Identification and replication of gene‐by‐stress interaction associations with Alzheimer’s disease and related dementias

Abstract

AbstractBackgroundSeveral mechanisms have been hypothesized for the pathogenesis of Alzheimer’s disease and related dementias (ADRD); however, we are still far from effective prevention and treatment of the disease, thus more basic research is needed to understand the etiological neuropathogenesis. We hypothesized that a part of increased ADRD‐risk could be due to a complex interplay of genes and daily‐life psychosocial stress.MethodWe used the Health and Retirement Study (HRS) surveys and Medicare‐linked data for the discovery analysis and the Long‐Life Family Study (LLFS) dataset for replication analysis, creating a synthetic stress measure using the algorithm based on stress proxy‐indicators, as described in Singh et al., 2015. The two datasets were compared by evaluating samples’ stress levels and socioeconomic status. We performed the HRS gene‐by‐stress discovery GWAS analyses on age‐at‐onset of ADRD using linear regression with SNP, STRESS, SEX, and ancestry principal components as other terms in model. We fitted the same regression model in the LLFS replication analysis, adjusting it additionally with field centers and Huber–White familial clustering.ResultThe HRS GWASs resulted in associations at p‐value of order 10−8 in both Blacks and Whites. Although most of the top 25 significant SNPs were mapped to non‐coding regions, we identified four characterized genes (BCR, MCC, KCNQ5, and DCP2) in Whites and three genes (EMCN, DPYD, and INSYN2A) in Blacks. Published literature from human and experimental studies suggested that five out of the eight genes were known for their association with neurodevelopmental disorders including Autism, intellectual disability, but also for cancers including colorectal carcinoma, gastric carcinoma, and leukemia. Although LLFS samples presented higher socioeconomic status and lower stress levels compared to HRS samples, the associations of one‐third tested SNPs from HRS Whites replicated in LLFS samples.ConclusionOur findings suggest that daily‐life stress may contribute to the risk of ADRD via complex interactions with genes. The associations with non‐coding genetic variants may indicate their influence through gene‐regulatory roles. In addition, the associations observed with cancer genes may possibly point towards the involvement of a common mechanistic feature, e.g., angiogenesis, which needs to be investigated further.