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Robins, C.

Publications and source records attributed to Robins, C..

2 recordsLinked to original sources
bioRxiv2019

Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline

ObjectiveCognitive decline is a hallmark of dementia; however, the brain epigenetic signature of cognitive decline is unclear. We investigated the associations between brain tissue-based DNA methylation and cognitive trajectory. MethodsWe performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the Religious Order Study and the Rush Memory and Aging Project (ROS/MAP) using DNA methylation profiles of the dorsal lateral prefrontal cortex (dPFC). To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits (GAMuT) test to analyze the five measured cognitive domains simultaneously. ResultsWe found an epigenome-wide association for differential methylation of sites in the Claudin-5 (CLDN5) locus and cognitive trajectory (p-value x 9.96 x 10-7), which was robust to adjustment for cell type proportions (p-value = 8.52 x 10-7). This association was primarily driven by association with declines in episodic (p-value = 4.65 x 10-6) and working memory (p-value = 2.54 x 10-7). This association between methylation in CLDN5 and cognitive decline was independent of beta-amyloid and neurofibrillary tangle pathology and present in participants with low levels of neuropathology. In addition, only 13-31% of the association between methylation and cognitive decline was mediated through levels of neuropathology, whereas the major part of the association was independent of it. InterpretationWe identified methylation in CLDN5 as new epigenetic factor associated with cognitive trajectory. Higher levels of methylation in CLDN5 were associated with faster cognitive decline implicating the blood brain barrier in maintenance of cognitive trajectory.

genetics↗
bioRxiv2019

Genetic control of the human brain proteome

Alteration of protein abundance and conformation are widely believed to be the hallmark of neurodegenerative diseases. Yet relatively little is known about the genetic variation that controls protein abundance in the healthy human brain. The genetic control of protein abundance is generally thought to parallel that of RNA expression, but there is little direct evidence to support this view. Here, we performed a large-scale protein quantitative trait locus (pQTL) analysis using single nucleotide variants (SNVs) from whole-genome sequencing and tandem mass spectrometry-based proteomic quantification of 12,691 unique proteins (7,901 after quality control) from the dorsolateral prefrontal cortex (dPFC) in 144 cognitively normal individuals. We identified 28,211 pQTLs that were significantly associated with the abundance of 864 proteins. These pQTLs were compared to dPFC expression quantitative trait loci (eQTL) in cognitive normal individuals (n=169; 81 had protein data) and a meta-analysis of dPFC eQTLs (n=1,433). We found that strong pQTLs are generally only weak eQTLs, and that the majority of strong eQTLs are not detectable pQTLs. These results suggest that the genetic control of mRNA and protein abundance may be substantially distinct and suggests inference concerning protein abundance made from mRNA in human brain should be treated with caution.

genetics↗