Oliver S. P. Davis

The heritability of general cognitive ability increases linearly from childhood to young adulthood

Although common sense suggests that environmental influences increasingly account for individual differences in behavior as experiences accumulate during the course of life, this hypothesis has not previously been tested, in part because of the large sample sizes needed for an adequately powered analysis. Here we show for general cognitive ability that, to the contrary, genetic influence increases with age. The heritability of general cognitive ability increases significantly and linearly from 41% in childhood (9 years) to 55% in adolescence (12 years) and to 66% in young adulthood (17 years) in a sample of 11 000 pairs of twins from four countries, a larger sample than all previous studies combined. In addition to its far-reaching implications for neuroscience and molecular genetics, this finding suggests new ways of thinking about the interface between nature and nurture during the school years. Why, despite lifes ‘slings and arrows of outrageous fortune’, do genetically driven differences increasingly account for differences in general cognitive ability? We suggest that the answer lies with genotype–environment correlation: as children grow up, they increasingly select, modify and even create their own experiences in part based on their genetic propensities.

Twins Early Development Study (TEDS): A Genetically Sensitive Investigation of Cognitive and Behavioral Development From Childhood to Young Adulthood

The Twins Early Development Study (TEDS) is a large longitudinal sample of twins born in England and Wales between 1994 and 1996. The focus of TEDS has been on cognitive and behavioral development, including difficulties in the context of normal development. TEDS began when multiple births were identified from birth records and the families were invited to take part in the study; 16,810 pairs of twins were originally enrolled in TEDS. More than 10,000 of these twin pairs remain enrolled in the study to date. DNA has been collected for more than 7,000 pairs, and genome-wide genotyping data for two million DNA markers are available for 3,500 individuals. The TEDS families have taken part in studies when the twins were aged 2, 3, 4, 7, 8, 9, 10, 12, 14, and 16 years of age. Data collection is currently underway to assess the adult destinations of the twins as they move from school to university and the workplace. Between January 2012 and December 2014, all of the TEDS twins will turn 18, and the study will transition to an adult sample. TEDS represents an outstanding resource for investigating the developmental effects of genes and environments on complex quantitative traits from childhood to young adulthood and beyond.

Increasing heritability of BMI and stronger associations with the FTO gene over childhood.

The growing evidence of health risks associated with the rise in childhood obesity adds to the urgency of understanding the determinants of BMI. Twin analyses on repeated assessments of BMI in a longitudinal sample of >7,000 children indicated that the genetic influence on BMI becomes progressively stronger, with heritability increasing from 0.48 at age 4 to 0.78 at age 11. In the same large twin sample, the association between a common variant in the FTO gene and BMI increased in parallel with the rise in heritability, going from R2 < 0.001 at age 4 to R2 = 0.01 at age 11. These findings suggest that expression of FTO may become stronger throughout childhood. Increases in heritability may also be due to children increasingly selecting environments correlated with their genetic propensities.

Genome‐wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500K single nucleotide polymorphism microarrays

General cognitive ability (g), which refers to what cognitive abilities have in common, is an important target for molecular genetic research because multivariate quantitative genetic analyses have shown that the same set of genes affects diverse cognitive abilities as well as learning disabilities. In this first autosomal genome‐wide association scan of g, we used a two‐stage quantitative trait locus (QTL) design with pooled DNA to screen more than 500 000 single nucleotide polymorphisms (SNPs) on microarrays, selecting from a sample of 7000 7‐year‐old children. In stage 1, we screened for allele frequency differences between groups pooled for low and high g. In stage 2, 47 SNPs nominated in stage 1 were tested by individually genotyping an independent sample of 3195 individuals, representative of the entire distribution of g scores in the full 7000 7‐year‐old children. Six SNPs yielded significant associations across the normal distribution of g, although only one SNP remained significant after a false discovery rate of 0.05 was imposed. However, none of these SNPs accounted for more than 0.4% of the variance of g, despite 95% power to detect associations of that size. It is likely that QTL effect sizes, even for highly heritable traits such as cognitive abilities and disabilities, are much smaller than previously assumed. Nonetheless, an aggregated ‘SNP set’ of the six SNPs correlated 0.11 (P < 0.00000003) with g. This shows that future SNP sets that will incorporate many more SNPs could be useful for predicting genetic risk and for investigating functional systems of effects from genes to brain to behavior.

