The mechanism by which vitD deficits confers risk is unknown. However, vitD is a transcriptional regulator, and the investigators recently found that vitD significantly up-regulates PRODH gene expression. This is important because the highest known genetic risk of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which PRODH maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism. Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with learning and memory deficits and neurotransmitter dysregulation in animal models, and in humans, with decreased intelligence quotient (IQ), cognitive impairment, and schizoaffective disorder. The investigators recently found that >25% of schizophrenia patients were hyperprolinemic and hypothesized a causal relationship between vitD, proline elevation, and schizophrenia, such that vitD insufficiency causes decreased PRODH expression and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in 64 patients and 90 controls, the investigators found that vitD insufficiency (<30ng/ml) was significantly associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively correlated with proline (p=0.01), and vitD insufficient subjects had three times greater odds of hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains >37% of the association between vitD insufficiency and schizophrenia, signifying that vitD insufficiency increases schizophrenia risk, at least in part by elevating proline. These findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating vitD insufficiency, may improve symptoms including neurocognitive deficits.