Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association.
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.
Movement Disorders and Molecular Psychiatry, The Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY, United States; Department of Psychiatry, New York University Langone Medical Center, 550 First Avenue, New York, NY, United States.
James D
JD
Clelland
Movement Disorders and Molecular Psychiatry, The Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY, United States; Department of Psychiatry, New York University Langone Medical Center, 550 First Avenue, New York, NY, United States.
Laura L
LL
Read
Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, United States; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, United States.
Valérie
V
Drouet
Movement Disorders and Molecular Psychiatry, The Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY, United States.
Angela
A
Kaon
Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, United States; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, United States.
Alexandra
A
Kelly
Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, United States; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, United States; New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, United States.
Karen E
KE
Duff
Department of Psychiatry, New York University Langone Medical Center, 550 First Avenue, New York, NY, United States; Bellevue Hospital Center, 462 First Avenue, New York, NY, United States.
Robert H
RH
Nadrich
Department of Psychiatry, New York University Langone Medical Center, 550 First Avenue, New York, NY, United States; Bellevue Hospital Center, 462 First Avenue, New York, NY, United States.
Amit
A
Rajparia
Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, New York, United States; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 West 168th Street, New York, United States. Electronic address: cc2786@columbia.edu.
Catherine L
CL
Clelland
D050842:1-Pyrroline-5-Carboxylate Dehydrogenase / Q000172:deficiency; D000293:Adolescent; D000328:Adult; D000368:Aged; D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000150:complications*; D005215:Fasting / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009154:Mutation / Q000235:genetics; D011392:Proline / Q000378:metabolism; D011394:Proline Oxidase / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000097:blood / Q000209:etiology / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D014808:Vitamin D Deficiency / Q000150:complications*; D055815:Young Adult
D014807:Vitamin D; D011392:Proline; C104450:25-hydroxyvitamin D; D050842:1-Pyrroline-5-Carboxylate Dehydrogenase; D011394:Proline Oxidase; C582834:PRODH protein, human
Hyperprolinemia; Mediator; Proline; Schizophrenia; Treatment; Vitamin D insufficiency