Chin Rowena, Zhang Xi-Han, Anderson Kevin M, Yendiki Anastasia, Holmes Avram J
Department of Psychology, Yale University, New Haven, CT, USA.
Wu Tsai Institute, Yale University, New Haven, CT, USA.
bioRxiv. 2025 Sep 3:2025.09.02.673734. doi: 10.1101/2025.09.02.673734.
The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be established. Here, we examined the genetic associates of individual differences in diffusion-based measures of white matter in a population-based cohort (N=29,862) from the UK Biobank. Estimates of heritability from Genome-Wide Association Study (GWAS) data revealed that genetic factors are linked to population variability in 96.1% of 432 tract microstructural measures. The presence of shared genetic influences was observed to be greater within, relative to between, broad tract classes (commissural, association, projection, and complex cerebellar). Age associations with microstructural changes were estimated across diffusivity measures, with association class tracts showing the greatest vulnerability to age-related decline in older adults. Analyses of imputed cellular associates of age-related changes in white matter revealed a preferential relationship with cell gene markers of oligodendrocytes and other glial cell types, with sparse relationships observed for inhibitory and excitatory cells. These data indicate that white matter tract microstructure is shaped by genetic factors and suggest a role for glial cell-related transcripts in late-life changes in the structural wiring properties of the human brain.
支持信息在局部回路和大规模网络中流动的白质微观结构在整个生命周期中都会发生变化。然而，白质微观结构中与年龄相关的变化背后的遗传和细胞因素尚未确定。在这里，我们在英国生物银行的一个基于人群的队列（N = 29862）中研究了基于扩散的白质测量中个体差异的遗传关联。全基因组关联研究（GWAS）数据的遗传力估计表明，遗传因素与432个脑区微观结构测量值中96.1%的人群变异性相关。相对于广泛的脑区类别（连合纤维、联络纤维、投射纤维和复杂小脑纤维）之间，观察到共享遗传影响在类别内部更大。通过扩散率测量估计了年龄与微观结构变化的关联，其中联络纤维类别在老年人中显示出对与年龄相关的衰退最敏感。对白质中与年龄相关变化的推断细胞关联分析表明，与少突胶质细胞和其他胶质细胞类型的细胞基因标记存在优先关系，而与抑制性和兴奋性细胞的关系较少。这些数据表明白质纤维束微观结构受遗传因素影响，并提示胶质细胞相关转录本在人类大脑结构布线特性的后期变化中起作用。
