Examining the associations between microglia genetic capacity, early life exposures and white matter development at the level of the individual

Shi Yu Chan; Eamon Fitzgerald; Zhen Ming Ngoh; Janice Lee; Jasmine Chuah; Joanne S M Chia; Marielle V Fortier; Elizabeth H Tham; Juan H Zhou; Patricia P Silveira; Michael J Meaney; Ai Peng Tan

doi:10.1016/j.bbi.2024.04.038

Examining the associations between microglia genetic capacity, early life exposures and white matter development at the level of the individual

Brain Behav Immun. 2024 Apr 26:119:781-791. doi: 10.1016/j.bbi.2024.04.038. Online ahead of print.

Authors

Affiliations

¹ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 30 Medical Dr, Singapore 117609, Singapore.
² Ludmer Centre for Neuroinformatics and Mental Health, McGill University, 1010 Rue Sherbrooke O, QC H3A 2R7, Canada; Douglas Mental Health University Institute, Department of Psychiatry, McGill University, 6875 Bd LaSalle, QC H4H 1R3, Canada.
³ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 30 Medical Dr, Singapore 117609, Singapore; Department of Diagnostic and Interventional Imaging, KK Women's and Children's Hospital, 100 Bukit Timah Rd, Singapore 229899, Singapore; Duke-NUS Medical School, 8 College Rd, Singapore 169857, Singapore.
⁴ Yong Loo Lin School of Medicine, National University of Singapore (NUS), 10 Medical Dr, Singapore 117597, Singapore; Khoo Teck Puat-National University Children's Medical Institute, National University Health System (NUHS), 5 Lower Kent Ridge Rd, Singapore 119074, Singapore.
⁵ Yong Loo Lin School of Medicine, National University of Singapore (NUS), 10 Medical Dr, Singapore 117597, Singapore; Department of Electrical and Computer Engineering, National University of Singapore, 4 Engineering Drive 3, Singapore 117583, Singapore.
⁶ Ludmer Centre for Neuroinformatics and Mental Health, McGill University, 1010 Rue Sherbrooke O, QC H3A 2R7, Canada; Douglas Mental Health University Institute, Department of Psychiatry, McGill University, 6875 Bd LaSalle, QC H4H 1R3, Canada; Yong Loo Lin School of Medicine, National University of Singapore (NUS), 10 Medical Dr, Singapore 117597, Singapore.
⁷ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 30 Medical Dr, Singapore 117609, Singapore; Douglas Mental Health University Institute, Department of Psychiatry, McGill University, 6875 Bd LaSalle, QC H4H 1R3, Canada; Yong Loo Lin School of Medicine, National University of Singapore (NUS), 10 Medical Dr, Singapore 117597, Singapore; Brain - Body Initiative Program, Agency for Science, Technology and Research (A*STAR), 1 Fusionopolis Way, Connexis North Tower, Singapore 138632, Singapore.
⁸ Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR), 30 Medical Dr, Singapore 117609, Singapore; Yong Loo Lin School of Medicine, National University of Singapore (NUS), 10 Medical Dr, Singapore 117597, Singapore; Brain - Body Initiative Program, Agency for Science, Technology and Research (A*STAR), 1 Fusionopolis Way, Connexis North Tower, Singapore 138632, Singapore; Department of Diagnostic Imaging, National University Health System, 1E Kent Ridge Rd, Singapore 119228, Singapore. Electronic address: dnrtanap@nus.edu.sg.

PMID: 38677627
DOI: 10.1016/j.bbi.2024.04.038

Abstract

There are inter-individual differences in susceptibility to the influence of early life experiences for which the underlying neurobiological mechanisms are poorly understood. Microglia play a role in environmental surveillance and may influence individual susceptibility to environmental factors. As an index of neurodevelopment, we estimated individual slopes of mean white matter fractional anisotropy (WM-FA) across three time-points (age 4.5, 6.0, and 7.5 years) for 351 participants. Individual variation in microglia reactivity was derived from an expression-based polygenic score(ePGS) comprised of Single Nucleotide Polymorphisms (SNPs) functionally related to the expression of microglia-enriched genes.A higher ePGS denotes an increased genetic capacity for the expression of microglia-related genes, and thus may confer a greater capacity to respond to the early environment and to influence brain development. We hypothesized that this ePGS would associate with the WM-FA index of neurodevelopment and moderate the influence of early environmental factors.Our findings show sex dependency, where a significant association between WM-FA and microglia ePGS was only obtained for females.We then examined associations with perinatal factors known to decrease (optimal birth outcomes and familial conditions) or increase (systemic inflammation) the risk for later mental health problems.In females, individuals with high microglia ePGS showed a negative association between systemic inflammation and WM-FA and a positive association between more advantageous environmental conditions and WM-FA. The microglia ePGS in females thus accounted for variations in the influence of the quality of the early environment on WM-FA.Finally, WM-FA slopes mediated the association of microglia ePGS with interpersonal problems and social hostility in females. Our findings suggest the genetic capacity for microglia function as a potential factor underlying differential susceptibility to early life exposuresthrough influences on neurodevelopment.

Keywords: Development; Diffusion tensor imaging; Early life; Fractional anisotropy; Inflammation; Microglia; Polygenic scores; White matter.