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Brouwer R.M.,University Utrecht | van Soelen I.L.C.,University Utrecht | van Soelen I.L.C.,VU University Amsterdam | van Soelen I.L.C.,Leiden University | And 6 more authors.
Human Brain Mapping | Year: 2014

Cognitive abilities are related to (changes in) brain structure during adolescence and adulthood. Previous studies suggest that associations between cortical thickness and intelligence may be different at different ages. As both intelligence and cortical thickness are heritable traits, the question arises whether the association between cortical thickness development and intelligence is due to genes influencing both traits. We study this association in a longitudinal sample of young twins. Intelligence was assessed by standard IQ tests at age 9 in 224 twins, 190 of whom also underwent structural magnetic resonance imaging (MRI). Three years later at age 12, 177/125 twins returned for a follow-up measurement of intelligence/MRI scanning, respectively. We investigated whether cortical thickness was associated with intelligence and if so, whether this association was driven by genes. At age 9, there were no associations between cortical thickness and intelligence. At age 12, a negative relationship emerged. This association was mainly driven by verbal intelligence, and manifested itself most prominently in the left hemisphere. Cortical thickness and intelligence were explained by the same genes. As a post hoc analysis, we tested whether a specific allele (rs6265; Val66Met in the BDNF gene) contributed to this association. Met carriers showed lower intelligence and a thicker cortex, but only the association between the BDNF genotype and cortical thickness in the left superior parietal gyrus reached significance. In conclusion, it seems that brain areas contributing to (verbal) intellectual performance are specializing under the influence of genes around the onset of puberty. © 2013 Wiley Periodicals, Inc. Source

Stoltenberg S.F.,University of Nebraska - Lincoln | Lehmann M.K.,Black Hills State University | Christ C.C.,University of Nebraska - Lincoln | Hersrud S.L.,University of South Dakota | And 3 more authors.
Drug and Alcohol Dependence | Year: 2011

Background: Some of the genetic vulnerability for addiction may be mediated by impulsivity. This study investigated relationships among impulsivity, substance use problems and six neurexin-3 (NRXN3) polymorphisms. Neurexins (NRXNs) are presynaptic transmembrane proteins that play a role in the development and function of synapses. Methods: Impulsivity was assessed with the Barratt Impulsiveness Scale Version 11 (BIS-11), the Boredom Proneness Scale (BPS) and the TIME paradigm; alcohol problems with the Michigan Alcoholism Screening Test (MAST); drug problems with the Drug Abuse Screening Test (DAST-20); and regular tobacco use with a single question. Participants (n= 439 Caucasians, 64.7% female) donated buccal cells for genotyping. Six NRXN3 polymorphisms were genotyped: rs983795, rs11624704, rs917906, rs1004212, rs10146997 and rs8019381. A dual luciferase assay was conducted to determine whether allelic variation at rs917906 regulated gene expression. Results: In general, impulsivity was significantly higher in those who regularly used tobacco and/or had alcohol or drug problems. In men, there were modest associations between rs11624704 and attentional impulsivity (p= 0.005) and between rs1004212 and alcohol problems (p= 0.009). In women, there were weak associations between rs10146997 and TIME estimation (p= 0.03); and between rs1004212 and drug problems (p= 0.03). The dual luciferase assay indicated that C and T alleles of rs917906 did not differentially regulate gene expression in vitro. Conclusions: Associations between impulsivity, substance use problems and polymorphisms in NRXN3 may be gender specific. Impulsivity is associated with substance use problems and may provide a useful intermediate phenotype for addiction. © 2011 Elsevier Ireland Ltd. Source

Rubin D.H.,New York Medical College | Althoff R.R.,University of Vermont | Ehli E.A.,Avera Institute for Human Genetics | Davies G.E.,Avera Institute for Human Genetics | And 4 more authors.
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

Background Social withdrawal is a core neuropsychiatric phenomenon in developmental psychopathology. Its presence predicts psychopathology across many domains, including depression, psychosis, autism, anxiety, and suicide. Withdrawn behavior is highly heritable, persistent, and characteristically worsens without intervention. To date, few studies have successfully identified genetic associations with withdrawn behavior, despite the abundance of evidence of its heritability. This may be due to reliance of categorical over dimensional measures of the behaviorally inhibited phenotype. The aim of this study is to identify associations between known psychiatric candidate genes and a dimensionally derived measure of withdrawn behavior. Methods Genetic information was collected on 20 single-nucleotide polymorphisms (SNPs) from a custom-designed SNP chip and TAQMAN arrays of 4 variable number of tandem repeat (VNTR) genes for 551 individuals from 187 families. Linear mixed modeling was employed to examine the relationship between genotypes of interest and Child Behavior Checklist (CBCL) Withdrawn Behavior Subscale Score (WBS) while controlling for gender and age through multiple linear regressions. Results Withdrawn behavior was highly associated with polymorphism rs6314 of the serotonin receptor 2A (HTR2A) [p =.009, estimate = 0.310 (bootstrap 95% CI 0.155-0.448), bootstrap p =.001] and rs1800544 of the alpha 2-adrenergic (ADRA2A) [p =.001, estimate = -0.310 (bootstrap 95% CI -0.479 to -0.126), bootstrap p =.001] genes after correction for gender and age. The association between withdrawn behavior and ADRA2A was stronger for younger children. Conclusions HTR2A and ADRA2A genes are associated with withdrawn behavior. This reinforces the role of catecholaminergic genes in the heritability of withdrawn behavior. © 2013 The Authors. Journal of Child Psychology and Psychiatry. Source

Benke K.S.,University of Western Australia | Nivard M.G.,VU University Amsterdam | Velders F.P.,Erasmus Medical Center | Walters R.K.,University of Notre Dame | And 19 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2014

Objective Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL). Method First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT. Results Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p <.03). Conclusion Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders. Source

Groen-Blokhuis M.M.,VU University Amsterdam | Middeldorp C.M.,VU University Amsterdam | Middeldorp C.M.,University Medical Center | Kan K.-J.,VU University Amsterdam | And 10 more authors.
Journal of the American Academy of Child and Adolescent Psychiatry | Year: 2014

Objective: Clinically, attention-deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity, impulsivity, and inattention and is among the most common childhood disorders. These same traits that define ADHD are variable in the general population, and the clinical diagnosis may represent the extreme end of a continuous distribution of inattentive and hyperactive behaviors. This hypothesis can be tested by assessing the predictive value of polygenic risk scores derived from a discovery sample of ADHD patients in a target sample from the general population with continuous scores of inattention and hyperactivity. In addition, the genetic overlap between ADHD and continuous ADHD scores can be tested across rater and age.Conclusion: These results indicate genetic overlap between a diagnosis of ADHD and AP scale scores across raters and age groups and provides evidence for a dimensional model of ADHD. Future GWA studies on ADHD can likely benefit from the inclusion of population-based cohorts and the analysis of continuous scores.Method: The Psychiatric Genomics Consortium has performed the largest genome-wide analysis (GWA) study of ADHD so far, including 5,621 clinical patients and 13,589 controls. The effects sizes of single nucleotide polymorphisms (SNPs) estimated in this meta-analysis were used to obtain individual polygenic risk scores in an independent population-based cohort of 2,437 children from the Netherlands Twin Register. The variance explained in Attention Problems (AP) scale scores by the polygenic risk scores was estimated by linear mixed modeling. Results The ADHD polygenic risk scores significantly predicted both parent and teacher ratings of AP in preschool- and school-aged children. © 2014 American Academy of Child and Adolescent Psychiatry. Source

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