Origins of learning difficulties and behaviour problems: from behavioural genetics to behavioural genomics

Learning difficulties and their associated behaviour problems incur major social cost because they affect so many children and their families, they often persist into adolescence and adulthood, and their effects spill into many areas of children?s lives. Understanding the genetic and environmental origins of these problems is critical to predicting and preventing them. Since 1995, MRC programme grant G500079 has provided continuous support for the UK Twins Early Development Study (TEDS) on the genetics of learning difficulties and associated behaviour problems in childhood, the world?s largest study of twins assessed from infancy to adolescence. TEDS findings have led to new ways of thinking about the genetic and environmental origins of learning difficulties and behaviour problems in childhood, most notably a ?generalist genes? theory of learning difficulties. These findings have charted the course for molecular genetic research that has begun to identify genes responsible for the substantial genetic influence on these disorders. During 2010-15, we will capitalise on this 15-year programme of research by assessing 5000 pairs of at age 16, a crucial developmental turning point socially and biologically coming as it does at the end of compulsory education and near the end of puberty. Using Web-based tests that have been developed as part of TEDS, we will test the twins for aspects of learning that have proven most important and interesting in our research: reading, language and speech, mathematics, science, and general cognitive ability. We will also assess school performance (GCSE), behaviour problems, and home and school environments. This research is not merely about the nature-nurture issue of how much genetics affects learning difficulties and their associated problems. The classic twin design comparing identical and non-identical twins allows us to ask key questions about development (e.g., do genetic effects change from age to age?), about links between disorders (e.g., do different genes affect different disorders such as reading and mathematics?), and about the interplay between genes and environment (e.g., do genes affect our experiences?). Great value has been added to TEDS by obtaining two million DNA markers on 4000 of the TEDS children, which will make it possible for the first time to conduct systematic searches across the genome for genes responsible for these genetic effects. Finding these genes will make it possible to identify children at risk long before they fail in school and to foster environmental interventions that prevent the onset of these disorders.

Learning difficulties are among the most common problems in childhood and can have a major impact on outcomes later in life. Our programme of research brings together quantitative genetic and molecular genetic strategies to understand the genetic and environmental origins of learning difficulties and associated behaviour problems. The research will capitalise on the Twins Early Development Study (TEDS), the premier study of UK twins assessed since infancy as part of our continuous MRC programme grant funding (G500079) since 1995. During 2010-15, we will assess 5000 TEDS twin pairs after age 16, a crucial developmental turning point at the end of school and puberty as children begin to make their own way in their worlds. Testing such a large sample has been made possible by the use of an innovative battery of Web-based tests developed in TEDS. In collaboration with 12 former TEDS students, we will focus on testing genetic hypotheses at age 16 that have emerged from our TEDS research in childhood in reading, language and speech, mathematics, science, general cognitive ability, as well as school performance (GCSE), co-morbid behaviour problems, and home and school environments. We will continue to apply state-of-the-art model-fitting analyses to test hypotheses about development (e.g., genetic change and continuity from age to age), multivariate links between disorders (e.g., genetic co-morbidity and heterogeneity), and genotype-environment (GE) interplay (e.g., GE correlation and GE interaction). These quantitative genetic analyses have charted the course for our molecular genetic research which will benefit from 2 million DNA markers (SNPs and CNVs) that we have recently obtained for each of 4000 TEDS children (Affymetrix 6.0 GeneChip microarrays). These genomic data will greatly increase our ability to conduct genome-wide association (GWA) studies of the major domains of TEDS. The overall hypothesis is that our multiple-stage QTL (quantitative trait locus) GWA design guided by our quantitative genetic analyses will be able to detect and replicate SNP/CNV associations. Although each SNP/CNV association is likely to have only a small effect, multiple SNP/CNV associations can be aggregated for each phenotype in what we call a ?QTL set?. These QTL sets will be uniquely useful as indices of genetic risk in behavioural genomic research on the developmental, multivariate and GE interplay origins of learning difficulties and associated behaviour problems.