25-Hydroxyvitamin D (25(
OH)D) deficits have been associated with
schizophrenia susceptibility and supplementation has been recommended for those at-risk. Although the mechanism by which a deficit confers risk is unknown,
vitamin D is a potent transcriptional modulator and can regulate
proline dehydrogenase (PRODH) expression. PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of
schizophrenia, and encodes
proline oxidase, which catalyzes
proline catabolism.
l-Proline is a
neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ,
cognitive impairment,
schizoaffective disorder, and
schizophrenia. We investigated the relationship between 25(
OH)D and
schizophrenia, comparing fasting plasma 25(
OH)D in 64 patients and 90 matched controls. We then tested for a mediating effect of hyperprolinemia on the association between 25(
OH)D and
schizophrenia. 25(
OH)D levels were significantly lower in patients, and 25(
OH)D insufficiency associated with
schizophrenia (OR 2.1, adjusted p=0.044, 95% CI: 1.02-4.46). Moreover, 25(
OH)D insufficient subjects had three times greater odds of hyperprolinemia than those with optimal levels (p=0.035, 95% CI: 1.08-8.91), and formal testing established that hyperprolinemia is a significantly mediating phenotype that may explain over a third of the effect of 25(
OH)D insufficiency on
schizophrenia risk. This study presents a mechanism by which 25(
OH)D insufficiency confers risk of
schizophrenia; via
proline elevation due to reduced PRODH expression, and a concomitant dysregulation of neurotransmission. Although definitive causality cannot be confirmed, these findings strongly support
vitamin D supplementation in patients, particularly for those with elevated
proline, who may represent a large subgroup of the
schizophrenia population.