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PRODH rs450046 and proline x COMT Val158Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome

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Abstract

Rationale

22q11 deletion syndrome (22q11DS) is associated with an increased risk for psychotic disorders, suggesting a relationship between genotypes and the pathophysiology of psychotic disorders. Two genes in the deleted region, catechol-O-methyl-transferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH), contain polymorphisms associated with neuropsychiatric phenotypes.

Objectives

Here, we explored the association between polymorphisms and full-scale intelligence (FSIQ), startle reactivity (SR) and prepulse inhibition (PPI) in adults with 22q11DS.

Methods

Forty-five adults with 22q11DS were genotyped for PRODH rs450046, rs372055 and COMT Val158Met. Plasma proline levels, FSIQ, SR and PPI were measured.

Results

Thirty-five percent of the subjects were hyperprolinemic with a median proline value of 456 μmol/L. C allele carriers of PRODH rs450046 had a lower FSIQ compared to T allele carriers, indicating the C allele to be a risk allele (C allele: mean FSIQ 60.2 (sd 8.7); T allele: mean FSIQ 73.7 (sd 11.5); F 1,43 = 7.59; p = 0.009; partial η 2 = 0.15). A significant interaction effect of proline levels and COMT Val158Met genotype was found for SR (F 1,16 = 7.9; p = 0.01; partial η 2 = 0.33), but not for PPI and FSIQ. In subjects with hyperprolinemia, the COMT Val158Met genotype effect on SR was stronger than in subjects with normal proline levels.

Conclusions

Overall, these data provide further evidence for the risk effect of elevated proline levels combined with the COMT Met allele and support the possibilities of using 22q11DS as a model to investigate genotype effects on psychiatric disorders.

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Acknowledgements

We are grateful to all subjects who participated in this study. We thank the Dutch 22q11DS family association, the Department of Clinical Genetics Academic Medical Centre Amsterdam (The Netherlands), the Department of Clinical Genetics Erasmus MC Rotterdam (The Netherlands), the Department of Clinical Genetics Leiden University Medical Centre (The Netherlands), the Department of Clinical Genetics Utrecht Medical Centre (The Netherlands) and the Centre for Human Genetics, Katholieke Universiteit Leuven (Belgium) for recruiting subjects with 22q11DS. We wish to thank Lot Schroeder, Sylvia van de Berg and Julia Meijer for the help with the data collection (Wechsler Adult Intelligence Scale-III). We thank Matthew Allin for his helpful comments.

Conflict of interest

All authors declare that they have no conflicts of interest.

Funding

This work was supported by “De Hersenstichting” (grant no. 15F07(2).55).

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Authors and Affiliations

  1. Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

    Mariken B. de Koning, Esther D. A. van Duin, Erik Boot & Thérèse A. M. J. van Amelsvoort

  2. Arkin Mental Health Care, Baron G.A. Tindalstraat 27, 1019 TS, Amsterdam, The Netherlands

    Mariken B. de Koning

  3. Ipse de Bruggen, Centre for People with Intellectual Disability, Zwammerdam, The Netherlands

    Erik Boot

  4. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands

    Jaap A. Bakker

  5. Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Centre, Leiden, The Netherlands

    Jaap A. Bakker

  6. Centre for Women’s Mental Health, Manchester Academy of Health Sciences, University of Manchester, Manchester, UK

    Kathryn M. Abel

  7. Department of Psychiatry and Psychology, Maastricht University, Maastricht, The Netherlands

    Esther D. A. van Duin, Oswald J. N. Bloemen & Thérèse A. M. J. van Amelsvoort

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  1. Mariken B. de Koning
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Correspondence to Mariken B. de Koning.

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de Koning, M.B., van Duin, E.D.A., Boot, E. et al. PRODH rs450046 and proline x COMT Val158Met interaction effects on intelligence and startle in adults with 22q11 deletion syndrome. Psychopharmacology 232, 3111–3122 (2015). https://doi.org/10.1007/s00213-015-3971-5

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