Brain white matter abnormalities are evident in individuals with
schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide
alpha-2,8-sialyltransferase 2 (
ST8SIA2) gene, which encodes the
alpha-2,8-sialyltransferase 8B
enzyme that
aids neuronal migration and synaptic plasticity, was previously implicated as a
schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in
ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of individuals with
schizophrenia (n = 281) and healthy controls (n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and
ST8SIA2 protective haplotype (p < 0.05, family-wise error rate (FWER) cluster-corrected). The protective haplotype was associated with increased FA in controls, but this effect was reversed in people with
schizophrenia. White matter fiber tracking revealed that the region-of-interest was traversed by portions of the superior longitudinal fasciculus, corona radiata, and posterior limb of internal capsule. Post hoc analysis revealed that reduced FA in this regional juncture correlated with reduced IQ in people with
schizophrenia. The
ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for
mental illness, providing further compelling evidence for involvement of
ST8SIA2 in the pathophysiology of
schizophrenia.