Polymorphisms of the Steroid Sulfatase [STS] Gene are Associated With Attention Deficit Hyperactivity Disorder and Influence Brain Tissue mRNA Expression

Previous studies in animals and humans have implicated the X-chromosome STS gene in the etiology of attentional difficulties and attention deficit hyperactivity disorder (ADHD). This family based association study has fine mapped a region of the STS gene across intron 1 and 2 previously associated with ADHD, in an extended sample of 450 ADHD probands and their parents. Significant association across this region is demonstrated individually with 7 of the 12 genotyped SNPs, as well as an allele specific haplotype of the 12 SNPs. The over transmitted risk allele of rs12861247 was also associated with reduced STS mRNA expression in normal human post-mortem frontal cortex brain tissue compared to the non-risk allele (P = 0.01). These results are consistent with the hypothesis arising from previous literature demonstrating that boys with deletions of the STS gene, and hence no STS protein are at a significantly increased risk of developing ADHD. Furthermore, this study has established the brain tissue transcript of STS, which except from adipose tissue, differs from that seen in all other tissues investigated. © 2010 Wiley-Liss, Inc

Porohyperelastic anatomical models for hydrocephalus and idiopathic intracranial hypertension

This is the accepted manuscript of a paper published in the Journal of Neurosurgery, Published online February 6, 2015; DOI: 10.3171/2014.12.JNS14516.OBJECT Brain deformation can be seen in hydrocephalus and idiopathic intracranial hypertension (IIH) via medical images. The phenomenology of local effects, brain shift, and raised intracranial pressure and herniation are textbook concepts. However, there are still uncertainties regarding the specific processes that occur when brain tissue is subject to the mechanical stress of different temporal and spatial profiles of the 2 neurological disorders. Moreover, recent studies suggest that IIH and hydrocephalus may be diseases with opposite pathogenesis. Nevertheless, the similarities and differences between the 2 subjects have not been thoroughly investigated. METHODS An anatomical porohyperelastic finite element model was used to assess the brain tissue responses associated with hydrocephalus and IIH. The same set of boundary conditions, with the exception of brain loading for development of the transmantle pressure gradient, was applied for the 2 models. The distribution of stress and strain during tissue distortion is described by the mechanical parameters. RESULTS The results of both the hydrocephalus and IIH models correlated with pathological characteristics. For the hydrocephalus model, periventricular edema was associated with the presence of positive volumetric strain and void ratio in the lateral ventricle horns. By contrast, the IIH model revealed edema across the cerebral mantle, including the centrum semiovale, with a positive void ratio and volumetric strain. CONCLUSIONS The model simulates all the clinical features in correlation with the MR images obtained in patients with hydrocephalus and IIH, thus providing support for the role of the transmantle pressure gradient and capillary CSF absorption in CSF-related brain deformation. The finite element methods can be used for a better understanding of the pathophysiological mechanisms of neurological disorders associated with parenchymal volumetric fluctuation.Dr. M. Czosnyka is a consultant for J&J (Codman), and has received payment for lectures from Integra Lifescience. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRFK) funded by the Ministry of Science, ICT, & Future Planning (2013R1A1A1004827); and the International Research & Development Program of the NRFK funded by the Ministry of Education, Science, and Technology of Korea (Grant No. 2014K1A3A1A21001366)

Genotyping of single nucleotide polymorphisms related to attention-deficit hyperactivity disorder

