib60" id="ref78">60</reflink>] ; Volkow et al., [<reflink idref="bib67" id="ref79">67</reflink>] ), were consistently shown to alter regional glucose transport and metabolism in brain. A correlation between catecholamine metabolite concentrations in cerebrospinal fluid and blood glucose levels also points to an interrelationship of glucose utilization with brain dopamine function (Umhau, Petrulis, Diaz, Rawlings, & George, [<reflink idref="bib64" id="ref80">64</reflink>] ), while excessive glucose intake in rats leads to altered dopamine receptor D2 binding (Colantuoni et al., [<reflink idref="bib11" id="ref81">11</reflink>] ) and dopamine release in the nucleus accumbens (Rada, Avena, & Hoebel, [<reflink idref="bib48" id="ref82">48</reflink>] ). Amphetamine‐evoked dopamine release in striatum is impaired in insulin‐depleted rats (Williams et al., [<reflink idref="bib73" id="ref83">73</reflink>] ), while dopamine transporter function is restored by amphetamine via a D2‐ERK1/2 mechanism (Owens et al., [<reflink idref="bib45" id="ref84">45</reflink>] ). Likewise, electrical currents that generate glutamatergic stimulation of NMDA receptors with consecutive calcium influx‐initiated and phosphorylation‐dependent activation of the nitric oxide synthase‐1 (NOS1) or activation of the phosphotidylinositol 3‐kinase (PI3K) and subsequently protein kinase B (AKT) or AMP‐activated protein kinase (AMPK), result in translocation of GLUT3 to the cell membrane (Owens et al., [<reflink idref="bib45" id="ref85">45</reflink>] ; Weisova, Concannon, Devocelle, Prehn, & Ward, [<reflink idref="bib69" id="ref86">69</reflink>] ) as well as increase GLUT3‐facilitated glucose uptake in terminals and synapses of cortical and hippocampal neurons (Ferreira, Burnett, & Rameau, [<reflink idref="bib16" id="ref87">16</reflink>] ). Both NOS1 and the CDH13‐AKT‐GSK3ß signaling pathway, playing a critical role in the plasticity of GABAergic synapses on inhibitory interneurons, have previously been implicated in ADHD pathophysiology (Reif et al., [<reflink idref="bib49" id="ref88">49</reflink>] ; Rivero et al., [<reflink idref="bib52" id="ref89">52</reflink>] , [<reflink idref="bib51" id="ref90">51</reflink>] ).</p> <p>In conclusion, our findings indicate that allelic variation of SLC2A3 function at the SNP and CNV level may contribute to altered cognitive processing associated with ADHD. Given the ongoing debate concerning the unique genetic architecture of ADHD as compared to other neurodevelopmental disorders, with studies supporting the relevance of common SNPs as well as underscoring the impact of low‐frequency and rare variants (Lesch, [<reflink idref="bib34" id="ref91">34</reflink>] ), our results show that both common and rare variants may converge on the same putative risk gene. Future research on the neurobiological impact of altered SLC2A3 functions in neuropsychiatric disorder may include advanced techniques and models such as positron emission tomography imaging of central glucose metabolism, specified neuronal cell cultures derived from inducible pluripotent stem cells (iPSCs) of SLCA3 variant carriers, and Slc2a3‐overexpressing mice.