Department of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA; Survey Research Center, Institute for Social Research, University of Michigan, 426 Thompson St, Ann Arbor, MI, 48104, USA.
Department of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA.
Soc Sci Med. 2021 Feb;271:112039. doi: 10.1016/j.socscimed.2018.11.019. Epub 2018 Nov 10.
Both social and genetic factors contribute to cognitive impairment and decline, yet genetic factors identified through genome-wide association studies (GWAS) explain only a small portion of trait variability. This "missing heritability" may be due to rare, potentially functional, genetic variants not assessed by GWAS, as well as gene-by-social factor interactions not explicitly modeled. Gene-by-social factor interactions may also operate differently across race/ethnic groups. We selected 39 genes that had significant, replicated associations with cognition, dementia, and related traits in published GWAS. Using gene-based analysis (SKAT/iSKAT), we tested whether common and/or rare variants were associated with episodic memory performance and decline either alone or through interaction with education in >10,000 European ancestry (EA) and >2200 African ancestry (AA) respondents from the Health and Retirement Study (HRS). Nine genes in EA and five genes in AA were associated with memory performance or decline (p < 0.05), and these effects did not attenuate after adjusting for education. Interaction between education and CLPTM1 on memory performance was significant in AA (p = 0.003; FDR-adjusted p = 0.038) and nominally significant in EA (p = 0.026). In both ethnicities, low memory performance was associated with CLPTM1 genotype (rs10416261) only for those with less than high school education, and effects persisted after adjusting for APOE ε4. For over 70% of gene-by-education interactions across the genome that were at least nominally significant in either ethnic group (p < 0.05), genetic effects were only observed for those with less than high school education. These results suggest that genetic effects on memory identified in this study are not mediated by education, but there may be important gene-by-education interactions across the genome, including in the broader APOE genomic region, which operate independently of APOE ε4. This work illustrates the importance of developing theoretical frameworks and methodological approaches for integrating social and genomic data to study cognition across ethnic groups.
社会和遗传因素都对认知障碍和认知能力下降有影响，但通过全基因组关联研究（GWAS）确定的遗传因素仅能解释部分特征的可变性。这种“遗传缺失”可能是由于 GWAS 未评估的罕见、潜在功能的遗传变异，以及未明确建模的基因-社会因素相互作用所致。基因-社会因素相互作用在不同种族/民族群体中可能有不同的作用方式。我们选择了 39 个在已发表的 GWAS 中与认知、痴呆症和相关特征有显著、复制关联的基因。我们使用基于基因的分析（SKAT/iSKAT），测试了常见和/或罕见变异是否单独或通过与教育的相互作用与超过 10000 名欧洲血统（EA）和超过 2200 名非洲血统（AA）的健康与退休研究（HRS）受访者的情景记忆表现和下降有关。在 EA 中有 9 个基因，在 AA 中有 5 个基因与记忆表现或下降有关（p < 0.05），这些影响在调整教育因素后并未减弱。在 AA 中，教育与 CLPTM1 之间的相互作用对记忆表现有显著影响（p = 0.003；经 FDR 调整后的 p = 0.038），在 EA 中也有显著的影响（p = 0.026）。在这两个种族中，低记忆表现仅与基因型（rs10416261）有关，只有那些接受不到高中教育的人，而且在调整 APOE ε4 后，这些影响仍然存在。对于超过 70%的基因-教育相互作用，在至少一个种族中至少具有名义上的显著性（p < 0.05），只有那些接受不到高中教育的人才能观察到遗传效应。这些结果表明，本研究中确定的与记忆有关的遗传效应不受教育的影响，但在整个基因组中可能存在重要的基因-教育相互作用，包括在更广泛的 APOE 基因组区域，这些作用独立于 APOE ε4。这项工作说明了开发理论框架和方法学方法的重要性，以整合社会和基因组数据来研究不同种族的认知。
