A Longitudinal Twin Study of the Direction of Effects between ADHD Symptoms and IQ

While the negative association between ADHD symptoms and IQ is well documented, our knowledge about the direction and aetiology of this association is limited. Here, we examine the association of ADHD symptoms with verbal and performance IQ longitudinally in a population-based sample of twins. In a population-based sample of 4,771 twin pairs, DSM-IV ADHD symptoms were obtained from the Conners’ Parent Rating Scale-Revised. Verbal (vocabulary) and performance (Raven’s Progressive Matrices) IQ were assessed online. ADHD symptom ratings and IQ scores were obtained at ages 12, 14 and 16 years. Making use of the genetic sensitivity and time-ordered nature of our data, we use a cross-lagged model to examine the direction of effects, while modelling the aetiologies of the association between ADHD symptoms with vocabulary and Raven’s scores over time. Although time-specific aetiological influences emerged for each trait at ages 14 and 16 years, the aetiological factors involved in the association between ADHD symptoms and IQ were stable over time. ADHD symptoms and IQ scores significantly predicted each other over time. ADHD symptoms at age 12 years were a significantly stronger predictor of vocabulary and Raven’s scores at age 14 years than vice versa, whereas no differential predictive effects emerged from age 14 to 16 years. The results suggest that ADHD symptoms may put adolescents at risk for decreased IQ scores. Persistent genetic influences seem to underlie the association of ADHD symptoms and IQ over time. Early intervention is likely to be key to reducing ADHD symptoms and the associated risk for lower IQ.     

Genetic contributions to the association between height and intelligence: Evidence from Dutch twin data from childhood to middle age

A positive association between intelligence (IQ) and height has been reported previously. It is generally assumed that this association reflects the effect of childhood environment on IQ, but there is still little research supporting directly this hypothesis. We studied the association between height and IQ in 209 Dutch twin pairs at the ages of 5, 7, 10 and 12 years, 208 twin pairs at 16 and 18 years of age and 567 twin pairs and their siblings in adulthood. The heritability of height was high in all cohorts and across all ages (a² = 0.93 − 0.96). In adulthood, heritability was also high for full-scale IQ (FSIQ: a² = 0.83–0.84) and somewhat lower for verbal IQ (VIQ: a² = 0.66–0.84). In early childhood, the heritability was lower, and common environmental factors had a substantial effect on FSIQ and VIQ. A positive association of height and IQ was found in early childhood and adolescence. In adulthood, a correlation was found between height and FSIQ in young adulthood and between height and VIQ in middle age. All correlations could be ascribed to genetic factors influencing both height and IQ. Thus, these results show that the association between height and IQ should not be directly regarded as evidence for childhood living conditions affecting IQ, but the effect of genetic factors affecting independently or interacting with environmental factors should be considered as well.     

A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibs.

Important risk factors for melanoma are densely clustered melanocytic nevi (common moles) and mutations in the p16 (CDKN2A) gene. Nevi may be subclassified as raised or flat. In our sample, raised nevi were 27% of the total, and the two kinds had a correlation of.33. Correlations for total-nevus count (TNC) in 153 MZ and 199 DZ twin pairs were.94 and.60, respectively, which are compatible with a very-high degree of genetic determination. We hypothesized that some of the genetic variance might be due to variation in the p16 gene. Analysis of linkage to a highly polymorphic marker (D9S942), located close to p16, detected quantitative-trait-loci (QTL) effects accounting for 27% of variance in TNC, rising to 33% if flat but not raised moles were considered. Total heritability was higher for raised (.69) than for flat (.42) moles, but QTL linkage was 0 for raised moles, whereas it accounted for 80% of the heritability of flat moles; additionally, family environment accounted for only 15% of variance in raised versus 46% in flat moles. These findings suggest that raised and flat nevi have very different etiologies. Longer alleles at D9S942 were associated with higher flat-mole counts, and a novel modification to a within-sibship association test showed that this association is genuine and not due to population stratification, although it accounts for only 1% of total variance. Since germline mutations in the exons of CDKN2A are rare, it is likely that variants in the noncoding regions of this gene, or in another gene nearby, are responsible for this major determinant of moliness and, hence, of melanoma risk.     

