An epigenetic predictor of death captures multi-modal measures of brain health

  • Mol Psychiatry. 2021 Aug;26(8):3806-3816. doi: 10.1038/s41380-019-0616-9.
Robert F Hillary  #  1 ,  Anna J Stevenson  #  1 ,  Simon R Cox  2  3 ,  Daniel L McCartney  1 ,  Sarah E Harris  2  3 ,  Anne Seeboth  1 ,  Jon Higham  4 ,  Duncan Sproul  4  5 ,  Adele M Taylor  2  3 ,  Paul Redmond  2  3 ,  Janie Corley  2  3 ,  Alison Pattie  2  3 ,  Maria Del C Valdés Hernández  2  6 ,  Susana Muñoz-Maniega  2  6 ,  Mark E Bastin  2  6 ,  Joanna M Wardlaw  2  6  7 ,  Steve Horvath  8  9 ,  Craig W Ritchie  10 ,  Tara L Spires-Jones  7  11 ,  Andrew M McIntosh  2  12 ,  Kathryn L Evans  1  2 ,  Ian J Deary  2  3 ,  Riccardo E Marioni  13  14
Affiliations
  • 1. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • 2. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
  • 3. Department of Psychology, University of Edinburgh, Edinburgh, UK.
  • 4. Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • 5. Edinburgh Cancer Research Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • 6. Department of Neuroimaging Sciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
  • 7. UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK.
  • 8. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
  • 9. Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, USA.
  • 10. Edinburgh Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
  • 11. Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
  • 12. Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
  • 13. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. [email protected].
  • 14. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. [email protected].
  • # Contributed equally.
PMID: 31796892 DOI: 10.1038/s41380-019-0616-9
Abstract

Individuals of the same chronological age exhibit disparate rates of biological ageing. Consequently, a number of methodologies have been proposed to determine biological age and primarily exploit variation at the level of DNA methylation (DNAm). A novel epigenetic clock, termed 'DNAm GrimAge' has outperformed its predecessors in predicting the risk of mortality as well as many age-related morbidities. However, the association between DNAm GrimAge and cognitive or neuroimaging phenotypes remains unknown. We explore these associations in the Lothian Birth Cohort 1936 (n = 709, mean age 73 years). Higher DNAm GrimAge was strongly associated with all-cause mortality over the eighth decade (Hazard Ratio per standard deviation increase in GrimAge: 1.81, P < 2.0 × 10-16). Higher DNAm GrimAge was associated with lower age 11 IQ (β = -0.11), lower age 73 general cognitive ability (β = -0.18), decreased brain volume (β = -0.25) and increased brain white matter hyperintensities (β = 0.17). There was tentative evidence for a longitudinal association between DNAm GrimAge and cognitive decline from age 70 to 79. Sixty-nine of 137 health- and brain-related phenotypes tested were significantly associated with GrimAge. Adjusting all models for childhood intelligence attenuated to non-significance a small number of associations (12/69 associations; 6 of which were cognitive traits), but not the association with general cognitive ability (33.9% attenuation). Higher DNAm GrimAge associates with lower cognitive ability and brain vascular lesions in older age, independently of early-life cognitive ability. This epigenetic predictor of mortality associates with different measures of brain health and may aid in the prediction of age-related cognitive decline.