Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline

Abstract

vivo magnetic resonance imaging transverse relaxation is associated with late-life cognitive decline even after controlling for common neuropathologic conditions. However, the underlying neurobiology of this association is unknown.OBJECTIVE To investigate the association between brain gene expression, DNA methylation, and alteration of magnetic resonance imaging transverse relaxation in late-life cognitive decline.DESIGN, SETTING, AND PARTICIPANTS Data came from 2 community-based longitudinal cohort studies of aging and dementia, the Religious Orders Study, which began in 1993, and the Rush Memory and Aging Project, which began in 1997. All participants agreed to undergo annual clinical evaluations and to donate their brains after death. By October 24, 2016, a total of 1358 individuals had died and had brain autopsies that were approved by board-certified neuropathologists. Of those, 552 had undergone ex vivo imaging. The gene expression analysis was limited to 174 individuals with both imaging and brain RNA sequencing data. The DNA methylation analysis was limited to 225 individuals with both imaging and brain methylation data. MAIN OUTCOMES AND MEASURESMaps of ex vivo magnetic resonance imaging transverse relaxation were generated using fast spin echo imaging. The target was a composite measure of the transverse relaxation rate (R 2 ) that was associated with cognitive decline after controlling for common neuropathologic conditions. Next-generation RNA sequencing and DNA methylation data were generated using frozen tissue from the dorsolateral prefrontal cortex. Genome-wide association analysis was used to investigate gene expression and, separately, DNA methylation for signals associated with the R 2 measure. RESULTSOf the 552 individuals with ex vivo imaging data, 394 were women and 158 were men, and the mean (SD) age at death was 90.4 (6.0) years. Four co-expressed genes (PADI2 [Ensembl ENSG00000117115], ZNF385A [Ensembl ENSG00000161642], PSD2 [Ensembl ENSG00000146005], and A2ML1 [Ensembl ENSG00000166535]) were identified, of which higher expressions were associated with slower R 2 . The association of R 2 with cognitive decline was attenuated when the gene expression signals were added to the model, such that the mean (SE) coefficient of association was reduced from 0.028 (0.008) (P < .001) to 0.019 (0.009) (P = .03). The DNA methylation scan did not detect a genome-wide significant signal, but it revealed an anticorrelation between R 2 and DNA methylation in many of the cytosine-guanine dinucleotides.CONCLUSIONS AND RELEVANCE Brain gene expression and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions.

Religious Orders Study and Rush Memory and Aging Project

“…We are still at the early stage of generating omics data, performing the quality control, and developing a basic understanding of relationships with AD quantitative endophenotypes with epigenomic and transcriptomic data [278–286]. We are just beginning to examine relations of omic between brain and blood and brain and neuroimaging as part of our nascent biomarker discovery protocol [287, 288]. This will be complemented in the future with multiple layers of blood omics that can be related to ante-mortem imaging and brain omics.…”

DNA methylation of insulin-like growth factor 2 and H19 cluster in cord blood and prenatal air pollution exposure to fine particulate matter

“…In addition, the varimax rotation of factor axes brought an easier interpretation of the latent factors since each CpG had a high loading on one factor and near zero on other factors, which made the factors to carry non-overlapping information. Factor analysis has been applied to omics data in previous studies [56][57][58], but the use in an epidemiological study on methylation data is rather new. Most of the CpG loci which mapped to one factor located within each other's close neighborhood and all factors distributed across the whole length of the genes, justifying our choice of the factors to represent all the CpG loci mapping to the genes.…”

Suicide and suicide behaviors: A review of transcriptomics and multiomics studies in psychiatric disorders

“…In these studies (see Table ), transcriptomic data were analyzed with or alongside genomic, epigenetic, proteomic, and even brain imaging data as a multisystems approach to determining the etiology and functional consequences of transcriptomic dysregulation associated with clinical psychiatric phenotypes. In addition, co‐expressed genes in the dorso‐lateral prefrontal cortex (PFC) have been associated with MRI measures of cognitive decline in later life (Yu et al, ). Other applications include characterizing co‐expression networks across different brain regions in the same subjects to shed light onto the molecular processes underlying the neural circuit processes.…”