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No evidence for association between a functional promoter variantof the Norepinephrine Transporter gene SLC6A2 and ADHDin a family-based sample T. J. Renner • T. T. Nguyen • M. Romanos •S. Walitza • C. Ro¨ser • A. Reif • H. Scha¨fer •A. Warnke • M. Gerlach • K. P. Lesch Received: 26 April 2011 / Accepted: 7 June 2011Ó Springer-Verlag 2011 shown to have major influence on the expression levels of executive functions, attentional performance, and general SLC6A2 due to sequence alteration at a repressor binding alertness, involving neuronal networks affected in attention site, with the T-allele being associated with ADHD. We deficit/hyperactivity disorder (ADHD). The norepinephrine tested this potential association of A-3081T in a German transporter facilitates the reuptake of norepinephrine and family-based ADHD sample of 235 children from 162 dopamine in the prefrontal cortex and represents the main families, which has a power [99% based on the previously target of atomoxetine, an effective drug in the treatment of reported odds ratios. There was no evidence for an over- ADHD. Due to its influence on catecholaminergic signal- transmission of the risk allele T (transmission rate: 48.5%, ing, variants of the coding gene (SLC6A2) have been widely P = 0.55). We conclude that A-3081T is not a major risk investigated in ADHD. Several previous studies report an variant in our ADHD sample, though SLC6A2 remains an association between single nucleotide polymorphisms interesting candidate gene in ADHD, especially for the located in SLC6A2 and ADHD; however, the findings are inconsistent. The variant A-3081T (rs28386840) has been A-3081T Á rs28386840 Á Functional Á NET T. J. Renner (&) Á M. Romanos Á A. Warnke Á M. GerlachDepartment of Child and Adolescent Psychiatry, Psychosomaticsand Psychotherapy, University of Wu¨rzburg, Fu¨chsleinstr. 15, 97080 Wu¨rzburg, Germanye-mail: [email protected] Attention deficit/hyperactivity disorder (ADHD) is esti- mated to affect about 3–6% of children in school age, and its Institute of Medical Biometry and Epidemiology, core symptoms are reported to persist in adulthood in a University of Marburg, Bunsenstr. 3, 35037 Marburg, Germany considerable percentage (Polanczyk and Rohde High heritability of up to 0.8 suggests a genetical predisposition Department of Child and Adolescent Psychiatry, and has been the incentive for comprehensive research on University Clinic of Munich, Nußbaumstr. 5a, the molecular genetic basis of this sociologically relevant disorder (Faraone et al. ). Based on pathophysiologic considerations, numerous studies investigating candidate Department of Child and Adolescent Psychiatry, genes encoding effectors of monoaminergic neurotrans- University of Zu¨rich, Neumuensterallee 9, mission have been conducted (Brookes et al. ; Schimmelmann et al. Albayrak et al. ).
One promising candidate in ADHD is the norepineph- Molecular Psychiatry, Laboratory of Translational Neuroscience rine transporter (NET) gene, also known as solute carrier Department of Psychiatry, Psychosomatics and Psychotherapy, family 6, member 2 (SLC6A2). Norepinephrine is suggested University of Wu¨rzburg, Fu¨chsleinstr. 15, 97080 Wu¨rzburg,Germany to play a crucial role in the neurotransmitter disequilibrium underlying ADHD pathophysiology. Interference with ADHD, the association between T-3081A and ADHD, has noradrenergic signal transduction in prefrontal brain areas to be confirmed in a larger sample. Though Kim et al.
was correlated with ADHD-like symptoms in rodents as ) further underlined the importance of SLC6A2 in well as in primates (Arnsten Kostrzewa et al. ; ADHD by an extended association study, the T-3081A Sontag et al. ). Dysbalance between dopamine and variant was not included in the set of investigated variants.
norepinephrine activity with a relative hypernoradrenergic In a recent combined case–control and family-based study state is also found in SNAP-25 knock-out mice as well as in on Korean children affected by ADHD, Cho et al. ) spontaneously hypertensive rats (SHR), animal models were not able to confirm the association for the T-3081A previously characterized to display ADHD-like behavior SNP, while Joung et al. reported association in a further (Bruno et al. Russell ). This is in line with Korean sample with relatively high odds ratios (Cho et al.
knowledge on noradrenaline’s capacity to influence atten- tion, executive functions, and general alertness.
