Dataset Information

Comorbidity between Alzheimer's disease and major depression: a behavioural and transcriptomic characterization study in mice.

ABSTRACT:

Background

Major depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer's disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown.

Methods

We investigated the cognitive and emotional behavioural responses in 3- and 6-month-old APP/PSEN1-Tg mice, before β-amyloid plaques were detected. We studied the genetic and pathway deregulation in the prefrontal cortex, striatum, hippocampus and amygdala of mice at both ages, using transcriptomic and functional data analysis.

Results

We found that depressive-like and anxiety-like behaviours, as well as memory impairments, are already present at 3-month-old APP/PSEN1-Tg mutant mice together with the deregulation of several genes, such as Ciart, Grin3b, Nr1d1 and Mc4r, and other genes including components of the circadian rhythms, electron transport chain and neurotransmission in all brain areas. Extending these results to human data performing GSEA analysis using DisGeNET database, it provides translational support for common deregulated gene sets related to MD and AD.

Conclusions

The present study sheds light on the shared genetic bases between MD and AD, based on a comprehensive characterization from the behavioural to transcriptomic level. These findings suggest that late MD could be an early manifestation of AD.

SUBMITTER: Martin-Sanchez A

PROVIDER: S-EPMC8017643 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Comorbidity between Alzheimer's disease and major depression: a behavioural and transcriptomic characterization study in mice.

Martín-Sánchez Ana A Piñero Janet J Nonell Lara L Arnal Magdalena M Ribe Elena M EM Nevado-Holgado Alejo A Lovestone Simon S Sanz Ferran F Furlong Laura I LI Valverde Olga O

Alzheimer's research & therapy 20210402 1

<h4>Background</h4>Major depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer's disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown.<h4>Methods</h4>We investigated the cognitive and emotional behavioural responses in 3- and 6-month-old APP/PSEN1-Tg mice, before β-amyloid plaques were detected. We studied the genetic and pathway deregulation in the pre ...[more]

PMID: 33795014

Similar Datasets

Project description:Importance-There is extensive comorbidity between anxiety disorders (ANX) and major depression (MD). Most studies on the genetics of ANX do not exclude comorbid cases of MD, and vice versa, therefore confounding genetic association analyses. Disorder-specific analysis of genomic data may reveal more precise biological pathways and causal relationships.Objective-To investigate the genetic relationship between disorder-specific ANX and MD compared to samples with comorbidity, including their causal relationship.Design setting and participants-Data from UK Biobank was used to perform genome-wide association studies (GWAS) of ANX-only and MD-only, and generate disorder-specific polygenic risk scores (PRS). The Norwegian Mother, Father, and Child Cohort (MoBa) was used to test the associations of PRS with diagnosis and symptoms. MD and ANX GWAS data including comorbidities (MD-co and ANX-co) were used as comparators. Genetic correlation was assessed using LDSC, and Mendelian randomization was employed to infer causal relationships.Main outcomes and measuresGWAS of ICD-10 diagnoses of ANX, MD, or both. Genetic correlations between pairs of ANX and MD phenotypes. PRS associations with diagnoses of ANX, MD, and their comorbid states, and anxiety or depressive symptoms.Results-The GWAS of ANX-only (9,980 cases and 179,442 controls) and MD-only (15,301 cases and 179,038 controls) showed a lower genetic correlation (0.53) than the one between ANX-co and MD-co (0.90). ANX-only showed a causal relationship with MD-only (PFDR=1.5e-02), but not vice versa, while comorbid cases showed a significant bidirectional causal relationship (PFDR=2.9e-12, PFDR =9.3e-06). The PRS-MD-only were differentially associated with MD-only compared to ANX-only cases (β= -0.08; 95%CI: -0.11, -0.03); however, this differential association was not observed for the PRS-MD-co. A similar pattern of differential association with anxiety and depressive symptoms was observed for PRS-ANX-only, but not for PRS-MD-co.Conclusions and relevance-The genetics and underlying biology of ANX and MD are more distinct when comorbid cases are excluded from analyses and reveals that ANX may be causal for MD. This confounding of genetic relationships as a result of comorbidity is likely to apply to other psychiatric disorders. Disorder-specific genetic studies may help uncover more relevant biological mechanisms and guide more targeted clinical interventions.

Project description:Background and aimsWhile the prevalence of major depression is elevated among cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits and localize regions of the genome that segregate in families with cannabis use and major depression.DesignFamily-based univariate and bivariate genetic analysis.SettingSan Antonio, Texas, USA.ParticipantsGenetics of Brain Structure and Function study (GOBS) participants: 1284 Mexican Americans from 75 large multi-generation families and an additional 57 genetically unrelated spouses.MeasurementsPhenotypes of life-time history of cannabis use and major depression, measured using the semistructured MINI-Plus interview. Genotypes measured using ~1 M single nucleotide polymorphisms (SNPs) on Illumina BeadChips. A subselection of these SNPs were used to build multi-point identity-by-descent matrices for linkage analysis.FindingsBoth cannabis use [h2 = 0.614, P = 1.00 × 10-6 , standard error (SE) = 0.151] and major depression (h2 = 0.349, P = 1.06 × 10-5 , SE = 0.100) are heritable traits, and there is significant genetic correlation between the two (ρg = 0.424, P = 0.0364, SE = 0.195). Genome-wide linkage scans identify a significant univariate linkage peak for major depression on chromosome 22 [logarithm of the odds (LOD) = 3.144 at 2 centimorgans (cM)], with a suggestive peak for cannabis use on chromosome 21 (LOD = 2.123 at 37 cM). A significant pleiotropic linkage peak influencing both cannabis use and major depression was identified on chromosome 11 using a bivariate model (LOD = 3.229 at 112 cM). Follow-up of this pleiotropic signal identified a SNP 20 kb upstream of NCAM1 (rs7932341) that shows significant bivariate association (P = 3.10 × 10-5 ). However, this SNP is rare (seven minor allele carriers) and does not drive the linkage signal observed.ConclusionsThere appears to be a significant genetic overlap between cannabis use and major depression among Mexican Americans, a pleiotropy that appears to be localized to a region on chromosome 11q23 that has been linked previously to these phenotypes.

Dataset Information

Comorbidity between Alzheimer's disease and major depression: a behavioural and transcriptomic characterization study in mice.

Background

Methods

Results

Conclusions

Publications

Comorbidity between Alzheimer's disease and major depression: a behavioural and transcriptomic characterization study in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets