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Genetic and epigenetic architectures of neurological protein biomarkers in the Lothian Birth Cohort 1936

By Robert F Hillary, Daniel L. McCartney, Sarah E Harris, Anna J Stevenson, Anne Seeboth, Qian Zhang, David C Liewald, Kathryn L Evans, Craig Ritchie, Elliot M Tucker-Drob, Naomi R. Wray, Allan F McRae, Peter M. Visscher, Ian J Deary, Riccardo E. Marioni

Posted 26 Feb 2019
bioRxiv DOI: 10.1101/558940

Although plasma proteins may serve as important markers of disease risk in neurological conditions, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. In this study, we conducted genome- and epigenome-wide association studies on the levels of 92 neurological proteins to identify genetic and epigenetic loci associated with their plasma concentrations (n = 750). We identified 62 independent genome-wide significant loci for 37 proteins (P < 5.4 x 10-10) and 68 epigenome-wide significant sites associated with the levels of 7 proteins (P < 3.9 x 10-10). Using this information, we identified biological pathways in which putative neurological biomarkers are implicated as well as molecular mechanisms through which genetic variation may perturb plasma protein levels. Additionally, we found evidence that poliovirus receptor is causally associated with Alzheimers disease. In conclusion, we identified many novel genetic and epigenetic factors that are associated with neurological protein levels which may inform disease biology and establish causal relationships between biomarkers and neurological diseases.

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