From genetic sequence to phenotypic consequence: Genetic and environmental links between cognitive ability, socioeconomic position, and health

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Cognitive ability is predictive of socioeconomic position (SEP), and health, with a higher level of cognitive ability being associated with a higher SEP, and lower risk of illness, and common genetic variants, in part, explain this link. The goal of this programme of research is to identify the regions of the genome (loci) and biological systems underlying this relationship, including those on the, as yet, unexamined mitochondrial genome, to quantify the genetic and environmental contributions to the relationship between cognitive ability, health, and SEP, and identify instances where these relationships are likely to be causal.The elucidation of which genetic variants are linked to cognitive differences has proceeded rapidly in the last 5 years. However, genome-wide association studies (GWAS) have four issues that limit their use. These issues include a constraint on the sample size due to the difficulty in measuring cognitive ability, the absence of the mitochondrial genome from association studies, not adequately examining causal relationships between traits, and that interpretations of the effects identified using GWAS focus of genetic effects, despite the known presence of non-direct (or environmental effects) that result in trait variation. My research programme will utilise creative, and novel techniques coupled with new data from the international collaborations I have forged to address unanswered questions pertaining to the genetic and environmental contributions to cognitive ability and its overlap with health and SEP. Specifically, I will generate the largest GWAS data set on cognitive ability using a design that allows for the combination of genetically linked phenotypes. The additional power afforded by this design will allow for more loci, associated specifically with cognitive ability, to be identified. These data will also be used to examine the biological systems and mechanisms that, once perturbed by genetic variation, are associated with differences in cognitive ability. Unlike previous genetic investigations of cognitive ability I will also be examining the mitochondrial genome for association with cognitive ability. This novel analysis will also be used to examine the health traits that are associated with differences in cognitive ability to determine if the same loci in the mitochondrial genome is associated with both. This would provide a, partial, explanation for the link between cognitive ability, SEP, and health. The loci identified in the multivariate design will next be used as genetic instruments in a series of Mendelian randomisation (MR) studies to examine causality. MR will be used to identify the causal role that cognitive ability plays in health differences as well as differences in brain imaging traits. Finally, the role of the environment will be examined using family based cohorts and the genetic variants a parent does not share with their child. These non-transmitted genetic variants function in an analogous manner to the genotype of an adoptive parent, i.e. they may contribute towards the environment a child is raised in, but are independent to any genetic effects. By deriving genetic predictors based on these non-transmitted genetic variants I will be able to ascertain if the environmental effects of parental cognitive ability is associated with the offspring's level of cognitive ability and their health in later life. These topics are important for expanding our knowledge of how cognitive ability and health are linked. By increasing statistical power, as well as including non-examined regions of the genome in my work we can have the best understanding of how genetic factors contribute towards cognitive and health differences. Furthermore, the use of MR and non-transmitted genetic effects will allow us to investigate the environmental consequences of cognitive ability on health and the health of the next generation.