# Potential Biological Processes Related to Brain SLC13A5 Across the Lifespan: Weighted Gene Co-Expression Network Analysis from Large Human Transcriptomic Data

## TL;DR

This study explores how the SLC13A5 gene, linked to brain disorders, changes across human development and identifies related biological processes in the brain.

## Contribution

The study reveals a mitochondria-centered gene network co-varying with SLC13A5 across the human lifespan.

## Key findings

- SLC13A5 expression peaks in the first postnatal year in the cerebrum and increases in the cerebellum across the lifespan.
- SLC13A5 is part of a gene module strongly associated with brain maturation and mitochondrial function.
- A subnetwork of genes closely connected to SLC13A5 includes CYP46A1, ITM2B, and others involved in oxidative phosphorylation.

## Abstract

Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho = 0.802, p = 8.62 × 10−6) and closely matched SLC13A5 abundance (rho = 0.884, p = 2.73 × 10−6), with a significant partial association after adjusting for developmental rank (rho = 0.672, p = 6.17 × 10−4). Functional enrichment converged on oxidative phosphorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mitochondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism.