Genome-wide association (GWA) studies of psychiatric disorders have been criticized for their lack in explaining a considerable proportion of the heritability established in twin and family studies. GWA studies of Major Depressive Disorder (MDD) in particular have so far been unsuccessful in detecting genome-wide significant SNPs. Using two different recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of MDD. To assess the consistency of these two different methods we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population.
The aim of this study was to investigate the relative influence of genetic and environmental factors on children’s leisure time exercise behavior, through the classical twin design.
Data were taken from the Netherlands Twin Register. The twins were 7 (N=3,966 subjects), 10 (N=3,562) and 12 years old (N=8,687), with longitudinal data for 27% of the sample. Parents were asked to indicate the children’s regular participation in leisure time exercise activities, including frequency and duration. Resemblance between monozygotic and dizygotic twins for weekly MET hours spent on exercise activities was analyzed as a function of their genetic relatedness.
Average weekly MET hours increased with age for both boys [age 7: 14.0 (SD=11.8); age 10: 22.6 (SD=18.7); age 12: 28.4 (SD=24.9)] and girls [age 7: 9.7 (SD=9.5); age 10: 15.3 (SD=15.1); age 12: 19.3 (SD=19.8)]. Around 13% of boys and girls across all age groups did not participate in any regular leisure time exercise activities. Tracking of exercise behavior from age 7 to age 12 was modest (.168 < r < .534). For boys, genetic effects accounted for 24% (CI: 18–30%) of the variance at age 7, 66% (53–81%) at age 10 and 38% (32–46%) at age 12. For girls, this was 22% (15–30%), 16% (9–24%), and 36% (30–43%), respectively. Environmental influences shared by children from the same family explained 71%, 25% and 50% of the variance in boys (aged 7, 10, 12) and 67%, 72% and 53% in girls. The shared environment influencing exercise behavior was partially different between boys and girls.
Our results stress the important role of shared environment for exercise behavior in young children.
Twin design; physical activity; heritability; genes; tracking; childhood
Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n=8) or anxiety disorders (n=3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, PSR and POR, were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant PSRP-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.
anxiety; neuroticism; panic disorder; linkage; meta-analysis
The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk for most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18 to 89 years old, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, inter-individual variation in locus specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2 fold larger at ABCA1 (p = 0.010) to 1.6 fold larger at INS (p = 3.7 * 10−07). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8 % increase in discordance each decade at CRH (p = 8.9 * 10−06) to a 16 % increase each decade at LEP (p = 2.0 * 10−08). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10 year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally due to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during ageing.
Epigenetics; Aging; MZ twin design; Full adult lifespan; DNA methylation; Stochastic variation
Large-scale population sequencing studies provide a complete picture of human genetic variation within the studied populations. A key challenge is to identify, among the myriad alleles, those variants that have an effect on molecular function, phenotypes, and reproductive fitness. Most non-neutral variation consists of deleterious alleles segregating at low population frequency due to incessant mutation. To date, studies characterizing selection against deleterious alleles have been based on allele frequency (testing for a relative excess of rare alleles) or ratio of polymorphism to divergence (testing for a relative increase in the number of polymorphic alleles). Here, starting from Maruyama's theoretical prediction (Maruyama T (1974), Am J Hum Genet USA 6:669–673) that a (slightly) deleterious allele is, on average, younger than a neutral allele segregating at the same frequency, we devised an approach to characterize selection based on allelic age. Unlike existing methods, it compares sets of neutral and deleterious sequence variants at the same allele frequency. When applied to human sequence data from the Genome of the Netherlands Project, our approach distinguishes low-frequency coding non-synonymous variants from synonymous and non-coding variants at the same allele frequency and discriminates between sets of variants independently predicted to be benign or damaging for protein structure and function. The results confirm the abundance of slightly deleterious coding variation in humans.
A key challenge in human genetics is to identify, among the multitude of genetic differences between individuals, those that have an effect on traits. Even though new genetic variants arise through mutation in each generation, most are present only in a small proportion of individuals because they have slightly negative effects on fitness. Detecting such slightly deleterious variants is a key challenge in analyzing how genetics influence human characteristics. In this paper, we test a theoretical prediction by Takeo Maruyama from 1974 that a slightly deleterious variant is, on average, younger than a neutral (non affecting fitness) variant present at the same population frequency. Thus our method detects selection by using estimated age of variants. We applied our method to human data from the Genome of the Netherlands Project, and we show that it distinguishes low-frequency protein-modifying variants from silent variants at the same population frequency and discriminates between sets of variants predicted to be benign or damaging for protein structure and function. Our results confirm the abundance of slightly deleterious protein-coding variation in humans.
Thoughts of self-harm and suicidal behavior are thought to be influenced by both genetics and environment. Molecular genetic studies are beginning to address the question of which genes may be involved and whether different genes may be expressed in men and women. We examined thoughts of self-harm and suicidal behavior in a large general population twin sample including male and female same- and opposite-sex twins. In this study, data on self-reported thoughts of self-harm and suicide were obtained from self-report questionnaires (Beck Depression Inventory and Youth or Adult Self Report forms) in 6265 twin pairs (11,008 individuals) aged 11–90 (62% female) from the Netherlands Twin Registry. Liability threshold models were compared including sex and age (linear and quadratic) effects. Models were compared using measures of parsimony to calculate the simplest model to the data. A model with additive genetic and unique environmental contributions fitted the data for both males and females. There were no qualitative sex differences, but the relative contributions differed between men and women. Heritability was higher in women (0.74, 95% CI 0.65 – 0.81) than men (0.45, 95% CI 0.28 – 0.61). The remaining variance was accounted for by environmental influence unique to an individual. These results suggest contributions from additive genetic factors to self-reported thoughts of self-harm and suicide and support the continued study of both molecular genetic and individual-specific environmental risk factors.
Suicide; Twins; Behavioral Genetics
Resting-state neuroimaging is a dominant paradigm for studying brain function in health and disease. It is attractive for clinical research because of its simplicity for patients, straightforward standardization, and sensitivity to brain disorders. Importantly, non-sensory experiences like mind wandering may arise from ongoing brain activity. However, little is known about the link between ongoing brain activity and cognition, as phenotypes of resting-state cognition—and tools to quantify them—have been lacking. To facilitate rapid and structured measurements of resting-state cognition we developed a 50-item self-report survey, the Amsterdam Resting-State Questionnaire (ARSQ). Based on ARSQ data from 813 participants assessed after 5 min eyes-closed rest in their home, we identified seven dimensions of resting-state cognition using factor analysis: Discontinuity of Mind, Theory of Mind, Self, Planning, Sleepiness, Comfort, and Somatic Awareness. Further, we showed that the structure of cognition was similar during resting-state fMRI and EEG, and that the test-retest correlations were remarkably high for all dimensions. To explore whether inter-individual variation of resting-state cognition is related to health status, we correlated ARSQ-derived factor scores with psychometric scales measuring depression, anxiety, and sleep quality. Mental health correlated positively with Comfort and negatively with Discontinuity of Mind. Finally, we show that sleepiness may partially explain a resting-state EEG profile previously associated with Alzheimer's disease. These findings indicate that the ARSQ readily provides information about cognitive phenotypes and that it is a promising tool for research on the neural correlates of resting-state cognition in health and disease.
consciousness; EEG; introspection; mental health; mind wandering
Personality traits and socioeconomic factors such as neighborhood income have been identified as risk factors for future alcohol abuse, but findings have been inconsistent possibly due to interactions between risk and protective factors. The present study examined the prediction of drinking behavior using empirically derived multi-trait patterns and tested for moderation by average neighborhood income. Using latent profile analysis (LPA) in a sample of 863 Dutch adolescents, four empirical personality profiles based on 6 traits were observed: Extraverted, Dysregulated, Neurotic, and Regulated. Dysregulated and Extraverted youth drank higher quantities of alcohol more frequently in young adulthood relative to the Regulated group, above and beyond the effects of baseline adolescent drinking, age, and sex. Profile levels of neuroticism did not appear to affect drinking behavior. Average neighborhood income did not moderate adolescent personality and young adult drinking. These findings suggest that future alcohol research should consider individual trait patterns to inform prevention and intervention efforts, and theories implicating both positive and negative emotionality traits as risk factors for drinking are preferable to those emphasizing the importance of the latter.