Genetics of Callous-Unemotional Behavior in Children

Callous-unemotional behavior (CU) is currently under consideration as a subtyping index for conduct disorder diagnosis. Twin studies routinely estimate the heritability of CU as greater than 50%. It is now possible to estimate genetic influence using DNA alone from samples of unrelated individuals, not relying on the assumptions of the twin method. Here we use this new DNA method (implemented in a software package called Genome-wide Complex Trait Analysis, GCTA) for the first time to estimate genetic influence on CU. We also report the first genome-wide association (GWA) study of CU as a quantitative trait. We compare these DNA results to those from twin analyses using the same measure and the same community sample of 2,930 children rated by their teachers at ages 7, 9 and 12. GCTA estimates of heritability were near zero, even though twin analysis of CU in this sample confirmed the high heritability of CU reported in the literature, and even though GCTA estimates of heritability were substantial for cognitive and anthropological traits in this sample. No significant associations were found in GWA analysis, which, like GCTA, only detects additive effects of common DNA variants. The phrase ‘missing heritability’ was coined to refer to the gap between variance associated with DNA variants identified in GWA studies versus twin study heritability. However, GCTA heritability, not twin study heritability, is the ceiling for GWA studies because both GCTA and GWA are limited to the overall additive effects of common DNA variants, whereas twin studies are not. This GCTA ceiling is very low for CU in our study, despite its high twin study heritability estimate. The gap between GCTA and twin study heritabilities will make it challenging to identify genes responsible for the heritability of CU.     

Effects of birth weight on later intelligence

Abstract

Identical twins are used to show the long‐term effects of birth weight when genetic and many environmental factors are controlled. Female twins between the ages of 6 and 10 are evaluated for performance IQ and other measures of activity. No relationship was found between any of these measures and birth weight except for IQ. The heavier cotwin had the higher IQ score even when the birth weight of each twin was above 2,500 grams. Birth order was not associated with intelligence within the twin pairs.     

Genetic simplex modeling of Eysenck's dimensions of personality in a sample of young Australian twins.

The relative stability and magnitude of genetic and environmental effects underlying major dimensions of adolescent personality across time were investigated. The Junior Eysenck Personality Questionnaire was administered to over 540 twin pairs at ages 12, 14 and 16 years. Their personality scores were analyzed using genetic simplex modeling which explicitly took into account the longitudinal nature of the data. With the exception of the dimension lie, multivariate model fitting results revealed that familial aggregation was entirely explained by additive genetic effects. Results from simplex model fitting suggest that large proportions of the additive genetic variance observed at ages 14 and 16 years could be explained by genetic effects present at the age of 12 years. There was also evidence for smaller but significant genetic innovations at 14 and 16 years of age for male and female neuroticism, at 14 years for male extraversion, at 14 and 16 years for female psychoticism, and at 14 years for male psychoticism.     

An assessment of the individual and collective effects of variants on height using twins and a developmentally informative study design

In a sample of 3,187 twins and 3,294 of their parents, we sought to investigate association of both individual variants and a genotype-based height score involving 176 of the 180 common genetic variants with adult height identified recently by the GIANT consortium. First, longitudinal observations on height spanning pre-adolescence through adulthood in the twin sample allowed us to investigate the separate effects of the previously identified SNPs on pre-pubertal height and pubertal growth spurt. We show that the effect of SNPs identified by the GIANT consortium is primarily on prepubertal height. Only one SNP, rs7759938 in LIN28B, approached a significant association with pubertal growth. Second, we show how using the twin data to control statistically for environmental variance can provide insight into the ultimate magnitude of SNP effects and consequently the genetic architecture of a phenotype. Specifically, we computed a genetic score by weighting SNPs according to their effects as assessed via meta-analysis. This weighted score accounted for 9.2% of the phenotypic variance in height, but 14.3% of the corresponding genetic variance. Longitudinal samples will be needed to understand the developmental context of common genetic variants identified through GWAS, while genetically informative designs will be helpful in accurately characterizing the extent to which these variants account for genetic, and not just phenotypic, variance.     

