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

从基因序列到表型结果：认知能力、社会经济地位和健康之间的遗传和环境联系

• 批准号: MR/T030852/1
• 负责人: William Hill
• 金额: $ 136.12万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT030852%2F1
• 关键词: genetic; sequence; phenotypic; consequence; Genetic

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.

认知能力是社会经济地位（SEP）和健康的预测指标，较高水平的认知能力与较高的SEP和较低的疾病风险相关，而常见的遗传变异在一定程度上解释了这种联系。本研究计划的目标是确定基因组区域（基因座）和这种关系背后的生物系统，包括那些尚未检查的线粒体基因组，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，对哪些基因变异与认知差异有关的研究进展迅速。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，以及尽管已知存在导致性状变异的非直接（或环境影响），但使用GWAS确定的效应的解释仍以遗传效应为重点。我的研究计划将利用创造性和新颖的技术，结合我所建立的国际合作的新数据，来解决有关遗传和环境对认知能力的贡献及其与健康和SEP的重叠的未解问题。具体而言，我将使用允许结合遗传相关表型的设计来生成最大的认知能力GWAS数据集。这种设计提供的额外能力将允许更多的位点被识别，特别是与认知能力相关的位点。这些数据还将用于检查生物系统和机制，这些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。与之前对认知能力的基因研究不同，我还将研究线粒体基因组与认知能力的关系。这种新颖的分析还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位点是否与两者相关。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，以检验因果关系。核磁共振将用于确定认知能力在健康差异和脑成像特征差异中所起的因果作用。最后，环境的作用将通过基于家庭的队列和父母不与孩子共享的基因变异来检查。这些非遗传变异的功能与养父母的基因型类似，即它们可能对儿童的成长环境有所影响，但不受任何遗传影响。通过基于这些非遗传变异的遗传预测，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和他们以后的健康状况有关。这些话题对于扩大我们对认知能力和健康之间关系的认识非常重要。通过提高统计能力，以及在我的工作中包括未检查的基因组区域，我们可以最好地了解遗传因素如何影响认知和健康差异。此外，核磁共振和非遗传效应的使用将使我们能够调查认知能力对健康和下一代健康的环境影响。

项目成果

Multivariate genetic analysis of personality and cognitive traits reveals abundant pleiotropy.

人格和认知特征的多变量遗传分析揭示了丰富的多效性。

• DOI: 10.1038/s41562-023-01630-9
• 发表时间: 2023
• 期刊: Nature human behaviour
• 影响因子: 29.9
• 作者: Hindley G

Environmental Influences on Genetic Contributions to Intelligence and Education.

环境对遗传对智力和教育的贡献的影响。

• DOI: 10.1176/appi.ajp.2021.21050545
• 发表时间: 2021
• 期刊: The American journal of psychiatry
• 作者: Hill WD

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.

• DOI: 10.1038/s41588-022-01062-7
• 发表时间: 2022-05
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Howe, Laurence J.;Nivard, Michel G.;Morris, Tim T.;Hansen, Ailin F.;Rasheed, Humaira;Cho, Yoonsu;Chittoor, Geetha;Ahlskog, Rafael;Lind, Penelope A.;Palviainen, Teemu;van der Zee, Matthijs D.;Cheesman, Rosa;Mangino, Massimo;Wang, Yunzhang;Li, Shuai;Klaric, Lucija;Ratliff, Scott M.;Bielak, Lawrence F.;Nygaard, Marianne;Giannelis, Alexandros;Willoughby, Emily A.;Reynolds, Chandra A.;Balbona, Jared V.;Andreassen, Ole A.;Ask, Helga;Baras, Aris;Bauer, Christopher R.;Boomsma, Dorret I.;Campbell, Archie;Campbell, Harry;Chen, Zhengming;Christofidou, Paraskevi;Corfield, Elizabeth;Dahm, Christina C.;Dokuru, Deepika R.;Evans, Luke M.;de Geus, Eco J. C.;Giddaluru, Sudheer;Gordon, Scott D.;Harden, K. Paige;Hill, W. David;Hughes, Amanda;Kerr, Shona M.;Kim, Yongkang;Kweon, Hyeokmoon;Latvala, Antti;Lawlor, Deborah A.;Li, Liming;Lin, Kuang;Magnus, Per;Magnusson, Patrik K. E.;Mallard, Travis T.;Martikainen, Pekka;Mills, Melinda C.;Njolstad, Pal Rasmus;Overton, John D.;Pedersen, Nancy L.;Porteous, David J.;Reid, Jeffrey;Silventoinen, Karri;Southey, Melissa C.;Stoltenberg, Camilla;Tucker-Drob, Elliot M.;Wright, Margaret J.;Kweon, Hyeokmoon;Hewitt, John K.;Keller, Matthew C.;Stallings, Michael C.;Lee, James J.;Christensen, Kaare;Kardia, Sharon L. R.;Peyser, Patricia A.;Smith, Jennifer A.;Wilson, James F.;Hopper, John L.;Hagg, Sara;Spector, Tim D.;Pingault, Jean-Baptiste;Plomin, Robert;Havdahl, Alexandra;Bartels, Meike;Martin, Nicholas G.;Oskarsson, Sven;Justice, Anne E.;Millwood, Iona Y.;Hveem, Kristian;Naess, Oyvind;Willer, Cristen J.;Asvold, Bjorn Olav;Koellinger, Philipp D.;Kaprio, Jaakko;Medland, Sarah E.;Walters, Robin G.;Benjamin, Daniel J.;Turley, Patrick;Evans, David M.;Smith, George Davey;Hayward, Caroline;Brumpton, Ben;Hemani, Gibran;Davies, Neil M.
• 通讯作者: Davies, Neil M.

Integrative analysis of clinical and epigenetic biomarkers of mortality.

• DOI: 10.1111/acel.13608
• 发表时间: 2022-06
• 期刊: Aging cell
• 影响因子: 7.8

Genetic variation, brain, and intelligence differences.

• DOI: 10.1038/s41380-021-01027-y
• 发表时间: 2022-01
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Deary IJ;Cox SR;Hill WD
• 通讯作者: Hill WD