Tinca J.C. Polderman

Meta-analysis of the heritability of human traits based on fifty years of twin studies

Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool.

Accounting for sequential trial effects in the flanker task: Conflict adaptation or associative priming?

The conflict-control loop theory proposes that the detection of conflict in information processing triggers an increase in cognitive control, resulting in improved performance on the subsequent trial. This theory seems consistent with the robust finding that conflict susceptibility is reduced following correct trials associated with high conflict: the conflict adaptation effect. However, despite providing favorable conditions for eliciting and detecting conflict-triggered performance adjustments, none of the five experiments reported here provide unequivocal evidence of such adjustments. Instead, the results corroborate and extend earlier findings by demonstrating that the conflict adaptation effect, at least in the flanker task, is only present for a specific subset of trial sequences that is characterized by a response repetition. This pattern of results provides strong evidence that the conflict adaptation effect reflects associative stimulus-response priming instead of conflict-driven adaptations in cognitive control.

A systematic review of prospective studies on attention problems and academic achievement

Polderman TJC, Boomsma DI, Bartels M, Verhulst FC, Huizink AC. A systematic review of prospective studies on attention problems and academic achievement.

The SNAP-25 gene is associated with cognitive ability: Evidence from a family-based study in two independent Dutch cohorts

The synaptosomal-associated protein of 25 kDa (SNAP-25) gene plays an integral role in synaptic transmission, and is differentially expressed in the mammalian brain in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra and cerebellar granular cells. Recent studies have suggested a possible involvement of SNAP-25 in learning and memory, both of which are key components of human intelligence. In addition, the SNAP-25 gene lies in a linkage area implicated previously in human intelligence. In two independent family-based Dutch samples of 391 (mean age 12.4 years) and 276 (mean age 37.3 years) subjects, respectively, we genotyped 12 single-nucleotide polymorphisms (SNPs) in the SNAP-25 gene on 20p12–20p11.2. From all individuals, standardized intelligence measures were available. Using a family-based association test, a strong association was found between three SNPs in the SNAP-25 gene and intelligence, two of which showed association in both independent samples. The strongest, replicated association was found between SNP rs363050 and performance IQ (PIQ), where the A allele was associated with an increase of 2.84 PIQ points (P=0.0002). Variance in this SNP accounts for 3.4 % of the phenotypic variance in PIQ.

Genetic analyses of the stability of executive functioning during childhood.

Executive functioning is an umbrella term for several related cognitive functions like selective- and sustained attention, working memory, and inhibition. Little is known about the stability of executive functioning during childhood. In this study the longitudinal stability of executive functioning was examined in young twins. The twin design enables to investigate genetic and environmental contributions to (the stability of) executive functioning. Computerized reaction time tasks on working memory, selective- and sustained attention were collected in twins at age 5 years (N=474 children) and at age 12 (N=346 children). The longitudinal correlations of processing speed on all tasks were substantial ( approximately 0.38). For slope (i.e., the delay caused by higher memory load) and fluctuation in tempo the longitudinal correlations were 0.08 and 0.26, respectively. The results hinted at genetic factors being an important mediator of stability of executive functioning over time. Also, genetic variation was the most important explanation for individual differences in executive functioning at both ages.

What have we learned from recent twin studies about the etiology of neurodevelopmental disorders

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. RECENT FINDINGS 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.

Common variants underlying cognitive ability: further evidence for association between the SNAP-25 gene and cognition using a family-based study in two independent Dutch cohorts.

The synaptosomal associated protein of 25 kDa (SNAP‐25) gene, located on chromosome 20 p12‐12p11.2 encodes a presynaptic terminal protein. SNAP‐25 is differentially expressed in the brain, and primarily present in the neocortex, hippocampus, anterior thalamic nuclei, substantia nigra and cerebellar granular cells. Recently, a family‐based genetic association was reported between variation in intelligence quotient (IQ) phenotypes and two intronic variants on the SNAP‐25 gene. The present study is a follow‐up association study in two Dutch cohorts of 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). It examines the complete genomic region of the SNAP‐25 gene to narrow down the location of causative genetic variant underlying the association. Two new variants in intron 1 (rs363043 and rs353016), close to the two previous reported variants (rs363039 and rs363050) showed association with variation in IQ phenotypes across both cohorts. All four single nucleotide polymorphisms were located in intron 1, within a region of about 13.8 kbp, and are known to affect transcription factor‐binding sites. Contrary to what is expected in monogenic traits, subtle changes are postulated to influence the phenotypic outcome of complex (common) traits. As a result, functional polymorphisms in (non)coding regulatory sequences may affect spatial and temporal regulation of gene expression underlying normal cognitive variation.

Catechol O -methyl transferase and dopamine D2 receptor gene polymorphisms: evidence of positive heterosis and gene–gene interaction on working memory functioning

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.

Attention Problems, Inhibitory Control, and Intelligence Index Overlapping Genetic Factors: A Study in 9-, 12-, and 18-Year-Old Twins

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.

The co-occurrence of autistic and ADHD dimensions in adults: an etiological study in 17 770 twins

Autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) often occur together. To obtain more insight in potential causes for the co-occurrence, this study examined the genetic and environmental etiology of the association between specific ASD and ADHD disorder dimensions. Self-reported data on ASD dimensions social and communication difficulties (ASDsc), and repetitive and restricted behavior and interests (ASDr), and ADHD dimensions inattention (IA), and hyperactivity/impulsivity (HI) were assessed in a community sample of 17 770 adult Swedish twins. Phenotypic, genetic and environmental associations between disorder dimensions were examined in a multivariate model, accounting for sex differences. ASDr showed the strongest associations with IA and HI in both sexes (rp 0.33 to 0.40). ASDsc also correlated moderately with IA (females rp 0.29 and males rp 0.35) but only modestly with HI (females rp 0.17 and males rp 0.20). Genetic correlations ranged from 0.22 to 0.64 and were strongest between ASDr and IA and HI. Sex differences were virtually absent. The ASDr dimension (reflecting restricted, repetitive and stereotyped patterns of behavior, interests and activities) showed the strongest association with dimensions of ADHD, on a phenotypic, genetic and environmental level. This study opens new avenues for molecular genetic research. As our findings demonstrated that genetic overlap between disorders is dimension-specific, future gene-finding studies on psychiatric comorbidity should focus on carefully selected genetically related dimensions of disorders.