Personality; Neighborhood Income; Socioeconomic Status; Alcohol; Drinking
Copy number variations (CNVs) have been reported to be causal suspects in a variety of
psychopathologic traits. We investigate whether de novo and/or inherited CNVs
contribute to the risk for Attention Problems (APs) in children. Based on longitudinal
phenotyping, 50 concordant and discordant monozygotic (MZ) twin pairs were selected from a
sample of ∼3200 MZ pairs. Two types of de novo CNVs were investigated: (1)
CNVs shared by both MZ twins, but not inherited (pre-twinning de novo CNVs),
which were detected by comparing copy number (CN) calls between parents and twins and (2)
CNVs not shared by co-twins (post-twinning de novo CNVs), which were investigated
by comparing the CN calls within MZ pairs. The association between the overall CNV burden
and AP was also investigated for CNVs genome-wide, CNVs within genes and CNVs outside of
genes. Two de novo CNVs were identified and validated using quantitative PCR: a
pre-twinning de novo duplication in a concordant-unaffected twin pair and a
post-twinning deletion in the higher scoring twin from a concordant-affected pair. For the
overall CNV burden analyses, affected individuals had significantly larger CNVs that
overlapped with genes than unaffected individuals (P=0.008). This study
suggests that the presence of larger CNVs may increase the risk for AP, because they are
more likely to affect genes, and confirms that MZ twins are not always genetically
copy number variation; twin; Attention Problem; ADHD
Previous studies exploring the heritability of cannabis initiation have been carried out in the United States, Australia and United Kingdom. In the present study we assess cannabis initiation in The Netherlands, where the use of cannabis in small amounts is permitted. The sample included 3115 twins with a mean age of 27.4 years (SD 4.7) who are registered with the Netherlands Twin Register (NTR). Individual differences in cannabis initiation showed moderate genetic influences (44%). The remaining variance was explained by environmental influences shared by twins (31%) and by unique environmental factors (24%). Compared to studies from other countries, these results suggest that the relative importance of genetic and environmental factors is not different in a country with a more liberal cannabis policy.
Cannabis initiation; Heritability; Twins
Structural brain abnormalities are consistently found in schizophrenia (Sz) and have been associated with the familial risk for the disorder. We aim to define the relative contributions of genetic and nongenetic factors to the association between structural brain abnormalities and Sz in a uniquely powered cohort (Schizophrenia Twins and Relatives consortium).
An international multicenter magnetic resonance imaging collaboration was set up to pool magnetic resonance imaging scans from twin pairs in Utrecht (The Netherlands), Helsinki (Finland), London (United Kingdom), and Jena (Germany). A sample of 684 subjects took part, consisting of monozygotic twins (n = 410, with 51 patients from concordant and 52 from discordant pairs) and dizygotic twins (n = 274, with 39 patients from discordant pairs). The additive genetic, common, and unique environmental contributions to the association between brain volumes and risk for Sz were estimated by structural equation modeling.
The heritabilities of most brain volumes were significant and ranged between 52% (temporal cortical gray matter) and 76% (cerebrum). Heritability of cerebral gray matter did not reach significance (34%). Significant phenotypic correlations were found between Sz and reduced volumes of the cerebrum (−.22 [−.30/−.14]) and white matter (−.17 [−.25/−.09]) and increased volume of the third ventricle (.18 [.08/.28]). These were predominantly due to overlapping genetic effects (77%, 94%, and 83%, respectively).
Some of the genes that transmit the risk for Sz also influence cerebral (white matter) volume.
Brain volumes; multicenter; phenotypic correlation; schizophrenia; sMRI; twins
We investigated the development of the brain's functional connectivity throughout the life span (ages 5 through 71 years) by measuring EEG activity in a large population-based sample. Connectivity was established with Synchronization Likelihood. Relative randomness of the connectivity patterns was established with Watts and Strogatz' (1998) graph parameters C (local clustering) and L (global path length) for alpha (∼10 Hz), beta (∼20 Hz), and theta (∼4 Hz) oscillation networks. From childhood to adolescence large increases in connectivity in alpha, theta and beta frequency bands were found that continued at a slower pace into adulthood (peaking at ∼50 yrs). Connectivity changes were accompanied by increases in L and C reflecting decreases in network randomness or increased order (peak levels reached at ∼18 yrs). Older age (55+) was associated with weakened connectivity. Semi-automatically segmented T1 weighted MRI images of 104 young adults revealed that connectivity was significantly correlated to cerebral white matter volume (alpha oscillations: r = 33, p<01; theta: r = 22, p<05), while path length was related to both white matter (alpha: max. r = 38, p<001) and gray matter (alpha: max. r = 36, p<001; theta: max. r = 36, p<001) volumes. In conclusion, EEG connectivity and graph theoretical network analysis may be used to trace structural and functional development of the brain.