In this study, we focussed on this functionally relevant The synaptic neurotransmitter homeostasis of dopamine SNP in the promoter of SLC6A2 and aimed to replicate the and norepinephrine in prefrontal areas is modulated by results of Kim et al. ) and Joung et al. ) in a reuptake into the presynaptic neuron via NET. While family-based ADHD sample with 162 families of German norepinephrine is the main substrate of NET, it is also descent. To detect the odds ratio reported by Kim and capable of mediating the reuptake of dopamine in pre- colleagues, our sample provides a power of more than frontal areas, underlining the importance of this effector in prefrontal brain activity. Moreover, atomoxetine, a drugalleviating ADHD symptoms, is suggested to bind pre-dominantly to NET, blocking its transporter function (Seneca et al. Based on this knowledge, SLC6A2,located on chromosome 16q12.2, is an interesting candi- date gene for molecular genetic studies in ADHD.
Several studies investigated the association between Two hundred and thirty-five children (178 boys) with genetic variants of SLC6A2 and ADHD with divergent ADHD from 162 families were recruited and phenotypi- results (Brookes et al. ; Retz et al. ; Xu et al.
cally characterized by a team of experienced child and adolescent psychiatrists in the outpatient unit of the Joung et al. while an a priori gene analysis of Department of Child and Adolescent Psychiatry and Psy- genome-wide association data pointed to SLC6A2 as one of chotherapy, University of Wu¨rzburg, according to DSM-IV the most promising candidates (Lasky-Su et al. criteria American Psychiatric Association (All However, most of the studies have been focussing on patients agreed to participate in the study, and written polymorphisms whose capacity to influence the function- informed consent was obtained from all participants. The ality of SLC6A2 is not clarified yet. Generally, genetic study was approved by the appropriate local Ethics Com- variants proven to be functional either by altering amino mittee of the University of Wu¨rzburg.
acid sequence or due to being located in regions with Families were included if they had one or more children potential influence on gene expression are valuable targets affected with ADHD to perform family-based association for association studies. Previously, Kim and colleagues and genome-wide linkage studies. The index patient was reported a T/A single nucleotide polymorphism (SNP) required to be older than 8 years and to fulfill DSM-IV rs28386840, located 3081 base pairs upstream the tran- criteria for the combined subtype, and further affected scription start site, and confirmed a markable loss of siblings had to be at least 6 years of age. The lower limit expression caused by the T-variant (Kim et al. ). In an was chosen in order to ensure relative persistence of elaborated set of assays, they showed that the E2-box motif ADHD symptoms and to exclude children who may show formed by the T-allele enables the binding of the repressing phenocopies of the disorder during preschool age, but do transcription factors Slug and Scratch, reducing the not fulfill diagnostic criteria for ADHD during subsequent expression of SCL6A2 (p \ 0.0005). Moreover, in a small developmental stages (Shelton et al. The mean age case–control sample including 90 ADHD patients, they of the affected children was 11.03 years (SD: 3.12 years).
identified the minor T-allele as a risk allele in ADHD In 107 families one child, in 40 families two, in 12 families with an odds ratio of 1.8 and 4.3 for the AT-genotype three and in 3 families four affected children were and the TT-genotype, respectively, compared with the Exclusion criteria were as follows: (a) general IQ B 85, However, this intriguing finding, linking a functional (b) potentially confounding psychiatric diagnoses such as genetic variant causing down regulation of SLC6A2 with schizophrenia, any pervasive developmental disorder, Tourette’s disorder, and primary mood or anxiety disorder, genotypes were identified by subsequent gel electrophore- (c) neurological disorders such as epilepsy, (d) history of any acquired brain damage or evidence of the fetal alcoholsyndrome, (e) premature deliveries, and/or (f) maternal reports of severe prenatal, perinatal, or postnatal compli-cations. Psychiatric classification was based on the Schedule Genotypes were checked for Mendelian inconsistencies for Affective Disorders and Schizophrenia for School-Age using PedCheck (O’Connell and Weeks Here, we Children Present and Lifetime version (K-SADS-PL).
found an inconsistency in a trio and set the genotypes of all Mothers received the unstructured Introductory Interview family members on missing. Hardy–Weinberg equilibrium and the Diagnostic Screening Interview including diag- was checked for on parental genotypes by chi-square tests.
nostic supplements when applicable. The child was inter- The two-sided pedigree disequilibrium test weighting on viewed with the screening interview of the K-SADS in case family size (PDT-sum) was performed to assess the of positive screening with the respective supplements of transmission rates and to test for association (Martin et al.
the K-SADS-PL. Additionally, we employed the Child ). A nominal p-value lower than 0.05 was considered Behavior Checklist and a German Teachers’ Report on ADHD symptoms according to DSM-IV. We consider our Given the number and the structure of our ADHD index patients as representative of ADHD patients of child families, we used the program TDT Power Calculator and adolescent psychiatric units in Germany. See Table (Version 1.2.1) (Chen and Deng ) to calculate power at the alpha level of 0.05 for an observation of the effectmagnitudes reported by Kim et al. (Therefore, ADHD prevalence of 5% and, according to Kim and col-leagues, a T-allele frequency of 22.5% and a genotypic DNA was extracted out of whole-blood samples according relative risk of 1.8 and 4.3 for the AT-genotype and the to standard protocols. To genotype the variant A-3081T TT-genotype, respectively, were assumed. This results in a (rs28386840), polymerase chain reaction was performed as described by Kim et al. (PCR products underwentenzymatic digestion by BsrI at 65°C over 3 h, and Table 1 Clinical characteristics of the ADHD sample To confirm the association between the functional SNP rs28386840 located in the promoter region of SLC6A2 and ADHD, a family-based association study including 162 families including 235 affected children was conducted.
