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

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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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Fig. 1: Manhattan plot for GWAS of SNP and SNP × MDD with cognitive domains.
Fig. 2: Tissue specific expression of top genes (p < 5.0 × 10-8) associated with cognitive function across all cognitive domains.
Fig. 3: Functional pathway analyses of cognition relevant genes using ingenuity pathway analyses.

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Acknowledgements

Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. This study was further supported by the EU-JPND Funding for BRIDGET (FKZ:01ED1615).

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KB (Klaus Berger), HM, DG, UD, SM, NO, JR, MG, IN, FS, KB (Katharina Brosch), TM, JP, AJF, PH, MMN, SW, MR, TK, MA, AMM, DJP, IJD, CH, AC, HJG, AT (Alexander Teumer), GH, SV contributed clinical and GWAS data, commented on results, and reviewed and approved the final manuscript. BTB conceived the study. AT (Anbupalam Thalamuthu), KOS, NTM, and BTB developed the design and analysis plan. AT (Anbupalam Thalamuthu) and KOS conducted the analyses. AT (Anbupalam Thalamuthu), KOS, NTM, and BTB interpreted the results, wrote and edited the manuscript. All authors approved the final manuscript.

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Correspondence to Bernhard T. Baune.

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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. The other authors declare no competing interests.

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Thalamuthu, A., Mills, N.T., Berger, K. et al. Genome-wide interaction study with major depression identifies novel variants associated with cognitive function. Mol Psychiatry 27, 1111–1119 (2022). https://doi.org/10.1038/s41380-021-01379-5

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