Genotype imputation has become an essential tool in the analysis of genome-wide association scans. This technique allows investigators to test association at ungenotyped genetic markers, and to combine results across studies that rely on different genotyping platforms. In addition, imputation is used within long-running studies to reuse genotypes produced across generations of platforms. Typically, genotypes of controls are reused and cases are genotyped on more novel platforms yielding a case–control study that is not matched for genotyping platforms. In this study, we scrutinize such a situation and validate GWAS results by actually retyping top-ranking SNPs with the Sequenom MassArray platform. We discuss the needed quality controls (QCs). In doing so, we report a considerable discrepancy between the results from imputed and retyped data when applying recommended QCs from the literature. These discrepancies appear to be caused by extrapolating differences between arrays by the process of imputation. To avoid false positive results, we recommend that more stringent QCs should be applied. We also advocate reporting the imputation quality measure (RT2) for the post-imputation QCs in publications.
GWAS; imputation; quality control
The objective of this study was to estimate the magnitude of genetic and environmental influences to variation in adolescent neuroticism as a function of age and sex. Neuroticism was assessed using the Amsterdamse Biografische Vragenlijst (ABV): a self-report personality instrument similar in content to the Eysenck Personality Questionnaire. Genetic modeling procedures, including age as modifier, were fitted to the total sample of 3301 Dutch adolescent twins aged 12 to 17 years (mean age 15.5). Significant influences of additive genetic factors (.59, 95% confidence intervals [CI] .54–.63) and unshared environmental factors (.41, 95% CI .37–.45) were found. Our data did not support a role of shared environment. Results showed that different genes may influence variation in neuroticism between girls and boys. No interaction was found between the variance components and age. Results generally support prior findings in adults and young children that neuroticism is influenced principally by additive genetic and unique environmental factors. The magnitude of the genetic component appears higher in the present sample of adolescents than in most studies of adults. The present study suggests that, in adolescence, different genes are expressed in boys and girls.
This study tests in a genetically informative design whether exercise behavior causally influences subjective wellbeing (SWB) and internalizing problems (INT). If exercise causally influences SWB and INT, genetic and environmental factors influencing exercise behavior will also influence SWB and INT. Furthermore, within genetically identical (MZ) twin pairs, the twin who exercises more should also show higher levels of SWB and lower levels of INT, than the co-twin who exercises less, because genetic confounding is excluded. Data on these phenotypes were available in a sample of 6317 adolescent twins and 1180 non-twin-siblings. Most participants had longitudinal data with 2-year follow-up. Exercise behavior was cross-sectionally and longitudinally associated with fewer internalizing problems and increased SWB (correlations ranged from 0.12 to 0.16). Cross-sectional and longitudinal associations were mainly accounted for by genetic factors, whereas the contribution of environmental factors was negligible. Within MZ twin pairs, the twin who exercised more did not show fewer internalizing problems and increased SWB. This was found cross-sectionally and longitudinally. We conclude that exercise behavior is associated with fewer internalizing problems and higher levels of SWB. The association largely reflects the effects of common genetic factors on these traits.
regular exercise; subjective wellbeing; internalizing behavior; causality; genetic pleiotropy; twin-sibling
Mass screening for cervical cancer precursors has decreased the incidence of cervical cancer in several countries, including the Netherlands. Persistent infections of certain types of human papillomavirus are strongly associated with the development of cervical cancer. A number of factors may affect the liability to infection and subsequent progression to cervical intraepithelial neoplasia and cancer. This paper examines whether genetic factors are involved in explaining individual differences in liability. Data of 3178 women registered with the Netherlands Twin Register were successfully linked to the nationwide Dutch Pathology database that contains all results of mass screening for cervical cancer. The data from mono- and dizygotic twins and their female relatives were used to disentangle the influence of heritable and environmental factors on cervix smear abnormalities. Results showed that differences in cervix smear results clustered within families and resemblance was stronger in monozygotic twins (correlation 0.37, 95% confidence interval: 0.12–0.58) compared with other first-degree relatives (correlation 0.14, 95% confidence interval: −0.01–0.29). The familial clustering for an abnormal cervix smear is due to shared genetic factors that explain 37% of the variance in liability. The largest proportion of the variation in cervical smear abnormalities is due to unique environmental factors.