Intelligence in Taiwan: Progressive Matrices means and sex differences in means and variances for 6- to 17-year-olds

Data for Raven's Progressive Matrices are reported for a sample of 6290 6- to 17-year-olds in Taiwan. The Taiwanese obtained a mean IQ of 109.5, in relation to a British mean of 100. There was no difference in mean scores of boys and girls at age 7 years. At age 10 years girls obtained significantly higher scores than boys, and at ages 13 and 16 years boys obtained significantly higher scores than girls. There was no sex difference in variance at age 7 years. At ages 10, 13 and 16 years variance was significantly greater in boys.     

Inbreeding effects on metrical phenotypes among North Indian Children

This study aimed to examine the effects of inbreeding on 12 quantitative phenotypes like body weight, height, sitting height, head circumference, head length, head breadth, chest circumference, verbal, performance and full scale intelligence quotients, systolic and diastolic blood pressures among North Indian Children. The sample consisted of 3,253 subjects (1,683 males and 1,570 females) including offspring of first cousins, first cousins once removed, second cousins, (inbred part of samples) and unrelated spouses (non-inbred part of samples) ranging in age from 6 to 14 years from the Aligarh district, Uttar Pradesh in North India. Samples were selected purposively to estimate the average inbreeding coefficients based on 3 ancestral generations and using Wright's path method. The average inbreeding coefficient of the present inbred part of sample is 0.04609. The mean ages of males and females were almost equal for both inbred and non-inbred individuals. A significant reduction of means (p < 0.05) or inbreeding depression has been observed in inbred series for all anthropometric and psychometric traits for both the sexes. A significant elevation of mean with inbreeding is observed for systolic and diastolic blood pressure. The average inbreeding depression per 10% inbreeding appeared very high in verbal IQ (> or =23), performance IQ (> or =40), full scale IQ (> or =28), systolic blood pressure (> or =10) and diastolic blood pressure (> or =12) among both sexes. On the whole, relatively greater amount of inbreeding effects are apparent among all measures of intelligence quotient and blood pressures compared to the anthropometric traits. The results of the present work have thrown light on the nature and mechanism of genetic effects of inbreeding on certain quantitative traits in human.     

Birth weight and cognitive function in the British 1946 birth cohort: longitudinal population based study

Objective: To examine the association between birth weight and cognitive function in the normal population. Design: A longitudinal, population based, birth cohort study. Participants: 3900 males and females born in 1946. Main outcome measures: Cognitive function from childhood to middle life (measured at ages 8, 11, 15, 26, and 43 years). Results: Birth weight was significantly and positively associated with cognitive ability at age 8 (with an estimated standard deviation score of 0.44 (95% confidence interval 0.28 to 0.59)) between the lowest and highest birthweight categories after sex, father's social class, mother's education, and birth order were controlled for. This association was evident across the normal birthweight range (>2.5 kg) and so was not accounted for exclusively by low birth weight. The association was also observed at ages 11, 15, and 26, and weakly at age 43, although these associations were dependent on the association at age 8. Birth weight was also associated with education, with those of higher birth weight more likely to have achieved higher qualifications, and this effect was accounted for partly by cognitive function at age 8. Conclusions: Birth weight was associated with cognitive ability at age 8 in the general population, and in the normal birthweight range. The effect at this age largely explains associations between birth weight and cognitive function at subsequent ages. Similarly, the association between birth weight and education was accounted for partly by earlier cognitive scores.     

Predicted birthweight for singletons and twins.

