Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.
Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val(158)Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (P<0.0001, n=95). In COMT Val/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.|Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
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Clelland
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
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Drouet
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
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Rilett
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
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Smeed
Bellevue Hospital Center, New York, NY, USA.|Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
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Nadrich
Bellevue Hospital Center, New York, NY, USA.|Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
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Rajparia
Movement Disorders and Molecular Psychiatry, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
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Read
Department of Psychiatry, New York University School of Medicine, New York, NY, USA.|Movement Disorders and Molecular Psychiatry, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA.
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Clelland
D000328:Adult; D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics* / Q000523:psychology; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000097:blood*; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology
D011392:Proline; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase