Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11177-x
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Funding
- Age UK (Disconnected Mind program)
- Medical Research Council [MR/M01311/1]
- Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award)
- Age UK
- Wellcome Trust Institutional Strategic Support Fund
- University of Queensland
- University of Edinburgh
- Medical Research Council
- Biotechnology and Biological Sciences Research Council [MR/K026992/1]
- NIH [R01AG054628, R01AG05462802S1, P2CHD042849]
- Wellcome Trust [108890/Z/15/Z]
- Medical Research Council PhD Studentship in Precision Medicine
- Medical Research Council Doctoral Training Programme
- University of Edinburgh College of Medicine and Veterinary Medicine
- Alzheimer's Research UK [ARUK-PG2017B-10]
- Australian National Health and Medical Research Council [1010374, 1046880, 1113400]
- Australian Research Council [DP160102400]
- NHMRC [1078037, 1078901, 1083656]
- BBSRC [BB/F019394/1] Funding Source: UKRI
- National Health and Medical Research Council of Australia [1083656, 1078901, 1078037] Funding Source: NHMRC
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Although plasma proteins may serve as markers of neurological disease risk, the molecular mechanisms responsible for inter-individual variation in plasma protein levels are poorly understood. Therefore, we conduct 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 healthy older adults). We identify 41 independent genome-wide significant (P < 5.4 x 10(-10)) loci for 33 proteins and 26 epigenome-wide significant (P < 3.9 x 10(-10)) sites associated with the levels of 9 proteins. Using this information, we identify biological pathways in which putative neurological biomarkers are implicated (neurological, immunological and extracellular matrix metabolic pathways). We also observe causal relationships (by Mendelian randomisation analysis) between changes in gene expression (DRAXIN, MDGA1 and KYNU), or DNA methylation profiles (MATN3, MDGA1 and NEP), and altered plasma protein levels. Together, this may help inform causal relationships between biomarkers and neurological diseases.
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