Association of the Schizophrenia Risk Locus rs10866912 with Cerebral Volumes, Diet, and Psychosis in the UK Biobank

Background: Leading schizophrenia GWAS signals require evaluation of their pathological significance across diverse ancestries. rs10866912 reached genome-wide significance in our Indian ancestry GWAS of schizophrenia; its risk allele reduces expression of NAPRT, the rate-limiting enzyme in the brain’s principal NAD+-synthesis pathway, giving a single mechanistic basis for testing associations with brain structure, dietary niacin intake, and psychosis risk. We evaluated this SNP in a large European ancestry population for associations with regional brain volumes, niacin-rich food consumption, and psychotic disorder diagnosis. Methods: Of approximately 500,000 UK Biobank participants, 36,492 met study criteria of European ancestry, brain MRI examination, and dietary questionnaire completion. Risk-allele count was regressed on each of 174 phenotypes—139 regional gray matter volumes, 26 psychological and 9 dietary variables—with age, sex, and BMI as covariates. Volumes were log-transformed and adjusted for total gray matter volume by residualization, and Bonferroni and false discovery rate corrections were applied within each domain. Results: Risk-allele count was negatively associated with gray matter volume in the left pallidum (β = −0.0143, p = 0.00016; Bonferroni-significant) and left caudate (β = −0.0142, p = 0.00038; FDR-significant), with the contralateral homologues in the same direction at nominal significance. No dietary or psychological variable survived correction. Nominally significant associations included increased wheat consumption and fewer years spent vegetarian, both implying higher dietary niacin. The association with a diagnosis of psychotic disorder, nominally significant in linear regression, was not significant when the binary outcome was re-examined by logistic regression (OR = 1.36, 95% CI 0.997–1.85, p = 0.053). Conclusions: The risk allele is associated with reduced pallidal and caudate gray matter volume in a large general-population sample, in a direction consistent with observations in unmedicated patients once antipsychotic effects are allowed for. The dietary and psychiatric associations are exploratory and warrant further study of the relationship between this locus, circulating niacin, and psychotic disorder.