Childhood intelligence is heritable, highly polygenic and associated with FNBP1L.

Intelligence in childhood, as measured by psychometric cognitive tests, is a strong predictor of many important life outcomes, including educational attainment, income, health and lifespan. Results from twin, family and adoption studies are consistent with general intelligence being highly heritable and genetically stable throughout the life course. No robustly associated genetic loci or variants for childhood intelligence have been reported. Here, we report the first genome-wide association study (GWAS) on childhood intelligence (age range 6–18 years) from 17 989 individuals in six discovery and three replication samples. Although no individual single-nucleotide polymorphisms (SNPs) were detected with genome-wide significance, we show that the aggregate effects of common SNPs explain 22–46% of phenotypic variation in childhood intelligence in the three largest cohorts (P=3.9 × 10−15, 0.014 and 0.028). FNBP1L, previously reported to be the most significantly associated gene for adult intelligence, was also significantly associated with childhood intelligence (P=0.003). Polygenic prediction analyses resulted in a significant correlation between predictor and outcome in all replication cohorts. The proportion of childhood intelligence explained by the predictor reached 1.2% (P=6 × 10−5), 3.5% (P=10−3) and 0.5% (P=6 × 10−5) in three independent validation cohorts. Given the sample sizes, these genetic prediction results are consistent with expectations if the genetic architecture of childhood intelligence is like that of body mass index or height. Our study provides molecular support for the heritability and polygenic nature of childhood intelligence. Larger sample sizes will be required to detect individual variants with genome-wide significance.

Socioeconomic Status (SES) and Children's Intelligence (IQ): In a UK-Representative Sample SES Moderates the Environmental, Not Genetic, Effect on IQ

Background The environment can moderate the effect of genes - a phenomenon called gene-environment (GxE) interaction. Several studies have found that socioeconomic status (SES) modifies the heritability of childrens intelligence. Among low-SES families, genetic factors have been reported to explain less of the variance in intelligence; the reverse is found for high-SES families. The evidence however is inconsistent. Other studies have reported an effect in the opposite direction (higher heritability in lower SES), or no moderation of the genetic effect on intelligence. Methods Using 8716 twin pairs from the Twins Early Development Study (TEDS), we attempted to replicate the reported moderating effect of SES on childrens intelligence at ages 2, 3, 4, 7, 9, 10, 12 and 14: i.e., lower heritability in lower-SES families. We used a twin model that allowed for a main effect of SES on intelligence, as well as a moderating effect of SES on the genetic and environmental components of intelligence. Results We found greater variance in intelligence in low-SES families, but minimal evidence of GxE interaction across the eight ages. A power calculation indicated that a sample size of about 5000 twin pairs is required to detect moderation of the genetic component of intelligence as small as 0.25, with about 80% power - a difference of 11% to 53% in heritability, in low- (−2 standard deviations, SD) and high-SES (+2 SD) families. With samples at each age of about this size, the present study found no moderation of the genetic effect on intelligence. However, we found the greater variance in low-SES families is due to moderation of the environmental effect – an environment-environment interaction. Conclusions In a UK-representative sample, the genetic effect on intelligence is similar in low- and high-SES families. Childrens shared experiences appear to explain the greater variation in intelligence in lower SES.

Common DNA Markers Can Account for More Than Half of the Genetic Influence on Cognitive Abilities

For nearly a century, twin and adoption studies have yielded substantial estimates of heritability for cognitive abilities, although it has proved difficult for genomewide-association studies to identify the genetic variants that account for this heritability (i.e., the missing-heritability problem). However, a new approach, genomewide complex-trait analysis (GCTA), forgoes the identification of individual variants to estimate the total heritability captured by common DNA markers on genotyping arrays. In the same sample of 3,154 pairs of 12-year-old twins, we directly compared twin-study heritability estimates for cognitive abilities (language, verbal, nonverbal, and general) with GCTA estimates captured by 1.7 million DNA markers. We found that DNA markers tagged by the array accounted for .66 of the estimated heritability, reaffirming that cognitive abilities are heritable. Larger sample sizes alone will be sufficient to identify many of the genetic variants that influence cognitive abilities.