cervix abnormalities; twins; cervical cancer
Considerable effort has been devoted to the analysis of genotype by environment (G × E) interactions in various phenotypic domains, such as cognitive abilities and personality. In many studies, environmental variables were observed (measured) variables. In case of an unmeasured environment, van der Sluis et al. (2006) proposed to study heteroscedasticity in the factor model using only MZ twin data. This method is closely related to the Jinks and Fulker (1970) test for G × E, but slightly more powerful. In this paper, we identify four challenges to the investigation of G × E in general, and specifically to the heteroscedasticity approaches of Jinks and Fulker and van der Sluis et al. We propose extensions of these approaches purported to solve these problems. These extensions comprise: (1) including DZ twin data, (2) modeling both A × E and A × C interactions; and (3) extending the univariate approach to a multivariate approach. By means of simulations, we study the power of the univariate method to detect the different G × E interactions in varying situations. In addition, we study how well we could distinguish between A × E, A × C, and C × E. We apply a multivariate version of the extended model to an empirical data set on cognitive abilities.
Genotype by environment interaction; ACE-model; Factor analysis; Heteroscedasticity; Marginal maximum likelihood; Power
In a large set of twin pairs, we compared twins born after IVF to naturally conceived twins with respect to birth characteristics, growth, attainment of motor milestones, and emotional and behavioral problems. Twin families were registered with the Netherlands Twin Register. We included 1534 dizygotic (DZ) twins born after IVF, 5315 naturally conceived (NC) DZ twins, and 1504 control NC DZ twins who were matched to the IVF twins based on maternal age, maternal educational level, smoking during pregnancy, gestational age, and offspring sex. Data were obtained by longitudinal surveys sent to fathers, mothers, and teachers at ages 1, 2, 3, 7, 10, and 12 years. Results showed no differences in growth, in attainment of motor milestones, and in behavioral development between IVF and matched NC twins. It can be concluded that for nearly all aspects, development in IVF and NC children is similar.
This study examined the heritability of problem drinking and investigated the phenotypic and genetic relationships between problem drinking and personality. In a sample of 5,870 twins and siblings and 4,420 additional family members from the Netherlands Twin Register. Data on problem drinking (assessed with the AUDIT and CAGE; 12 items) and personality [NEO Five-Factor Inventory (FFI); 60 items] were collected in 2009/2010 by surveys. Confirmatory factor analysis on the AUDIT and CAGE items showed that the items clustered on two separate but highly correlated (r = 0.74) underlying factors. A higher-order factor was extracted that reflected those aspects of problem drinking that are common to the AUDIT and CAGE, which showed a heritability of 40%. The correlations between problem drinking and the five dimensions of personality were small but significant, ranging from 0.06 for Extraversion to −0.12 for Conscientiousness. All personality dimensions (with broad-sense heritabilities between 32 and 55%, and some evidence for non-additive genetic influences) were genetically correlated with problem drinking. The genetic correlations were small to modest (between |0.12| and |0.41|). Future studies with longitudinal data and DNA polymorphisms are needed to determine the biological mechanisms that underlie the genetic link between problem drinking and personality.
problem drinking; personality; five-factor model; factor analysis; heritability; genetic correlation; twins
Relatively little is known about how genetic influences on alcohol abuse and dependence (AAD) change with age. We examined the change in influence of genetic and environmental factors which explain symptoms of AAD from adolescence into early adulthood. Symptoms of AAD were assessed using the four AAD screening questions of the CAGE inventory. Data were obtained up to six times by self-report questionnaires for 8,398 twins from the Netherlands Twin Register aged between 15 and 32 years. Longitudinal genetic simplex modeling was performed with Mx. Results showed that shared environmental influences were present for age 15–17 (57%) and age 18–20 (18%). Unique environmental influences gained importance over time, contributing 15% of the variance at age 15–17 and 48% at age 30–32. At younger ages, unique environmental influences were largely age-specific, while at later ages, age-specific influences became less important. Genetic influences on AAD symptoms over age could be accounted for by one factor, with the relative influence of this factor differing across ages. Genetic influences increased from 28% at age 15–17 to 58% at age 21–23 and remained high in magnitude thereafter. These results are in line with a developmentally stable hypothesis that predicts that a single set of genetic risk factors acts on symptoms of AAD from adolescence into young adulthood.
