Epigenome-wide association study of hippocampal volume.

Abstract

Decreased hippocampal volume has been associated with age-related memory decline as well as several neurodegenerative and neuropsychiatric disorders. However, the molecular determinants of hippocampal volume are still poorly understood. Epigenetic changes alter the expression of many neurotrophic genes and may mediate the effects of gene/environment interactions on age-related hippocampal atrophy. Therefore, we aimed toidentify the epigenetic signatures associated with hippocampal volume through genome-wide DNA methylation profiling. We based our study onthe first 4,000 participantsof the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Left, right, and mean hippocampalvolumeswere obtained from 3T MRI scans using standard FreeSurfer6.0 pipeline (Fischl et al. 2002). Besides, a volumetric asymmetry index, defined as the difference between the left and right hippocampal volumes divided by their sum, was calculated. DNA methylation levels were quantified using Infinium MethylationEPIC(850K)BeadChip.Multivariable regression models were used to examine the association betweenDNA methylation levels and hippocampal volume or asymmetry, while adjusting for age, sex, intracranial volume, batch information, population stratification, smoking, and education. False discovery rate (FDR)-adjusted p-values were applied to account for multiple comparisons. A total of 2295 participants (57.3% female, age 54.3± 14.0years (range 30 - 95 years)) with both brain imaging and methylation data were included in the analyses. Methylation at a probe mapping to ERCC6L2was associated with higher mean hippocampal volume (ß =0.006 ± 0.001, FDR-adjusted p=0.011), whereas methylation at two other probes, mapping to INTS8 and KIAA0564, was associated with the hippocampal asymmetry index (ß =-0.122 ± 0.019, FDR-adjusted p= 0.007, and ß =0.062 ± 0.011, FDR-adjusted p=0.023, respectively). In silico pathway analyses revealed that ERCC6L2is associated with DNA repair, mitochondrial function, and response to reactive oxygen species, while INTS8 andKIAA0564 have been associated with neurodevelopmental disorders. We discovered three novel DNA methylation markers of hippocampal volume and asymmetry, which could be instrumental in the further elucidation of the molecular basis of neurodevelopmental variations in hippocampal volume as well as age-and disease-related hippocampal atrophy. Reference: Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. 2002. Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron 33:341-355.