This population-based study determined the impact of co-twin gender on twin intrauterine growth in addition to their infant gender, maternal height, maternal age and parity on intrauterine growth rate of singletons and twins. All singletons and twins born in Western Australia during the period of 1980 to 1995 were considered for the study. The multiple linear regression models showed that 76% of the variance in the mean birthweight was explained by the selected variables for twins and 51% for singletons. Twins grew more slowly than singletons from 26 weeks gestation. Among twins, opposite-sex twin pairs grew consistently faster than like-sex twins. Primiparous twin pairs grew more slowly than subsequently born twins. These regression equations can be used to assess the appropriateness of intrauterine growth in twin pairs of various gender combinations.     

Lifetime exposure to environmental lead and children's intelligence at 11-13 years: the Port Pirie cohort study.

OBJECTIVE--To examine the association between environmental exposure to lead and children''s intelligence at age 11-13 years, and to assess the implications of exposure in the first seven years of life for later childhood development. DESIGN--Prospective cohort study. SUBJECTS--375 children born in or around the lead smelting town of Port Pirie, Australia, between 1979 and 1982. MAIN OUTCOME MEASURE--Children''s intelligence quotient (IQ) measured at 11-13 years of age. RESULTS--IQ was inversely associated with both antenatal and postnatal blood lead concentrations. Verbal, performance, and full scale IQ were inversely related to blood lead concentration with no apparent threshold. Multivariate analyses indicated that after adjustment for a wide range of confounders, the postnatal blood lead concentrations (particularly within the age range 15 months to 7 years) exhibited inverse associations with IQ. Strong associations with IQ were observed for lifetime average blood lead concentrations at various ages. The expected mean full scale IQ declined by 3.0 points (95% confidence interval 0.07 to 5.93) for an increase in lifetime average blood lead concentration from 0.48 to 0.96 mumol/l (10 to 20 micrograms/dl). CONCLUSION--Exposure to environmental lead during the first seven years of life is associated with cognitive deficits that seem to persist into later childhood.     

Expression discordance of monozygotic twins at birth: Effect of intrauterine environment and a possible mechanism for fetal programming

Within-pair comparison of monozygotic (MZ) twins provides an ideal model for studying factors that regulate epigenetic profile, by controlling for genetic variation. Previous reports have demonstrated epigenetic variability within MZ pairs, but the contribution of early life exposures to this variation remains unclear. As epigenetic marks govern gene expression, we have used gene expression discordance as a proxy measure of epigenetic discordance in MZ twins at birth in two cell types. We found strong evidence of expression discordance at birth in both cell types and some evidence for higher discordance in twin pairs with separate placentas. Genes previously defined as being involved in response to the external environment showed the most variable expression within pairs, independent of cell type, supporting the idea that even slight differences in intrauterine environment can influence expression profile. Focusing on birthweight, previously identified as a predisposing factor for cardiovascular, metabolic and other complex diseases, and using a statistical model that estimated association based on within-pair variation of expression and birthweight, we found some association between birthweight and expression of genes involved in metabolism and cardiovascular function. This study is the first to examine expression discordance in newborn twins. It provides evidence of a link between birthweight and activity of specific cellular pathways and, as evidence points to gene expression profiles being maintained through cell division by epigenetic factors, provides a plausible biological mechanism for the previously described link between low birthweight and increased risk of later complex disease.     

The effects of chorion type on variation in IQ in the NCPP twin population.

The 7-year IQ scores (WISC) of 116 white and 143 black nonmalformed twins of known zygosity and placental type were ascertained from the NINCDS Collaborative Perinatal Project (NCPP). The type of chorion and zygosity had no significant effect on the mean IQ or among-pair variation. In white monozygotic twins, however, analysis of variance revealed a significantly greater within-pair mean square for dichorionic twins than monochorionic twins. On the other hand, the white dichorionic monozygotic (MZ) and dizygotic (DZ) within-pair mean squares were quite similar. These findings were not evident in blacks for either of the within-pair comparisons. In addition, estimates of genetic variance were dependent upon MZ chorion type in both races. These data suggest to us that (1) in white twin pairs dichorionic placentas are of greater influence than the similarity or dissimilarity of genomes with regard to intrapair IQ development, and (2) failure to consider chorion type may introduce a serious bias in the interpretation of genetic variance estimates of IQ variability.     