Pharmacological treatment of several diseases, such as attention-deficit hyperactivity disorder (ADHD), presents marked variability in efficiency and its adverse effects. The genotyping of specific single nucleotide polymorphisms (SNPs) can support the prediction of responses to drugs and the genetic risk of presenting comorbidities associated with ADHD. This study presents two rapid and affordable microarray-based strategies to discriminate three clinically important SNPs in genes ADRA2A, SL6CA2, and OPRM1 (rs1800544, rs5569, and rs1799971, respectively). These approaches are allele-specific oligonucleotide hybridization (ASO) and a combination of allele-specific amplification (ASA) and solid-phase hybridization. Buccal swab and blood samples taken from ADHD patients and controls were analyzed by ASO, ASA, and a gold-reference method. The results indicated that ASA is superior in genotyping capability and analytical performance.This research has been funded through projects FEDER MINECO INNPACTO IPT-2011-1132-010000, CTQ/2013/45875R, and PrometeoII/2014/040 (GVA).Tortajada-Genaro, LA.; Mena-Mollá, S.; Niñoles Rodenes, R.; Puigmule, M.; Viladevall, L.; Maquieira Catala, Á. (2016). Genotyping of single nucleotide polymorphisms related to attention-deficit hyperactivity disorder. Analytical and Bioanalytical Chemistry. 408(9):2339-2345. https://doi.org/10.1007/s00216-016-9332-3S233923454089Cortese S. The neurobiology and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD): what every clinician should know. Eur J Paediatr Neurol. 2012;16:422–33.Contini V, Rovaris DL, Victor MM, Grevet EH, Rohde LA, Bau CH. Pharmacogenetics of response to methylphenidate in adult patients with attention-deficit/hyperactivity disorder (ADHD): a systematic review. Eur Neuropsychopharmacol. 2013;23:555–60.Gardiner SJ, Begg EJ. 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PharmGKB: the Pharmacogenomics Knowledge Base. Annu Rev Biomed Eng. 2007;9:289–320.Lucarelli F, Tombelli S, Minunni M, Marrazza G, Mascini M. Electrochemical and piezoelectric DNA biosensors for hybridisation detection. Anal Chim Acta. 2008;609:139–59.Knez K, Spasic D, Janssen KP, Lammertyn J. Emerging technologies for hybridization based single nucleotide polymorphism detection. Analyst. 2014;139:353–70.Choi JY, Kim YT, Byun JY, Ahn J, Chung S, Gweon DG, et al. Integrated allele-specific polymerase chain reaction–capillary electrophoresis microdevice for single nucleotide polymorphism genotyping. Lab Chip. 2012;12:5146–54.Ragoussis J. Genotyping Technologies for Genetic Research. Annu Rev Genomics Hum Genet. 2009;10:117–33.Sethi D, Gandhi RP, Kuma P, Gupta KC. Chemical strategies for immobilization of oligonucleotides. Biotechnol J. 2009;4:1513–29.Bañuls MJ, Morais SB, Tortajada-Genaro LA, Maquieira A. Microarray Developed on Plastic Substrates. Microarray Technology: Methods and Applications, 2016; 37-51.Tortajada-Genaro LA, Rodrigo A, Hevia E, Mena S, Niñoles R, Maquieira A. Microarray on digital versatile disc for identification and genotyping of Salmonella and Campylobacter in meat products. Anal Bioanal Chem. 2015;407:7285–94.Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics. 2010;11:407–19.Kim BN, Kim JW, Cummins TD, Bellgrove MA, Hawi Z, Hong SB, et al. Norepinephrine genes predict response time variability and methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder. J Clin Psychopharmacol. 2013;33:356–62.Carpentier PJ, Arias Vasquez A, Hoogman M, Onnink M, Kan CC, Kooij JJS, et al. Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: A pilot study of six candidate genes. 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Association of Impulsivity and Polymorphic MicroRNA-641 Target Sites in the SNAP-25 Gene.

Impulsivity is a personality trait of high impact and is connected with several types of maladaptive behavior and psychiatric diseases, such as attention deficit hyperactivity disorder, alcohol and drug abuse, as well as pathological gambling and mood disorders. Polymorphic variants of the SNAP-25 gene emerged as putative genetic components of impulsivity, as SNAP-25 protein plays an important role in the central nervous system, and its SNPs are associated with several psychiatric disorders. In this study we aimed to investigate if polymorphisms in the regulatory regions of the SNAP-25 gene are in association with normal variability of impulsivity. Genotypes and haplotypes of two polymorphisms in the promoter (rs6077690 and rs6039769) and two SNPs in the 3' UTR (rs3746544 and rs1051312) of the SNAP-25 gene were determined in a healthy Hungarian population (N = 901) using PCR-RFLP or real-time PCR in combination with sequence specific probes. Significant association was found between the T-T 3' UTR haplotype and impulsivity, whereas no association could be detected with genotypes or haplotypes of the promoter loci. According to sequence alignment, the polymorphisms in the 3' UTR of the gene alter the binding site of microRNA-641, which was analyzed by luciferase reporter system. It was observed that haplotypes altering one or two nucleotides in the binding site of the seed region of microRNA-641 significantly increased the amount of generated protein in vitro. These findings support the role of polymorphic SNAP-25 variants both at psychogenetic and molecular biological levels

Validation of the Internet Addiction Test in Students at a Pakistani Medical and Dental School

Despite growing concerns over pathological internet usage, studies based on validated psychometric instruments are still lacking in Pakistan. This study aimed to examine the psychometric properties of the Internet Addiction Test (IAT) in a sample of Pakistani students. A total of 522 students of medicine and dentistry completed the questionnaire, which consisted of four sections: (a) demographics, (b) number of hours spent on the Internet per day, (c) English version of the IAT, and (d) the Defense Style Questionnaire-40. Maximum likelihood analysis and principal axis factoring were used to validate the factor structure of the IAT. Convergent and criterion validity were assessed by correlating IAT scores with number of hours spent online and defense styles. Exploratory and confirmatory factor analysis reflected the goodness of fit of a unidimensional structure of the IAT, with a high alpha coefficient. The IAT had good face and convergent validity and no floor and ceiling effects, and was judged easy to read by participants