A genome-wide association study identifies multiple loci associated with mathematics ability and disability

Numeracy is as important as literacy and exhibits a similar frequency of disability. Although its etiology is relatively poorly understood, quantitative genetic research has demonstrated mathematical ability to be moderately heritable. In this first genome‐wide association study (GWAS) of mathematical ability and disability, 10 out of 43 single nucleotide polymorphism (SNP) associations nominated from two high‐ vs. low‐ability (n = 600 10‐year‐olds each) scans of pooled DNA were validated (P < 0.05) in an individually genotyped sample of *2356 individuals spanning the entire distribution of mathematical ability, as assessed by teacher reports and online tests. Although the effects are of the modest sizes now expected for complex traits and require further replication, interesting candidate genes are implicated such as NRCAM which encodes a neuronal cell adhesion molecule. When combined into a set, the 10 SNPs account for 2.9% (F = 56.85; df = 1 and 1881; P = 7.277e–14) of the phenotypic variance. The association is linear across the distribution consistent with a quantitative trait locus (QTL) hypothesis; the third of children in our sample who harbour 10 or more of the 20 risk alleles identified are nearly twice as likely (OR = 1.96; df = 1; P = 3.696e–07) to be in the lowest performing 15% of the distribution. Our results correspond with those of quantitative genetic research in indicating that mathematical ability and disability are influenced by many genes generating small effects across the entire spectrum of ability, implying that more highly powered studies will be needed to detect and replicate these QTL associations.

Dramatic Increase in Heritability of Cognitive Development from Early to Middle Childhood An 8-Year Longitudinal Study of 8,700 Pairs of Twins

The generalist genes hypothesis implies that general cognitive ability (g) is an essential target for understanding how genetic polymorphisms influence the development of the human brain. Using 8,791 twin pairs from the Twins Early Development Study, we examine genetic stability and change in the etiology of g assessed by diverse measures during the critical transition from early to middle childhood. The heritability of a latent g factor in early childhood is 23%, whereas shared environment accounts for 74% of the variance. In contrast, in middle childhood, heritability of a latent g factor is 62%, and shared environment accounts for 33%. Despite increasing importance of genetic influences and declining influence of shared environment, similar genetic and shared environmental factors affect g from early to middle childhood, as indicated by a cross-age genetic correlation of .57 and a shared environmental correlation of .65. These findings set constraints on how genetic and environmental variation affects the developing brain.

The future of genetics in psychology and psychiatry: microarrays, genome-wide association, and non-coding RNA.

BACKGROUND Much of what we thought we knew about genetics needs to be modified in light of recent discoveries. What are the implications of these advances for identifying genes responsible for the high heritability of many behavioural disorders and dimensions in childhood? METHODS Although quantitative genetics such as twin studies will continue to yield important findings, nothing will advance the field as much as identifying the specific genes responsible for heritability. Advances in molecular genetics have been driven by technology, especially DNA microarrays the size of a postage stamp that can genotype a million DNA markers simultaneously. DNA microarrays have led to a dramatic shift in research towards genome-wide association (GWA) studies. The ultimate goal of GWA is to sequence each individuals entire genome, which has begun to happen. RESULTS GWA studies suggest that for most complex traits and common disorders genetic effects are much smaller than previously considered: The largest effects account for only 1% of the variance of quantitative traits. This finding implies that hundreds of genes are responsible for the heritability of behavioural problems in childhood, and that it will be difficult to identify reliably these genes of small effect. Another discovery with far-reaching implications for future genetic research is the importance of non-coding RNA (DNA transcribed into RNA but not translated into amino acid sequences), which redefines what the word gene means. Non-coding RNA underlines the need for a genome-wide approach that is not limited to the 2% of DNA responsible for specifying the amino acid sequences of proteins. CONCLUSIONS The only safe prediction is that the fast pace of genetic discoveries will continue and will increasingly affect research in child psychology and psychiatry. DNA microarrays will make it possible to use hundreds of genes to predict genetic risk and to use these sets of genes in top-down behavioural genomic research that explores developmental change and continuity, multivariate heterogeneity and co-morbidity, and gene-environment interaction and correlation. A crucial question is whether the prediction of genetic risk will be sufficiently robust to translate into genetically based diagnoses, personalized treatments, and prevention programmes.