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

认知能力可以预测社会经济地位（SEP）和健康状况，较高水平的认知能力与较高的SEP相关，疾病风险较低，常见的遗传变异部分解释了这种联系。这项研究计划的目标是确定这种关系背后的基因组（基因座）和生物系统的区域，包括尚未检查的线粒体基因组上的区域，以量化遗传和环境对认知能力，健康和SEP之间关系的贡献，并确定这些关系可能是因果关系的实例。在过去的5年里，阐明哪些遗传变异与认知差异有关的工作进展迅速。然而，全基因组关联研究（GWAS）有四个问题限制了它们的使用。这些问题包括由于难以测量认知能力而对样本量的限制，关联研究中缺乏线粒体基因组，没有充分检查性状之间的因果关系，以及使用GWAS确定的遗传效应的影响的解释，尽管已知存在导致性状变异的非直接（或环境效应）。我的研究计划将利用创造性的，新颖的技术，再加上新的数据，从国际合作，我已经伪造，以解决悬而未决的问题有关的遗传和环境的贡献，认知能力及其重叠与健康和SEP。具体来说，我将产生最大的GWAS数据集的认知能力使用的设计，允许基因连锁表型的组合。该设计提供的额外功效将允许鉴定更多的位点，特别是与认知能力相关的位点。这些数据还将用于研究生物系统和机制，一旦受到遗传变异的干扰，就会与认知能力的差异有关。 与以前对认知能力的遗传学研究不同，我还将研究线粒体基因组与认知能力的关系。这种新的分析也将用于检查与认知能力差异相关的健康特征，以确定线粒体基因组中的相同基因座是否与两者相关。这将为认知能力、SEP和健康之间的联系提供部分解释。 在多变量设计中确定的基因座接下来将被用作一系列孟德尔随机化（MR）研究中的遗传工具，以检查因果关系。MR将用于确定认知能力在健康差异以及脑成像特征差异中所起的因果作用。最后，将使用基于家庭的队列和父母不与孩子共享的遗传变异来检查环境的作用。这些非传播的遗传变异以类似于养父母的基因型的方式起作用，即它们可能对儿童成长的环境有贡献，但不受任何遗传效应的影响。通过推导基于这些非传播的遗传变异的遗传预测因子，我将能够确定父母认知能力的环境影响是否与后代的认知能力水平及其晚年的健康状况有关。这些主题对于扩展我们对认知能力和健康如何联系的知识非常重要。通过增加统计能力，以及在我的工作中包括基因组的未检查区域，我们可以最好地了解遗传因素如何导致认知和健康差异。此外，使用MR和非传递的遗传效应将使我们能够调查认知能力对健康和下一代健康的环境后果。

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.