Genome-wide association studies of brain diffusion kurtosis imaging phenotypes

As an extension of diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI) quantifies non-Gaussian water diffusion and has been applied to explore brain disorders. However, the genetic architecture of brain DKI phenotypes remains unknown.

Here, we estimated heritability and conducted genome-wide association studies (GWASs) for 804 DKI phenotypes across 188 brain structures in 4183 participants. To determine whether DKI-GWASs provides genetic insights beyond DTI-GWASs, we compared results from 804 DKI-GWASs and 752 DTI-GWASs in the same cohort. To clarify the biological significance of DKI phenotypes, we examined associations between DKI phenotypes and brain health-related outcomes within the CHIMGEN, and explored associations between polygenic risk scores (PRSs) of DKI phenotypes and mental disorders in the UK Biobank.

Of 804 DKI phenotypes, 275 showed significant heritability (P < 0.05; h² range: 0.143-0.602). We detected 280 significant associations (P < 5 × 10^-8), with 38 surviving Bonferroni correction (P < 1.54 × 10^-10). These associations were unevenly distributed across chromosomes, DKI phenotype subgroups, and brain structures. Among 229 independent variant-structure associations for DKI, 175 (76.4%) were DKI-specific. We observed 930 associations between DKI phenotypes and brain health-related outcomes (P < 0.05; ten Bonferroni-significant with P < 1.02 × 10^-5), and 200 between PRSs and mental disorders (P < 0.05; one Bonferroni-significant with P < 9.61 × 10^-5).

This study delineates the genetic architecture of brain DKI phenotypes, identifies complementary genetic insights into brain microstructure, and provides biologically relevant endophenotypes for investigating neural mechanisms underlying brain disorders.

National Natural Science Foundation of China, National Key Research and Development Program of China, Tianjin Key Medical Discipline Construction Project, and Tianjin Natural Science Foundation.