</p> <hd id="AN0123648582-22">Acknowledgements</hd> <p>We are grateful to all patients and controls for their participation in the study. KPL is supported by the Deutsche Forschungsgemeinschaft (DFG: KFO 125 CRC TRR 58 A1/A5), BMBF (01GV0605; 01EW1602B to CJ), the European Community's Seventh Framework Programme (FP7/2007–2013) under Grant No. 602805 (Aggressotype) and the Horizon 2020 Programme (H2020/2014–2020) under Grant Nos. 643051 (MiND), and 5‐100 Russian Academic Excellence Project. AR is supported by the Deutsche Forschungsgemeinschaft (DFG: KFO 125, CRC TRR 58 B06 and Z02, CRC 1193 Z03, and RE1632/5‐1), the MBMF (BipoLife) and the European Community's Seventh Framework Programme (FP7/2007–2013) under Grant No. 602805 (Aggressotype) and the Horizon 2020 Programme (H2020/2014–2020) under Grant No. 643051 (MiND) and No. 667302 (CoCA). MR is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Spain (CP09/00119 and CPII15/00023). MR and JARQ are supported by Instituto de Salud Carlos III (PI11/00571, PI11/01629, PI12/01139, PI14/01700), and cofinanced by the European Regional Development Fund (ERDF), Agència de Gestió d'Ajuts Universitaris i de Recerca‐AGAUR, Generalitat de Catalunya (2014SGR1357, 014SGR0932), Ministerio de Economía y Competitividad, Spain (SAF2012‐33484, SAF2015‐68341‐R), the European College of Neuropsychopharmacology (ECNP network: ADHD across the lifespan), Departament de Salut, Government of Catalonia, Spain and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. This project has also received funding from the European Union's Horizon 2020 Research and Innovation Programme under the grant agreement No. 667302 and No. 643051. The research by BF, AAV, and JKB is supported by grants from the Netherlands Organization for Scientific Research (NWO), that is the NWO Brain & Cognition Excellence Program (grant 433‐09‐229) and a Vici grant to BF (016‐130‐669), and by grants from the Netherlands Brain Foundation (15F07[<reflink idref="bib2" id="ref92">2</reflink>]27) and BBMRI‐NL (CP2010‐33). The research leading to these results also received funding from the European Community's Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 602805 (Aggressotype), and from the European Community's Horizon 2020 Programme (H2020/2014–2020) under grant agreement No. 643051 (MiND) and No. 667302 (CoCA). T. Töpner, N. Steigerwald, C. Gagel, J. Auer, C.F. Keles, J. Groothuismink, M. Naber, and R. Makkinje are credited for excellent technical assistance.</p> <p>JKB has been a consultant to/member of advisory board of/and/or speaker for Janssen Cilag BV, Eli Lilly, Lundbeck, Shire, Roche, Medice, Novartis, and Servier in the past 3 years. He received research support from Roche and Vifor. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. AR received a research grant from Medice, and speaker's honoraria from Neuraxpharm and Boehringer. KPL served as a speaker for Eli Lilly and received research support from Medice, both outside the submitted work. JARQ has served on the speakers' bureau and acted as consultant for Eli Lilly, Novartis, Lundbeck, Shire, Ferrer and Laboratorios Rubió. He received travel awards from Eli Lilly, Janssen‐Cilag and Shire for participating in psychiatric meetings. The ADHD Program chaired by JARQ has received unrestricted educational and research support from Eli Lilly, Janssen‐Cilag, Shire, Rovi and Laboratorios Rubió, Ferrer in the past two years. BF received educational speaking fees from Merz and Shire, independent of the work reported here. None of the other authors reported any financial interests or potential conflicts of interest.</p> <p>Key points</p> <p>Although substantial heritability of attention‐deficit/hyperactivity disorder (ADHD) is recognized, genome‐wide screenings, and cross‐disorder approaches failed to identify the genetic architecture of ADHD.</p> <p>Case–control association analyses conducted in several cohorts revealed evidence for an association with a single‐nucleotide polymorphism tagging SLC2A3.</p> <p>Enrichment of SLC2A3 duplications in ADHD may be population‐specific.