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Title: Genome-wide interaction study with major depression identifies novel variants associated with cognitive function.
Austin Authors: Thalamuthu, Anbupalam;Mills, Natalie T;Berger, Klaus;Minnerup, Heike;Grotegerd, Dominik;Dannlowski, Udo;Meinert, Susanne;Opel, Nils;Repple, Jonathan;Gruber, Marius;Nenadić, Igor;Stein, Frederike;Brosch, Katharina;Meller, Tina;Pfarr, Julia-Katharina;Forstner, Andreas J;Hoffmann, Per;Nöthen, Markus M;Witt, Stephanie;Rietschel, Marcella;Kircher, Tilo;Adams, Mark;McIntosh, Andrew M;Porteous, David J;Deary, Ian J;Hayward, Caroline;Campbell, Archie;Grabe, Hans Jörgen;Teumer, Alexander;Homuth, Georg;van der Auwera-Palitschka, Sandra;Oliver Schubert, K;Baune, Bernhard T
Affiliation: The Florey Institute of Neuroscience and Mental Health
Division of Psychiatry, University of Edinburgh, Edinburgh, UK
Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK
Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK
Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
Department of Psychiatry and Psychotherapy, University Hospital Münster, University of Münster, Münster, Germany.
Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia
Northern Adelaide Mental Health Service, Salisbury, SA, Australia
Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
Institute for Translational Psychiatry, University of Münster, Münster, Germany
Institute for Translational Neuroscience, University of Münster, Münster, Germany
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany
Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg - UKGM Marburg, Marburg, Germany
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany
Centre for Human Genetics, University of Marburg, Marburg, Germany
Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
Issue Date: Feb-2022
Date: 2021-11-15
Publication information: Molecular Psychiatry 2022; 27(2): 1111-1119
Abstract: Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from four large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA®). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development (REST), oligodendrocyte maturation (TNFRSF21), and myelination (ARFGEF1). IPA® identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions (MPO, FOXO1, PDE3A, TSLP, NLRP9, ADAMTS5, ROBO1, REST). Furthermore, IPA® identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.
DOI: 10.1038/s41380-021-01379-5
Journal: Molecular Psychiatry
PubMed URL: 34782712
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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