The mediating role of self/everyday creativity and depression on the relationship between creative personality traits and problematic social media use among emerging adults

Personality is one of the important contributory factors in the development of problematic technology use. The purpose of the present study was to investigate the direct and indirect associations of creative personality traits with problematic social media use via self/everyday creativity, depression, and loneliness. A total of 460 Turkish emerging adults aged between 18 and 26 years (61% female) were surveyed. Findings indicated that (i) task-orientedness was indirectly associated with problematic social media use via self/everyday creativity, (ii) self-confidence was directly and indirectly associated with problematic social media use via self/everyday creativity and depression, (iii) risk-taking was indirectly associated with problematic social media use via depression, and (iv) self/everyday creativity and depression were directly associated with problematic social media use. The present study is the first to suggest that creative personality traits (i.e., task-orientedness, self-confidence, and risk-taking) and self/everyday creativity are associated with problematic social media use and that these factors should be taken into account when considering the etiology of problematic social media use

No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent and highly heritable childhood disorder. The dopamine D4 receptor (DRD4) gene has shown a genetic association with ADHD in Caucasian populations with meta-analysis indicating a small but significant effect across datasets. It remains uncertain whether this association can be generalised to non-Caucasian ethnic groups. Here we investigate two markers within the DRD4 gene in a Taiwanese population, the exon 3 variable number tandem repeat (VNTR) and a 5' 120 base-pair duplication. METHODS: Within-family transmission disequilibrium tests of association of the 5' 120 base-pair duplication, and exon 3 VNTR in a Taiwanese population. RESULTS: No evidence of association of ADHD with either polymorphism in this population was observed. CONCLUSION: The DRD4 gene markers investigated were not found to be associated with ADHD in this Taiwanese sample. Further work in Taiwanese and other Asian populations will therefore be required to establish whether the reports of association of DRD4 genetic variants in Caucasian samples can be generalised to Asian populations

Validation and psychometric analysis of the Internet Addiction Test in Spanish among college students

BACKGROUND: The wide use of the Internet in the workplace, academic or social field, can have an impact on daily life. One of the most used questionnaires worldwide to analyse these problems is the Internet Addiction Test (IAT). Our aim was to validate a Spanish version of the IAT and analyse its psychometric properties. METHODS: Population of study were college students participating in the uniHcos project (Universities of Granada, Huelva, Jaén, León, Salamanca, and Vigo). The questionnaire was translated and back-translated by two native English speakers. Reliability of scores was analysed using Pearson's correlation coefficient and agreement was analysed using the Bland-Altman and Kappa techniques. Test dimensions were analysed by exploratory and confirmatory factor analysis. RESULTS: The reliability of scores was good (r = 0.899, Kappa = 0.650 and mean difference using Bland-Altman = -3.5). The psychometric assessment identified two factors (Emotional Investment; Performance and Time Management) which explained 55 % of the variance (total internal consistency of 0.91) and only 19 items. The confirmatory analysis showed an acceptable goodness of fit, especially when items 6 and 8 were related (RMSEA = 0.07 90%IC = 0.06 - 0.08; WRMR = 1.01, CFI = 0.96; TLI = 0.95). The two dimensions were negatively correlated with age and positively correlated with time spent online, especially for the purposes of leisure and entertainment. DISCUSSION: The results show good reliability and psychometric properties of the Spanish version of IAT with a two-dimensional solution. This result is partially in concordance with previous validations of the IAT in other languages that have found uni- and multi-dimensional solutions using different methodologies. Moreover, we want to highlight the possibility that some item of this questionnaire is outdated due to the technological and lifestyles changes and should be not taken into account. CONCLUSION: The reliability and psychometric properties obtained in this study support the conclusion that this Spanish short version of the IAT represents a useful tool for the analysis of problems arising from misuse of the Internet

Psychiatric gene discoveries shape evidence on ADHD's biology

The Wellcome Trust, MRC and Action Medical Research have provided ADHD research support for AT, PH, JM, NW, MJO, MCO; we also acknowledge support from NIH grants R1 3MH059126, R0 1MH62873 and R0 1MH081803 to Dr SV Faraone. Dr E Mick received funding through the UMass Center for Clinical and Translational Science (P30HD004147) supported by the NIH.A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10-4) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders.Publisher PDFPeer reviewe