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Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets

Neuropsychopharmacology volume 49, pages 1033–1041 (2024)Cite this article

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Abstract

Patients with severe mental disorders such as bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) show a substantial reduction in life expectancy, increased incidence of comorbid medical conditions commonly observed with advanced age and alterations of aging hallmarks. While severe mental disorders are heritable, the extent to which genetic predisposition might contribute to accelerated cellular aging is not known. We used bivariate causal mixture models to quantify the trait-specific and shared architecture of mental disorders and 2 aging hallmarks (leukocyte telomere length [LTL] and mitochondrial DNA copy number), and the conjunctional false discovery rate method to detect shared genetic loci. We integrated gene expression data from brain regions from GTEx and used different tools to functionally annotate identified loci and investigate their druggability. Aging hallmarks showed low polygenicity compared with severe mental disorders. We observed a significant negative global genetic correlation between MDD and LTL (rg = −0.14, p = 6.5E−10), and no significant results for other severe mental disorders or for mtDNA-cn. However, conditional QQ plots and bivariate causal mixture models pointed to significant pleiotropy among all severe mental disorders and aging hallmarks. We identified genetic variants significantly shared between LTL and BD (n = 17), SCZ (n = 55) or MDD (n = 19), or mtDNA-cn and BD (n = 4), SCZ (n = 12) or MDD (n = 1), with mixed direction of effects. The exonic rs7909129 variant in the SORCS3 gene, encoding a member of the retromer complex involved in protein trafficking and intracellular/intercellular signaling, was associated with shorter LTL and increased predisposition to all severe mental disorders. Genetic variants underlying risk of SCZ or MDD and shorter LTL modulate expression of several druggable genes in different brain regions. Genistein, a phytoestrogen with anti-inflammatory and antioxidant effects, was an upstream regulator of 2 genes modulated by variants associated with risk of MDD and shorter LTL. While our results suggest that shared heritability might play a limited role in contributing to accelerated cellular aging in severe mental disorders, we identified shared genetic determinants and prioritized different druggable targets and compounds.

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Fig. 1: Network of upstream regulators of genes modulated by SNPs associated with increased risk of SCZ and shorter LTL.
Fig. 2: Network of upstream regulators of genes modulated by SNPs associated with increased risk of MDD and shorter LTL.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy

    Claudia Pisanu, Donatella Congiu, Anna Meloni, Giovanni Severino & Alessio Squassina

  2. Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy

    Pasquale Paribello & Mirko Manchia

  3. Unit of Clinical Psychiatry, University Hospital Agency of Cagliari, Cagliari, Italy

    Pasquale Paribello & Mirko Manchia

  4. Laboratory of Pharmacogenomics and Individualized Therapy, School of Health Sciences, Department of Pharmacy, University of Patras, Patras, Greece

    George P. Patrinos

  5. College of Medicine and Health Sciences, Department of Genetics and Genomics, United Arab Emirates University, Al‑Ain, Abu Dhabi, UAE

    George P. Patrinos

  6. Zayed Center for Health Sciences, United Arab Emirates University, Al‑Ain, Abu Dhabi, UAE

    George P. Patrinos

  7. Unit of Clinical Pharmacology, University Hospital Agency of Cagliari, Cagliari, Italy

    Raffaella Ardau & Caterina Chillotti

  8. Department of Pharmacology, Dalhousie University, Halifax, NS, Canada

    Mirko Manchia

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Contributions

CP, conceptualization, data curation, data analysis, visualization, writing and review; DC, writing – review & editing; AM, writing – review & editing; PP, visualization, writing – review & editing; GPP, writing – review & editing; GS, writing – review & editing; RA, writing – review & editing; CC, writing – review & editing; MM, visualization, writing – review & editing; AS, conceptualization, writing – review & editing. All authors read and approved the final manuscript.

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Correspondence to Claudia Pisanu or Alessio Squassina.

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Pisanu, C., Congiu, D., Meloni, A. et al. Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets. Neuropsychopharmacol. 49, 1033–1041 (2024). https://doi.org/10.1038/s41386-024-01822-5

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