Hyperprolinemia is a risk factor for schizoaffective disorder

doi:doi:10.1038/sj.mp.4001597

Molecular Psychiatry (2005) 10, 479–485. doi:10.1038/sj.mp.4001597 Published online 19 October 2004

Hyperprolinemia is a risk factor for schizoaffective disorder

H Jacquet^1,*, C Demily^1,2,*, E Houy^1,2, B Hecketsweiler³, J Bou¹, G Raux¹, J Lerond⁴, G Allio², S Haouzir², A Tillaux⁵, C Bellegou², G Fouldrin², P Delamillieure⁶, J F Ménard⁷, S Dollfus⁶, T D'Amato⁴, M Petit^1,2, F Thibaut^1,2, T Frébourg^1,2 and D Campion^1,2

¹Inserm U614, IFRMP, Faculté de Médecine, Rouen, France
²Services de Psychiatrie, CH du Rouvray and CHU, Rouen, France
³Laboratoire de Biochimie, CHU, Rouen, France
⁴EA 3092, Université Claude Bernard, IFR Neurosciences Lyon, Bron, France
⁵Centre Hospitalier, Dieppe, France
⁶Centre Esquirol, CHU, Caen, France
⁷Unité de biométrie, CIC, Rouen, France

Correspondence: Dr D Campion, Inserm U614, Faculté de Médecine, 22 bd Gambetta, Rouen 76183, France. E-mail: dominique.campion@univ-rouen.fr

^*These authors contributed equally to this work

Received 20 April 2004; Revised 20 July 2004; Accepted 6 September 2004; Published online 19 October 2004.

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Abstract

DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case–control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P=0.02, Odds ratio=4.6, 95% confidence interval 1.3–16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an intermediate phenotype associated with certain forms of psychosis.