</p> <p>Duplication carriers display elevated SLC2A3 mRNA expression, altered event‐related potentials reflecting deficits in working memory and cognitive response control.</p> <p>Both common and rare SLC2A3 variation impacting regulation of neuronal glucose utilization and energy homeostasis may result in ADHD‐associated neurocognitive deficits.</p> <ref id="AN0123648582-23"> <title>Footnotes</title> <blist> <bibl id="bib1" idref="ref76" type="bt">1</bibl> <bibtext>Conflict of interest statement: See Acknowledgements. </bibtext> </blist> <blist> <bibl id="bib2" idref="ref54" type="bt">2</bibl> <bibtext>These authors contributed equally to this work. </bibtext> </blist> </ref> <ref id="AN0123648582-24"> <title>References</title> <blist> <bibtext>Abdul Muneer, P.M., Alikunju, S., Szlachetka, A.M., & Haorah, J. 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Neuronal glucose transporter isoform 3 deficient mice demonstrate features of autism spectrum disorders. Molecular Psychiatry, 15, 286 – 299. </bibtext> </blist> </ref> <p>Graph: Forest plot of the single‐nucleotide polymorphism ( SNP ) rs12842 T‐allele (A), the copy number variant ( CNV ) (B) and the additive model ( SNP  +  CNV ) of one or more risk alleles (C) for the adult attention‐deficit/hyperactivity disorder ( ADHD ) meta‐analytic case–control study</p> <p>Graph: q RT ‐ PCR for SLC2A3. Mean normalized relative expression (mean Qn  ±  SEM in arbitrary units) for carriers of the SLC2A3 duplication ( CN 3) and control individuals ( CN 2). (A) Peripheral blood mononuclear cell ( PBMC ) samples. (B) Lymphoblastoid cell line ( LCL ) samples. Mann–Whitney U test: ** p  < .01, *** p  < .001</p> <p>Graph: GLUT 3 immunoblotting. (A) Representative immunoblot reflecting whole‐cell GLUT 3 protein amounts of SLC2A3 duplication carriers ( CN 3) and control subjects ( CN 2) in peripheral blood mononuclear cells ( PBMC s). (B) GLUT 3 levels were normalized by means of the loading control beta‐actin. (C) Relative GLUT 3 protein expression in PBMC s (± SEM in arbitrary units) for SLC2A3 duplication carriers and individuals with two gene copies</p> <p>Graph: Effect of SLC2A3 genotype on EEG recordings during Continuous Performance Test ( CPT ). (A) NoGo‐Anteriorization ( NGA ) values for attention‐deficit/hyperactivity disorder ( ADHD ) patients and healthy controls, carrying either two ( CN 2) or three ( CN 3) SLC2A3 gene copies. (B) NGA values for ADHD patients and healthy controls, carrying either rs12842 C‐ or T‐allele. ± SEM , * p  < .05, ** p  < .01</p> <p>Graph: Effect of SLC2A3 copy number variant ( CNV ) and single‐nucleotide polymorphism ( SNP ) rs12842 on different EEG parameters during n‐back test. (A) For a time window of 1,000 ms, mean amplitudes ( μ V) of attention‐deficit/hyperactivity disorder ( ADHD ) patients with different SLC2A3 copy number ( CN 2/ CN 3) are depicted at electrode position PZ (midline parietal). (B) N200 latencies are displayed for ADHD patients with rs12842 C‐ or T‐allele during different n‐back test conditions (1‐back vs. 2‐back) and trial types (target vs. nontarget stimuli). ± SEM , *** p  < .001, ** p  < .01</p> <p>Graph: Figure S1. TagSNP selection on HapMap CEU Population (A) and LD structure of genotyped SNPs (B). Figure S2. Array CGH data (chr12:7166455‐8822108; hg19) in a human individual with three SLC2A3 copies according to TaqMan‐based genotyping. Figure S3. Fluorescence in situ hybridization with the BAC RP11‐277E18 comprising the SLC2A3 locus on chromosome 12. Figure S4. GLUT‐mediated glucose uptake in lymphoblastoid cell lines (LCLs). Figure S5. Forest and Funnel plots of rs741361 (A), rs2244822 (B), rs933552 (C) and rs7309332 (D) minor alleles for the aADHD meta‐analytic case–control study. Figure S6. Effect of SLC2A3 genotype on ratings of palatability and estimated amount of calories (mean ± SEM) of low‐ and high‐caloric food stimuli in ADHD patients carrying either two (CN2) or three (CN3) SLC2A3 copies as well as healthy controls carrying two (CN2) SLC2A3 copies. Table S1. SLC2A3 SNPs analysis. Table S2. SLC2A3 haplotype analysis. Table S3. SLC2A3 CNV analysis. Table S4. Combined model (rs12842 + CNV) analysis.