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

Danni A. Gadd; Robert Francis Hillary; Daniel L. McCartney; Liu Shi; Aleks Stolicyn; Neil Robertson; Rosie May Walker; Robert I. McGeachan; Archie I Campbell; Xueyi Shen; Miruna C. Barbu; Claire Green; Stewart W. Morris; Mathew A. Harris; Ellen V. Backhouse; Joanna Marguerite Wardlaw; J. Douglas Steele; Diego A. Oyarzún; Graciela Muniz Terrera; Craig William Ritchie; Alejo J. Nevado‐Holgado; Tamir Chandra; Caroline Hayward; Kathryn Louise Evans; David John Porteous; Simon R. Cox; Heather Clare Whalley; Andrew Mark McIntosh; Riccardo Emilio Marioni

doi:10.1038/s41467-022-32319-8

Genetic & Genomic MedicineNature CommunicationsAug 9, 2022

Peer-reviewed journal article

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

Danni A. Gadd iD, Robert Francis Hillary iD, Daniel L. McCartney iD, Liu Shi iD, Aleks Stolicyn iD, Neil Robertson iD, Rosie May Walker iD, Robert I. McGeachan iD, Archie I Campbell iD, Xueyi Shen iD, Miruna C. Barbu iD, Claire Green iD, Stewart W. Morris, Mathew A. Harris iD, Ellen V. Backhouse iD, Joanna Marguerite Wardlaw iD, J. Douglas Steele iD, Diego A. Oyarzún iD, Graciela Muniz Terrera iD, Craig William Ritchie iD, Alejo J. Nevado‐Holgado iD, Tamir Chandra iD, Caroline Hayward iD, Kathryn Louise Evans iD, David John Porteous iD, , Riccardo Emilio Marioni iD

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 4,058 plasma proteins are performed (N=774), identifying 2,928 CpG-protein associations after adjustment for multiple testing. These were 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.

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