Size at birth, fasting glucose and insulin levels and insulin resistance in adult twins.

Studies in singletons have found an association between birthweight and Type 2 diabetes in adult life. The aim of this study was to investigate whether this association could also be seen in twins. 59 monozygotic (MZ) and 69 dizygotic (DZ) same-sex twin pairs aged 19-50 years and 89 singleton controls matched for age, gestational age, gender, maternal age and parity were recruited from a local obstetric database. Associations between adult glucose, HbA(1)C and insulin levels and insulin resistance and birthweight were assessed by linear regression with adjustment for confounding variables. Twins were significantly lighter at birth than singleton controls, but there were no significant differences in adult weight, glucose, HbA(1)C and insulin levels or insulin resistance between twins and controls. The relationship between birthweight and fasting glucose and insulin levels, and insulin resistance was not significantly different from zero in either twins or controls, but birthweight was significantly negatively associated with HbA(1)C only in controls. There was no evidence of a difference between MZ and DZ twins in unpaired or within-pair analysis. These results provide little evidence that low birthweight in twins increases the risk of impaired glucose-insulin metabolism in young adults or that genetic factors can account for the association observed in singletons.     

Breastfeeding and IQ Growth from Toddlerhood through Adolescence

Objectives

The benefits of breastfeeding for cognitive development continue to be hotly debated but are yet to be supported by conclusive empirical evidence.

Methods

We used here a latent growth curve modeling approach to test the association of breastfeeding with IQ growth trajectories, which allows differentiating the variance in the IQ starting point in early life from variance in IQ gains that occur later in childhood through adolescence. Breastfeeding (yes/ no) was modeled as a direct predictor of three IQ latent growth factors (i.e. intercept, slope and quadratic term) and adjusted for the covariates socioeconomic status, mother''s age at birth and gestational stage. Data came from the Twins Early Development Study (TEDS), a prospective cohort study of twins born between 1996 and 1994 in the United Kingdom, who were assessed 9 times on IQ between age 2 and 16 years (N = 11,582).

Results

Having been breastfed was associated with a small yet significant advantage in IQ at age 2 in girls (β = .07, CI 95% from 0.64 to 3.01; N = 3,035) but not in boys (β = .04, CI 95% from -0.14 to 2.41). Having been breastfeeding was neither associated with the other IQ growth factors in girls (slope: β = .02, CI 95% from -0.25 to 0.43; quadratic: β = .01, CI 95% from -0.02 to 0.02) nor in boys (slope: β = .02, CI 95% from -0.30 to 0.47; quadratic: β = -.01, CI 95% from -0.01 to 0.01).

Conclusions

Breastfeeding has little benefit for early life intelligence and cognitive growth from toddlerhood through adolescence.     

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune‐relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene‐set with an identified role in “complement” function (excluding C4A), we used MAGMA to test if this gene‐set was enriched for genes associated with human intelligence and SZ risk, using genome‐wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene‐set analysis with a complement gene‐set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene‐based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome‐wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.     

Effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) on somatic mutation in a soybean test system.

The mutagenic activity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was assayed in heterozygous soybean plants (Y11y11), based on the appearance of mutational spots (yellow, dark green and twin) on the leaves. When soybean seeds were treated with IQ at concentrations of 0.01-0.1 microgram/ml, the frequency of mutational spots per leaf increased significantly in proportion to the concentration of IQ. At higher concentrations IQ was toxic. The mutagenicity of IQ was enhanced by pretreatment with the hepatic S9 fraction from Aroclor-induced rats. The numbers of yellow and dark green spots per leaf increased markedly by the treatment with IQ and S9-activated IQ, but the number of twin spots did not increase.     

Birth Weight and Adult IQ,but Not Anxious-Depressive Psychopathology,Are Associated with Cortical Surface Area: A Study in Twins

Background

Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles.

Aims

We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects.

Results

Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders.

Conclusion

The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.