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Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression.

ABSTRACT: It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

SUBMITTER: Hagenaars SP

PROVIDER: S-EPMC7991693 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression.

Hagenaars Saskia P SP Coleman Jonathan R I JRI Choi Shing Wan SW Gaspar Héléna H Adams Mark J MJ Howard David M DM Hodgson Karen K Traylor Matthew M Air Tracy M TM Andlauer Till F M TFM Arolt Volker V Baune Bernhard T BT Binder Elisabeth B EB Blackwood Douglas H R DHR Boomsma Dorret I DI Campbell Archie A Cearns Micah M Czamara Darina D Dannlowski Udo U Domschke Katharina K de Geus Eco J C EJC Hamilton Steven P SP Hayward Caroline C Hickie Ian B IB Hottenga Jouke Jan JJ Ising Marcus M Jones Ian I Jones Lisa L Kutalik Zoltan Z Lucae Susanne S Martin Nicholas G NG Milaneschi Yuri Y Mueller-Myhsok Bertram B Owen Michael J MJ Padmanabhan Sandosh S Penninx Brenda W J H BWJH Pistis Giorgio G Porteous David J DJ Preisig Martin M Ripke Stephan S Shyn Stanley I SI Sullivan Patrick F PF Whitfield John B JB Wray Naomi R NR McIntosh Andrew M AM Deary Ian J IJ Breen Gerome G Lewis Cathryn M CM

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20200718 6

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether di ...[more]

PMID: 32681593

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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.

Project description:BackgroundAssociations of low lung function with features of poor cardio-metabolic health have been reported. It is, however, unclear whether these co-morbidities reflect causal associations, shared genetic heritability or are confounded by environmental factors.MethodsWe performed three analyses: (1) cardio-metabolic health to lung function association tests in Northern Finland Birth cohort 1966, (2) cross-trait linkage disequilibrium score regression (LDSC) to compare genetic backgrounds and (3) Mendelian randomisation (MR) analysis to assess the causal effect of cardio-metabolic traits and disease on lung function, and vice versa (bidirectional MR). Genetic associations were obtained from the UK Biobank data or published large-scale genome-wide association studies (N > 82,000).ResultsWe observed a negative genetic correlation between lung function and cardio-metabolic traits and diseases. In Mendelian Randomisation analysis (MR), we found associations between type 2 diabetes (T2D) instruments and forced vital capacity (FVC) as well as FEV1/FVC. Body mass index (BMI) instruments were associated to all lung function traits and C-reactive protein (CRP) instruments to FVC. These genetic associations provide evidence for a causal effect of cardio-metabolic traits on lung function. Multivariable MR suggested independence of these causal effects from other tested cardio-metabolic traits and diseases. Analysis of lung function specific SNPs revealed a potential causal effect of FEV1/FVC on blood pressure.ConclusionsThe present study overcomes many limitations of observational studies by using Mendelian Randomisation. We provide evidence for an independent causal effect of T2D, CRP and BMI on lung function with some of the T2D effect on lung function being attributed to inflammatory mechanisms. Furthermore, this analysis suggests a potential causal effect of FEV1/FVC on blood pressure. Our detailed analysis of the interplay between cardio-metabolic traits and impaired lung function provides the opportunity to improve the quality of existing intervention strategies.

Dataset Information

Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression.

Publications

Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression.

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