http://repub.eur.nl/res/aut/18905/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39340/ 2013-04-01T00:00:00Z Purpose of Review: The relative influence of genes and environment on the liability to neurodevelopmental disorders (NDDs) can be investigated using a twin design. This review highlights the results of the most recent twin studies of NDDs. Purpose of Review: Recent twin studies have confirmed that NDDs show moderate-to-high heritability, and that from an etiological viewpoint both autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are best regarded as the extremes on a continuous liability distribution. Both ASD and ADHD show high heritability in childhood and a substantial drop in heritability in adulthood, which is likely explained by the use of different assessment strategies in childhood versus adulthood, or by a complex mechanism of gene-by-environment interaction. NDDs show substantial comorbidity among each other, and with other mental health problems, which is partly because of a shared genetic etiology between different disorders. Summary: The findings of twin studies implicate substantial heritability of NDDs, and warrant large-scale molecular genetic studies for such traits. http://repub.eur.nl/res/pub/28349/ 2010-05-01T00:00:00Z Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], Β = 1.03, standard error (s.e.) = 0.053, P = 2.8 × 10 73). Two 10q25 SNPs (rs1329650[G], Β = 0.367, s.e. = 0.059, P = 5.7 × 10 10; and rs1028936[A], Β = 0.446, s.e. = 0.074, P = 1.3 × 10 9) and one 9q13 SNP in EGLN2 (rs3733829[G], Β = 0.333, s.e. = 0.058, P = 1.0 × 10 8) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 × 10 8). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 × 10 8) was significantly associated with smoking cessation. http://repub.eur.nl/res/pub/28243/ 2010-02-01T00:00:00Z Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes. http://repub.eur.nl/res/pub/16396/ 2009-05-01T00:00:00Z It is assumed that attention problems (AP) are related to impaired executive functioning. We investigated the association between AP and inhibitory control and tested to what extent the association was due to genetic factors shared with IQ. Data were available from 3 independent samples of 9-, 12-, and 18-year-old twins and their siblings (1,209 participants). AP were assessed with checklists completed by multiple informants. Inhibitory control was measured with the Stroop Color Word Task (Stroop, 1935), and IQ with the Wechsler Intelligence Scale for Children (Wechsler et al., 2002) or Wechsler Adult Intelligence Scale (Wechsler, 1997). AP and inhibitory control were only correlated in the 12-year-old cohort (r = .18), but appeared non-significant after controlling for IQ. Significant correlations existed between AP and IQ in 9- and 12-year olds (r = -.26/-.34). Inhibitory control and IQ were correlated in all cohorts (r = -.16, -.24 and -.35, respectively). Genetic factors that influenced IQ also influenced inhibitory control. We conclude that the association between AP and inhibitory control as reported in the literature may largely derive from genetic factors that are shared with IQ. http://repub.eur.nl/res/pub/25019/ 2009-01-01T00:00:00Z Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior. http://repub.eur.nl/res/pub/15972/ 2008-08-29T00:00:00Z The COMT Val108/158Met polymorphism has been extensively studied in relation to individual differences in working memory (WM) performance. The present study tested the association of the COMT Val108/158Met polymorphism with WM performance in two independent family-based Dutch samples: 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). A significant association was found between the COMT polymorphism and WM scores in the combined adult and young cohorts. The association reflected positive heterosis such that the Met/Met and Val/Val homozygotes did not perform as well as the Met/Val heterozygotes on the WM tasks. A secondary analysis was conducted in which a DRD2-tagging SNP (rs2075654) was tested for an interactive effect with the COMT polymorphism on WM performance. A significant interactive effect of the DRD2 and COMT genes was found such that heterosis was present only in the DRD2 genotype that has been linked to lower receptor density. Our results support previous findings that WM performance needs an optimal level of dopamine signaling within the PFC. This optimum level depends on enzymatic activity controlling dopamine level as well as dopamine receptor sensitivity, both of which may differ as a function of age and genotype. We conclude that the effects of a single polymorphism in a dopaminergic gene on a well-defined cognitive trait may easily remain hidden if the interaction with age and other genes in the pathway are not taken into account. http://repub.eur.nl/res/pub/29295/ 2008-01-01T00:00:00Z Sex differences on the Dutch WISC-R were examined in Dutch children (350 boys, 387 girls, age 11-13 years) and Belgian children (370 boys, 391 girls, age 9.5-13 years). Multi-group covariance and means structure analysis was used to establish whether the WISC-R was measurement invariant across sex, and whether sex differences on the level of the subtests were indicative of sex differences in general intelligence (g). In both samples, girls outperformed boys on the subtest Coding, while boys outperformed girls on the subtests Information and Arithmetic. The sex differences in the means of these three subtests could not be accounted for by the first-order factors Verbal, Performance, and Memory. Measurement invariance with respect to sex was however established for the remaining 9 subtest. Based on these subtests, no significant sex differences were observed in the means of the first-order factors, or the second-order g-factor. In conclusion, the cognitive differences between boys and girls concern subtest-specific abilities, and these sizeable differences are not attributable to differences in first-order factors, or the second-order factor g. http://repub.eur.nl/res/pub/35116/ 2007-11-01T00:00:00Z Introduction: Most behavior checklists for attention problems or attention deficit/hyperactivity disorder (ADHD) such as the Child Behavior Checklist (CBCL) have a narrow range of scores, focusing on the extent to which problems are present. It has been proposed that measuring attention on a continuum, from positive attention skills to attention problems, will add value to our understanding of ADHD and related problems. The Strengths and Weaknesses of ADHD symptoms and Normal behavior scale (SWAN) is such a scale. Items of the SWAN are scored on a seven-point scale, with in the middle 'average behavior' and on the extremes 'far below average' and 'far above average'. Method: The SWAN and the CBCL were completed by mothers of respectively 560 and 469 12-year-old twin pairs. The SWAN consists of nine DSM-IV items for Attention Deficit (AD) and nine DSM-IV items for Hyperactivity/Impulsivity (HI). The CBCL Attention Problem (AP) scale consists of 11 items, which are rated on a three-point scale. Results: Children who had a score of zero on the CBCL AP scale can be further differentiated using the SWAN, with variation seen between the average behavior and far above average range. In addition, SWAN scores were normally distributed, rather than kurtotic or skewed as is often seen with other behavioral checklists. The CBCL AP scale and the SWAN-HI and AD scale were strongly influenced by genetic factors (73%, 90% and 82%, respectively). However, there were striking differences in genetic architecture: variation in CBCL AP scores is in large part explained by non-additive genetic influences. Variation in SWAN scores is explained by additive genetic influences only. Conclusion: Ratings on the SWAN cover the continuum from positive attention skills to attention and hyperactivity problems that define ADHD. Instruments such as the SWAN offer clinicians and researchers the opportunity to examine variation in both strengths and weaknesses in attention skills.