</p> <aug> <p>By Sören Merker; Andreas Reif; Georg C. Ziegler; Heike Weber; Ute Mayer; Ann‐Christine Ehlis; Annette Conzelmann; Stefan Johansson; Clemens Müller‐Reible; Indrajit Nanda; Thomas Haaf; Reinhard Ullmann; Marcel Romanos; Andreas J. Fallgatter; Paul Pauli; Tatyana Strekalova; Charline Jansch; Alejandro Arias Vasquez; Jan Haavik; Marta Ribasés; Josep Antoni Ramos‐Quiroga; Jan K. Buitelaar; Barbara Franke and Klaus‐Peter Lesch</p> </aug>
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  Data: 'SLC2A3' Single-Nucleotide Polymorphism and Duplication Influence Cognitive Processing and Population-Specific Risk for Attention-Deficit/Hyperactivity Disorder
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  Data: <searchLink fieldCode="AR" term="%22Merker%2C+Sören%22">Merker, Sören</searchLink><br /><searchLink fieldCode="AR" term="%22Reif%2C+Andreas%22">Reif, Andreas</searchLink><br /><searchLink fieldCode="AR" term="%22Ziegler%2C+Georg+C%2E%22">Ziegler, Georg C.</searchLink><br /><searchLink fieldCode="AR" term="%22Weber%2C+Heike%22">Weber, Heike</searchLink><br /><searchLink fieldCode="AR" term="%22Mayer%2C+Ute%22">Mayer, Ute</searchLink><br /><searchLink fieldCode="AR" term="%22Ehlis%2C+Ann-Christine%22">Ehlis, Ann-Christine</searchLink><br /><searchLink fieldCode="AR" term="%22Conzelmann%2C+Annette%22">Conzelmann, Annette</searchLink><br /><searchLink fieldCode="AR" term="%22Johansson%2C+Stefan%22">Johansson, Stefan</searchLink><br /><searchLink fieldCode="AR" term="%22Müller-Reible%2C+Clemens%22">Müller-Reible, Clemens</searchLink><br /><searchLink fieldCode="AR" term="%22Nanda%2C+Indrajit%22">Nanda, Indrajit</searchLink><br /><searchLink fieldCode="AR" term="%22Haaf%2C+Thomas%22">Haaf, Thomas</searchLink><br /><searchLink fieldCode="AR" term="%22Ullmann%2C+Reinhard%22">Ullmann, Reinhard</searchLink><br /><searchLink fieldCode="AR" term="%22Romanos%2C+Marcel%22">Romanos, Marcel</searchLink><br /><searchLink fieldCode="AR" term="%22Fallgatter%2C+Andreas+J%2E%22">Fallgatter, Andreas J.</searchLink><br /><searchLink fieldCode="AR" term="%22Pauli%2C+Paul%22">Pauli, Paul</searchLink><br /><searchLink fieldCode="AR" term="%22Strekalova%2C+Tatyana%22">Strekalova, Tatyana</searchLink><br /><searchLink fieldCode="AR" term="%22Jansch%2C+Charline%22">Jansch, Charline</searchLink><br /><searchLink fieldCode="AR" term="%22Vasquez%2C+Alejandro+Arias%22">Vasquez, Alejandro Arias</searchLink><br /><searchLink fieldCode="AR" term="%22Haavik%2C+Jan%22">Haavik, Jan</searchLink><br /><searchLink fieldCode="AR" term="%22Ribasés%2C+Marta%22">Ribasés, Marta</searchLink><br /><searchLink fieldCode="AR" term="%22Ramos-Quiroga%2C+Josep+Antoni%22">Ramos-Quiroga, Josep Antoni</searchLink><br /><searchLink fieldCode="AR" term="%22Buitelaar%2C+Jan+K%2E%22">Buitelaar, Jan K.</searchLink><br /><searchLink fieldCode="AR" term="%22Franke%2C+Barbara%22">Franke, Barbara</searchLink><br /><searchLink fieldCode="AR" term="%22Lesch%2C+Klaus-Peter%22">Lesch, Klaus-Peter</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="SO" term="%22Journal+of+Child+Psychology+and+Psychiatry%22"><i>Journal of Child Psychology and Psychiatry</i></searchLink>. Jul 2017 58(7):798-809.