Genetics; Development; Alcohol abuse; Dependence; Longitudinal twin study
We report a genome-wide association study to iron status. We identify an association of SNPs in TPMRSS6 to serum iron (rs855791, combined P = 1.5×10−20), transferrin saturation (combined P = 2.2×10−23), and erythrocyte mean cell volume (MCV, combined P = 1.1×10−10). We also find suggestive evidence of association with blood haemoglobin levels (combined P = 5.3×10−7). These findings demonstrate the involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis.
The first aim of this study was to identify developmental trajectories of Attention Problems in twins followed from age 6 to 12 years. Second, we investigated whether singletons follow similar trajectories. Maternal longitudinal ratings on the Attention Problems (AP) subscale of the Child Behavior Checklist were obtained for a sample of 12,486 twins from the Netherlands Twin Register and for a general population sample of 1,346 singletons. Trajectories were analyzed by growth mixture modeling in twins, and compared with singletons. Teacher ratings on the AP subscale of the Teachers’ Report Form were available for 7,179 twins and 1,211 singletons, and were used for cross-sectional mean comparisons at each age. All analyses were conducted for boys and girls separately. We identified three linear trajectories in both boys and girls, i.e., stable low (62–71%), low-increasing (15–18%), and high-decreasing (14–21%). Singletons followed three identical trajectories, with similar class proportions. Teacher ratings yielded no differences in mean levels of Attention Problems between twins and singletons. The development of Attention Problems from age 6 to 12 years can be characterized by stable low, low-increasing, and high-decreasing developmental trajectories. Twins and singletons are comparable with respect to the development of Attention Problems in childhood.
ADHD; Attention Problems; Developmental trajectories; Twins; Singletons
This study investigates the longitudinal heritability in Thought Problems (TP) as measured with ten items from the Adult Self Report (ASR). There were ~9,000 twins, ~2,000 siblings and ~3,000 additional family members who participated in the study and who are registered at the Netherlands Twin Register. First an exploratory factor analysis was conducted to examine the underlying factor structure of the TP-scale. Then the TP-scale was tested for measurement invariance (MI) across age and sex. Next, genetic and environmental influences were modeled on the longitudinal development of TP across three age groups (12–18, 19–27 and 28–59 year olds) based on the twin and sibling relationships in the data. An exploratory factor analysis yielded a one-factor solution, and MI analyses indicated that the same TP-construct is assessed across age and sex. Two additive genetic components influenced TP across age: the first influencing TP throughout all age groups, while the second arises during young adulthood and stays significant throughout adulthood. The additive genetic components explained 37% of the variation across all age groups. The remaining variance (63%) was explained by unique environmental influences. The longitudinal phenotypic correlation between these age groups was entirely explained by the additive genetic components. We conclude that the TP-scale measures a single underlying construct across sex and different ages. These symptoms are significantly influenced by additive genetic factors from adolescence to late adulthood.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-011-9478-x) contains supplementary material, which is available to authorized users.
Thought problems; Measurement invariance; Longitudinal study; Extended twin design; Heritability
The tendency to conceive dizygotic (DZ) twins is a complex trait influenced by genetic and environmental factors. To search for new candidate loci for twinning, we conducted a genome-wide linkage scan in 525 families using microsatellite and single nucleotide polymorphism marker panels.
METHODS AND RESULTS
Non-parametric linkage analyses, including 523 families containing a total of 1115 mothers of DZ twins (MODZT) from Australia and New Zealand (ANZ) and The Netherlands (NL), produced four linkage peaks above the threshold for suggestive linkage, including a highly suggestive peak at the extreme telomeric end of chromosome 6 with an exponential logarithm of odds [(exp)LOD] score of 2.813 (P = 0.0002). Since the DZ twinning rate increases steeply with maternal age independent of genetic effects, we also investigated linkage including only families where at least one MODZT gave birth to her first set of twins before the age of 30. These analyses produced a maximum expLOD score of 2.718 (P = 0.0002), largely due to linkage signal from the ANZ cohort, however, ordered subset analyses indicated this result is most likely a chance finding in the combined dataset. Linkage analyses were also performed for two large DZ twinning families from the USA, one of which produced a peak on chromosome 2 in the region of two potential candidate genes. Sequencing of FSHR and FIGLA, along with INHBB in MODZTs from two large NL families with family specific linkage peaks directly over this gene, revealed a potentially functional variant in the 5′ untranslated region of FSHR that segregated with the DZ twinning phenotype in the Utah family.
Our data provide further evidence for complex inheritance of familial DZ twinning.
dizygotic twinning; linkage