Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

Anbupalam Thalamuthu^#¹, Natalie T Mills^#², Klaus Berger³, Heike Minnerup³, Dominik Grotegerd⁴, Udo Dannlowski⁴, Susanne Meinert^{4

5}, Nils Opel⁴, Jonathan Repple⁴, Marius Gruber⁴, Igor Nenadić⁶, Frederike Stein⁶, Katharina Brosch⁶, Tina Meller⁶, Julia-Katharina Pfarr⁶, Andreas J Forstner^{7

8

9}, Per Hoffmann⁷, Markus M Nöthen⁷, Stephanie Witt¹⁰, Marcella Rietschel¹⁰, Tilo Kircher⁶, Mark Adams¹¹, Andrew M McIntosh¹¹, David J Porteous¹², Ian J Deary¹³, Caroline Hayward¹⁴, Archie Campbell¹², Hans Jörgen Grabe^{15

16}, Alexander Teumer¹⁷, Georg Homuth¹⁸, Sandra van der Auwera-Palitschka^{15

16}, K Oliver Schubert^{2

19}, Bernhard T Baune^{20

21

22

23}

Affiliations

¹ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
² Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
³ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
⁴ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁵ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁶ Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg - UKGM Marburg, Marburg, Germany.
⁷ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
⁸ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
⁹ Centre for Human Genetics, University of Marburg, Marburg, Germany.
¹⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
¹¹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹² Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
¹³ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
¹⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
¹⁵ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹⁶ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
¹⁷ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁸ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁹ Northern Adelaide Mental Health Service, Salisbury, SA, Australia.
²⁰ Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia. Bernhard.Baune@ukmuenster.de.
²¹ Department of Psychiatry and Psychotherapy, University Hospital Münster, University of Münster, Münster, Germany. Bernhard.Baune@ukmuenster.de.
²² Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia. Bernhard.Baune@ukmuenster.de.
²³ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. Bernhard.Baune@ukmuenster.de.

^# Contributed equally.

PMID: 34782712
PMCID: PMC7612684
DOI: 10.1038/s41380-021-01379-5

Meta-Analysis

Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

Anbupalam Thalamuthu et al. Mol Psychiatry. 2022 Feb.

. 2022 Feb;27(2):1111-1119.

doi: 10.1038/s41380-021-01379-5. Epub 2021 Nov 15.

Authors

Affiliations

¹ Centre for Healthy Brain Ageing (CHeBA), School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
² Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
³ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
⁴ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁵ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁶ Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg - UKGM Marburg, Marburg, Germany.
⁷ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
⁸ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
⁹ Centre for Human Genetics, University of Marburg, Marburg, Germany.
¹⁰ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
¹¹ Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
¹² Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
¹³ Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK.
¹⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
¹⁵ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
¹⁶ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
¹⁷ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁸ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
¹⁹ Northern Adelaide Mental Health Service, Salisbury, SA, Australia.
²⁰ Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia. Bernhard.Baune@ukmuenster.de.
²¹ Department of Psychiatry and Psychotherapy, University Hospital Münster, University of Münster, Münster, Germany. Bernhard.Baune@ukmuenster.de.
²² Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia. Bernhard.Baune@ukmuenster.de.
²³ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia. Bernhard.Baune@ukmuenster.de.

^# Contributed equally.

PMID: 34782712
PMCID: PMC7612684
DOI: 10.1038/s41380-021-01379-5

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.

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Conflict of interest statement

Conflicts of Interest

HJG has received travel grants and speaker honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. KOS reports having received lecture fees and research funding from Janssen Australia, research funding from Lundbeck Otsuka, and research funding from Gilead. BTB reports having received speaker and consultation fees from AstraZeneca, Lundbeck, Pfizer, Takeda, Servier, Bristol Myers Squibb, Otsuka, LivaNova and Janssen-Cilag.

Figures

**Figure 1. Manhattan plot for GWAS of SNP and SNP x MDD with cognitive domains**
Joint test of SNP and SNP x MDD interaction with cognitive domains. GWAS significant (p <= 5x10^-8) loci are highlighted with the gene name closest to the top SNP. Identified SNPs are associated with cognitive function domains and/or moderated by MDD status.

**Figure 2. Tissue specific expression of top genes (p < 5.0 x 10^-8) associated with cognitive function across all cognitive domains**
Tissue types are on the x-axis and gene symbols are on the y-axis. Scale bar on the right gives colour coding and level of gene expression.

**Figure 3. IPA® – functional networks 1 & 2 for all cognition-associated genes**

See this image and copyright information in PMC

References

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Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

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Genome-wide interaction study with major depression identifies novel variants associated with cognitive function

Authors

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Conflict of interest statement

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