The parent genotype distribution (AA: 159, AT: 136, TT: 27) and the offspring genotype distribution (AA: 125, AT: 88, TT: 21) did not show significant difference from Hardy–Weinberg equilibrium (P = 0.78 and 0.34, respec- tively). There was no evidence for an overtransmission of the risk T-allele (transmission rate: 48.5%, P = 0.55; a Current DSM-IV diagnosis according to K-SADSb Multiple scoring possible c Diagnoses: major depression and dysthymic disordersd In this study, we aimed to replicate the reported association Diagnoses: separation anxiety disorder, social phobia, specific of a functional genetic variant rs28386840 located in the association analysis of SLC6A3marker rs28386840 (numbers of promoter region of SLC6A2 in a family-based German sample (Kim et al. ). In our opinion, the promoter SNP ADHD sample. This SNP was shown to downregulate the qualifies as a preferable polymorphism in studies especially expression of SLC6A2 significantly, representing a very on atomoxetine, since it is considered to interact mainly interesting candidate for molecular genetic studies in with SLC6A2. Thus, a change in genetic expression could ADHD. In contrast to the results reported by Kim et al.
be linked with altered general response to pharmacological () and Joung et al. (and in line with the findings therapy. However, the only study on the pharmacoge- of Cho et al. ), we did not detect significant trans- nomics of SLC6A2 and atomoxetine response did not mission disequilibrium for the T-allele in our sample (Kim include the functional SNP rs2838680 (Ramoz et al.
et al. ; Joung et al. ; Cho et al. ). Our study is ). Further molecular genetic studies with a special based on family data and provides robust results against emphasis on ADHD subtypes are recommended to clarify stratification admixture in contrast to case–control studies.
the pathophysiologic role of SLC6A2 and its regulation in In addition, since the study size allowed considerable power ([99%) to detect genotype effects of the magnitude In conclusion, the present study showed no association reported by Kim et al. (we assume that the func- of a functional variant, capable to downregulate the tional variant rs2838680 plays no major role in our German expression of SLC6A2, in a German family-based ADHD sample. Since the study design provided sufficient power to Since norepinephrine is considered to be regulating detect the reported odds ratios, we conclude that it has no attentive and executive functions (Brennan and Arnsten major impact in this sample, consisting mostly of combined ), SLC6A2 is suggested to impact specific clinical type ADHD patients. Due to its impact on monoaminergic ADHD features. In the present study, the investigated neurotransmission including norepinephrine as well as sample consists of children predominantly affected by dopamine, SLC6A2 remains an interesting candidate gene combined type ADHD, as was the sample investigated by in ADHD. Further studies on genetic variants of SLC6A2 Cho et al. ). Considering that the sample in the study will focus on its role in specific subtypes of ADHD with of Kim et al. (reporting positive association between deficiencies in attentional networks and their response to two SNPs of SLC6A2 and ADHD comprised 30% inat- tentive subtype, the negative finding in this study mayindicate that SLC6A2 could be of higher importance in the We are grateful to all participants for their support. We would like to thank Nicole Do¨ring for excellent technical assistance. The work was supported by the Deutsche Forschungs- For most of the investigated variants in candidate gene gemeinschaft (KFO 125/1-1 & 125/1-2; SCHA 542/10-3; LE 629/11-1) studies, functional impact is unknown, as it is the case with and the Bundesministerium fu¨r Bildung und Forschung (BMBF two SNPs of SLC6A2 for which Kim et al. ) reported frequently in case of positive association results linkagedisequilibrium with a variant harboring, the actual func-tionality is assumed for the respective SNPs. In this study,we focussed on a genetic variant that to our knowledge is the only one in SLC6A2 whose capacity to influence geneexpression directly has been shown in biochemical assays, Albayrak O, Friedel S, Schimmelmann BG, Hinney A, Hebebrand J confirming the formation of a new transcription factor (2008) Genetic aspects in attention-deficit/hyperactivity disor- binding site. Genetic variants of candidate genes recently have been reported to influence the efficacy of pharmaco- American Psychiatric Association (2009) Diagnostic and statistical manual of mental disorders, 4th ed., text rev., 13. print.
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