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De Santana Villasboas Arruda, A.L. ; Khandaker, G.M.* ; Morris, A.P.* ; Smith, G.D.* ; Huckins, L.M.* ; Zeggini, E.

Genomic insights into the comorbidity between type 2 diabetes and schizophrenia.

Schizophr. 10:22 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Multimorbidity represents an increasingly important public health challenge with far-reaching implications for health management and policy. Mental health and metabolic diseases have a well-established epidemiological association. In this study, we investigate the genetic intersection between type 2 diabetes and schizophrenia. We use Mendelian randomization to examine potential causal relationships between the two conditions and related endophenotypes. We report no compelling evidence that type 2 diabetes genetic liability potentially causally influences schizophrenia risk and vice versa. Our findings show that increased body mass index (BMI) has a protective effect against schizophrenia, in contrast to the well-known risk-increasing effect of BMI on type 2 diabetes risk. We identify evidence of colocalization of association signals for these two conditions at 11 genomic loci, six of which have opposing directions of effect for type 2 diabetes and schizophrenia. To elucidate these colocalizing signals, we integrate multi-omics data from bulk and single-cell gene expression studies, along with functional information. We identify putative effector genes and find that they are enriched for homeostasis and lipid-related pathways. We also highlight drug repurposing opportunities including N-methyl-D-aspartate (NMDA) receptor antagonists. Our findings provide insights into shared biological mechanisms for type 2 diabetes and schizophrenia, highlighting common factors that influence the risk of the two conditions in opposite directions and shedding light on the complex nature of this comorbidity.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Nogo-b Receptor; R Package; Risk; Association; Expression; Digoxin; Brain; Mechanisms; Regression; Disorders
ISSN (print) / ISBN 2754-6993
e-ISSN 2754-6993
Zeitschrift Schizophrenia
Quellenangaben Band: 10, Heft: 1, Seiten: , Artikelnummer: 22 Supplement: ,
Verlag Nature Publishing Group
Verlagsort Heidelberger Platz 3, Berlin, 14197, Germany
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Translational Genomics (ITG)
Förderungen NIEHS
NCI
NHGRI
NHLBI
NIDA
NIMH
NINDS - Medical Research Council (MRC)
University of Bristol
Wellcome Trust
UK Medical Research Council
UK National Institute of Health Research Bristol Biomedical Research Centre
National Institutes of Health: NIMH
Common Fund of the Office of the Director of the National Institutes of Health