Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health

Danni A. Gadd, Robert F. Hillary, Daniel L. McCartney, Liu Shi, Aleks Stolicyn, Neil A. Robertson, Rosie M. Walker, Robert I. McGeachan, Archie Campbell, Shen Xueyi, Miruna C. Barbu, Claire Green, Stewart W. Morris, Mathew A. Harris, Ellen V. Backhouse, Joanna M. Wardlaw, J. Douglas Steele, Diego A. Oyarzún, Graciela Muniz-Terrera, Craig Ritchie, Alejo Nevado-Holgado, Tamir Chandra, Caroline Hayward, Kathryn L. Evans, David J. Porteous, Simon R. Cox, Heather C. Whalley, Andrew M. McIntosh and Riccardo E. Marioni ()
Additional contact information
Danni A. Gadd: University of Edinburgh
Robert F. Hillary: University of Edinburgh
Daniel L. McCartney: University of Edinburgh
Liu Shi: University of Oxford
Aleks Stolicyn: University of Edinburgh, Royal Edinburgh Hospital
Neil A. Robertson: University of Edinburgh
Rosie M. Walker: Centre for Clinical Brain Sciences, Chancellor’s Building
Robert I. McGeachan: University of Edinburgh
Archie Campbell: University of Edinburgh
Shen Xueyi: University of Edinburgh, Royal Edinburgh Hospital
Miruna C. Barbu: University of Edinburgh, Royal Edinburgh Hospital
Claire Green: University of Edinburgh, Royal Edinburgh Hospital
Stewart W. Morris: University of Edinburgh
Mathew A. Harris: University of Edinburgh, Royal Edinburgh Hospital
Ellen V. Backhouse: Centre for Clinical Brain Sciences, Chancellor’s Building
Joanna M. Wardlaw: Centre for Clinical Brain Sciences, Chancellor’s Building
J. Douglas Steele: University of Dundee
Diego A. Oyarzún: University of Edinburgh
Graciela Muniz-Terrera: University of Edinburgh
Craig Ritchie: University of Edinburgh
Alejo Nevado-Holgado: University of Oxford
Tamir Chandra: University of Edinburgh
Caroline Hayward: University of Edinburgh
Kathryn L. Evans: University of Edinburgh
David J. Porteous: University of Edinburgh
Simon R. Cox: University of Edinburgh
Heather C. Whalley: University of Edinburgh, Royal Edinburgh Hospital
Andrew M. McIntosh: University of Edinburgh, Royal Edinburgh Hospital
Riccardo E. Marioni: University of Edinburgh

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health.

Date: 2022
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DOI: 10.1038/s41467-022-32319-8

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