Imprinting methylation predicts hippocampal volumes and hyperintensities and the change with age in later life

Marlene Lorgen-Ritchie,Alison D Murray,Louise H Phillips,Gwen Hoad,Roger Staff,Antonio Ribeiro,Anne C Ferguson-Smith,Graham W Horgan,Chris Mcneil,Paul Haggarty,Marcus Richards

doi:10.1038/s41598-020-78062-2

Abstract

Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. Epigenetic imprinting may underpin these associations. Methylation was measured at 982 sites in 13 imprinted locations in blood samples from a longitudinal cohort by bisulphite amplicon sequencing. Hippocampal volumes and hyperintensities were determined at age 64y and 72y using MRI. Hyperintensities were determined in white matter, grey matter and infratentorial regions. Permutation methods were used to adjust for multiple testing. At 64y, H19/IGF2 and NESPAS methylation predicted hippocampal volumes. PEG3 predicted hyperintensities in hippocampal grey matter, and white matter. GNASXL predicted grey matter hyperintensities. Changes with age were predicted for hippocampal volume (MEST1, KvDMR, L3MBTL, GNASXL), white matter (MEST1, PEG3) and hippocampal grey matter hyperintensities (MCTS2, GNASXL, NESPAS, L3MBTL, MCTS2, SNRPN, MEST1). Including childhood cognitive ability, years in education, or socioeconomic status as additional explanatory variables in regression analyses did not change the overall findings. Imprinting methylation in multiple genes predicts brain structures, and their change over time. These findings are potentially relevant to the development of novel tests of brain structure and function across the life-course, strategies to improve cognitive outcomes, and our understanding of early influences on brain development and function.

Highlights

Epigenetic imprinting is important for neurogenesis and brain function
Hippocampal volume was positively correlated with total intracranial volume and the number of grey matter hyperintensities specific to the hippocampus
Total intracranial volume was positively corelated with the number of grey matter hyperintensities specific to the hippocampus, and with the number of periventricular white matter hyperintensities

Summary

Introduction

Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. In this study we hypothesize that associations exist between imprint methylation and hippocampal volume and the prevalence of brain MRI hyperintensities in the seventh decade of life in a well-characterised cohort born in 1936 and recruited at 64 years of a ge[21].

Results

Conclusion