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D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women

Molecular Psychiatry volume 7, pages 460–467 (2002)Cite this article

Abstract

Recurrent, early-onset, major depressive disorder (RE-MDD) is a strongly familial condition whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. Sixteen of the 19 candidate susceptibility loci identified by a recent genome survey revealed allelic associations with RE-MDD in men or women, but not in both sexes. The association of D2S2944 alleles and genotypes with RE-MDD and related disorders was evaluated using a case-control study design employing 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. The results of the case-control study were subsequently evaluated in a sample of 81 families ascertained through probands with RE-MDD using the transmission/disequilibrium test. The frequency of the D2S2944 124-bp allele among women with RE-MDD was approximately three times that for female controls (P = 0.0003). Women who carried the D2S2944 124-bp allele revealed a significantly elevated risk of developing RE-MDD, as indicated by an odds ratio of 4.5 compared to female controls (P<0.001). In contrast, men with RE-MDD did not have an increased frequency of this allele compared to male controls, and men who were carriers did not exhibit an increased risk of developing RE-MDD or related disorders. Our findings also suggest that the D2S2944 124-bp allele increases the risk of alcohol and other substance use disorders among women with RE-MDD. The transmission/disequilibrium test provided confirmatory evidence of these sex-specific findings within families. The results of this study confirm the existence of sex-specific susceptibility loci for RE-MDD, and suggest that there may be important differences in the molecular pathophysiology of RE-MDD in men and women. Alternatively, our findings may reflect the existence of sex-specific differences in the molecular mechanisms that determine resilience to endogenous or environmental depressogenic stimuli. The identification and characterization of the D2S2944 susceptibility locus for RE-MDD and related substance use disorders is likely to provide important new insights into the clinical biology, treatment, and prevention of these disorders.

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Acknowledgements

This research was supported by research project grants MH48969, MH60866, and MH43261, and center grant MH30915. Dr Zubenko was the recipient of Independent Scientist Award MH00540 from the National Institute of Mental Health.

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Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA

    G S Zubenko, H B Hughes III, J S Stiffler, W N Zubenko & B B Kaplan

  2. Department of Biological Sciences, Mellon College of Science, Carnegie-Mellon University, Pittsburgh, PA, USA

    G S Zubenko

  3. Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD, USA

    B B Kaplan

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  1. G S Zubenko
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Correspondence to W N Zubenko.

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Zubenko, G., Hughes III, H., Stiffler, J. et al. D2S2944 identifies a likely susceptibility locus for recurrent, early-onset, major depression in women. Mol Psychiatry 7, 460–467 (2002). https://doi.org/10.1038/sj.mp.4001121

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