– Name: Avail
  Label: Availability
  Group: Avail
  Data: Wiley-Blackwell. 350 Main Street, Malden, MA 02148. Tel: 800-835-6770; Tel: 781-388-8598; Fax: 781-388-8232; e-mail: cs-journals@wiley.com; Web site: http://www.wiley.com/WileyCDA
– Name: PeerReviewed
  Label: Peer Reviewed
  Group: SrcInfo
  Data: Y
– Name: Pages
  Label: Page Count
  Group: Src
  Data: 12
– Name: DatePubCY
  Label: Publication Date
  Group: Date
  Data: 2017
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: Journal Articles<br />Reports - Research
– Name: Subject
  Label: Descriptors
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Attention+Deficit+Hyperactivity+Disorder%22">Attention Deficit Hyperactivity Disorder</searchLink><br /><searchLink fieldCode="DE" term="%22Neurological+Impairments%22">Neurological Impairments</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+Disorders%22">Genetic Disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Physiology%22">Physiology</searchLink><br /><searchLink fieldCode="DE" term="%22Metabolism%22">Metabolism</searchLink><br /><searchLink fieldCode="DE" term="%22Children%22">Children</searchLink><br /><searchLink fieldCode="DE" term="%22Adults%22">Adults</searchLink><br /><searchLink fieldCode="DE" term="%22Foreign+Countries%22">Foreign Countries</searchLink><br /><searchLink fieldCode="DE" term="%22Correlation%22">Correlation</searchLink><br /><searchLink fieldCode="DE" term="%22Meta+Analysis%22">Meta Analysis</searchLink><br /><searchLink fieldCode="DE" term="%22At+Risk+Persons%22">At Risk Persons</searchLink><br /><searchLink fieldCode="DE" term="%22Cognitive+Processes%22">Cognitive Processes</searchLink>
– Name: Subject
  Label: Geographic Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Europe%22">Europe</searchLink><br /><searchLink fieldCode="DE" term="%22Germany%22">Germany</searchLink><br /><searchLink fieldCode="DE" term="%22Spain%22">Spain</searchLink>
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1111/jcpp.12702
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 0021-9630
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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 EEG recordings 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.
– Name: AbstractInfo
  Label: Abstractor
  Group: Ab
  Data: As Provided
– Name: DateEntry
  Label: Entry Date
  Group: Date
  Data: 2017
– Name: AN
  Label: Accession Number
  Group: ID
  Data: EJ1144957
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=eric&AN=EJ1144957
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        Value: 10.1111/jcpp.12702
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      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 12
        StartPage: 798
    Subjects:
      – SubjectFull: Attention Deficit Hyperactivity Disorder
        Type: general
      – SubjectFull: Neurological Impairments
        Type: general
      – SubjectFull: Genetic Disorders
        Type: general
      – SubjectFull: Physiology
        Type: general
      – SubjectFull: Metabolism
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      – SubjectFull: Children
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      – SubjectFull: Adults
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    Titles:
      – TitleFull: 'SLC2A3' Single-Nucleotide Polymorphism and Duplication Influence Cognitive Processing and Population-Specific Risk for Attention-Deficit/Hyperactivity Disorder
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