New insights into the genetics of subcortical volumes across the adult lifespan

Background Subcortical brain structures play a key role in pathological processes of many age‐related neurodegenerative disorders. Mounting evidence suggests that factors already present at an early age play a crucial role in the development of common late‐life neurological diseases, including genetic factors that can influence both brain maturation and neurodegeneration. Using large population‐based brain imaging datasets across the adult lifespan, we aimed to identify whether genetic loci associated with subcortical brain structures in older persons also show significant association with the same structures in early adulthood and explore underlying genes using transcriptome‐wide association studies (TWAS). Method We first tested variants, previously identified in genome‐wide association study (GWAS) of subcortical volumes in older adults, in young adults (i‐Share cohort, 18‐35y) individually and aggregated in genetic risk scores (GRS). We conducted a TWAS using the summary statistics from the GWAS of subcortical volumes. For the significant signals, we generated gene expression scores in i‐Share and tested them in association with subcortical volumes. Result We observed that GRS for smaller caudate nucleus and putamen volume in older adults were associated with smaller volumes of the same structures in young adults. Individually, ten independent loci associated with subcortical volumes in older adults also showed associations with the corresponding volume in young adults, with the strongest association between a variant near KTN1 and putamen volume. In TWAS, expression of several genes in brain tissues was significantly associated with caudate nucleus, putamen and pallidum volumes both in older and young adults, pointing to biological pathways underlying structural brain changes across the adult lifespan, with particularly strong evidence for a causal implication of MYLK2 and TUFM, in relation with caudate nucleus and putamen volume. We observed an association of genetically predicted Alzheimer’s disease with smaller volumes of most subcortical structures in older adults, but not in young adults. Conclusion Our findings provide novel insight into the genetic determinants of changes in subcortical brain structures across the adult lifespan. Further research is needed to decipher the underlying biological mechanisms and inform prevention strategies for common late life neurological diseases.