Genetic overlap between mood disorders and Alzheimer's disease: Could it explain the clinical and epidemiological overlap of these disorders?

Abstract

Mood disorders such as major depressive (MD) and bipolar (BD), are major risk factors for Alzheimer's disease (AD). History of MD and BD can double the risk of developing AD in older adults, and this risk is even higher when depressive symptoms co-occur with mild cognitive impairment. These evidences suggest that mood disorders and AD may share common biological mechanisms, such as genetic risk factors. However, challenges on conducting multi-phenotype long-follow up studies limit the direct assessment of this hypothesis. Recently, bioinformatics methods using Genome-wide association studies (GWAS) results have been developed and applied to assess the existence of genetic overlap among disorders. Herein, we carried out a multilevel approach to investigate the genetic overlap between mood disorders (MD and BD) and AD, by assessing their genetic correlation, polygenic overlap and shared biological pathways. Summary statistics of three large GWAS for MD, BD and AD were assessed. Genetic overlap and correlation were obtained using LDSC and MiXer. ConjFDR was used to identify pleiotropic loci. Finally, a gene-based approach was applied to obtain a list of overlapping genes and pathways for mood disorders and AD. Pathway enrichment analysis and visualization have been carried out using g:Profiler and Enrichment Map App. Each network (MD&AD, B&AD and MD&BD&AD) was visualized using Cytoscape. Positive genetic correlation among both mood disorders and AD (rG=0.162; p=0.012 for MD&AD; and rG=0.162; p=0.018 for BD&AD) was observed, and further confirmed by all approaches. TMEM106B and THSD7A were identified as pleiotropic candidate genes for MD&AD; and MTSS2, VAC14 and FAF1, for BD&AD. Important biological pathways and functions linking these disorders were highlighted, such as acute inflammatory response, programmed cell death, amyloid-beta response, neuronal death, cell growth, respiratory electron transport chain, lipid metabolism and absorption and membrane trafficking. Our results confirm for the first time the existence of genetic correlation between mood disorders and AD, identify candidate pleiotropic genes and reinforce the existence of a structured biological network among mood disorders and AD. The results obtained herein, once confirmed, may contribute to shed light on future efforts for precision medicine applied to neurodegenerative and mood disorders and their comorbidities.