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. 2022 May 13;18(5):e1010161.
doi: 10.1371/journal.pgen.1010161. eCollection 2022 May.

Shared genetic loci between depression and cardiometabolic traits

Kristin Torgersen  1 , Zillur Rahman  2 , Shahram Bahrami  2 , Guy Frederick Lanyon Hindley  2 , Nadine Parker  2 , Oleksandr Frei  2   3 , Alexey Shadrin  2 , Kevin S O'Connell  2 , Martin Tesli  2   4 , Olav B Smeland  2 , John Munkhaugen  1   5 , Srdjan Djurovic  6   7 , Toril Dammen  8   9 , Ole A Andreassen  2
Affiliations

Shared genetic loci between depression and cardiometabolic traits

Kristin Torgersen et al. PLoS Genet. .

Abstract

Epidemiological and clinical studies have found associations between depression and cardiovascular disease risk factors, and coronary artery disease patients with depression have worse prognosis. The genetic relationship between depression and these cardiovascular phenotypes is not known. We here investigated overlap at the genome-wide level and in individual loci between depression, coronary artery disease and cardiovascular risk factors. We used the bivariate causal mixture model (MiXeR) to quantify genome-wide polygenic overlap and the conditional/conjunctional false discovery rate (pleioFDR) method to identify shared loci, based on genome-wide association study summary statistics on depression (n = 450,619), coronary artery disease (n = 502,713) and nine cardiovascular risk factors (n = 204,402-776,078). Genetic loci were functionally annotated using FUnctional Mapping and Annotation (FUMA). Of 13.9K variants influencing depression, 9.5K (SD 1.0K) were shared with body-mass index. Of 4.4K variants influencing systolic blood pressure, 2K were shared with depression. ConjFDR identified 79 unique loci associated with depression and coronary artery disease or cardiovascular risk factors. Six genomic loci were associated jointly with depression and coronary artery disease, 69 with blood pressure, 49 with lipids, 9 with type 2 diabetes and 8 with c-reactive protein at conjFDR < 0.05. Loci associated with increased risk for depression were also associated with increased risk of coronary artery disease and higher total cholesterol, low-density lipoprotein and c-reactive protein levels, while there was a mixed pattern of effect direction for the other risk factors. Functional analyses of the shared loci implicated metabolism of alpha-linolenic acid pathway for type 2 diabetes. Our results showed polygenic overlap between depression, coronary artery disease and several cardiovascular risk factors and suggest molecular mechanisms underlying the association between depression and increased cardiovascular disease risk.

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Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: OAA received speaker’s honorarium from Lundbeck and Sunovion, and is a consultant to HealthLytix.

Figures

Fig 1
Fig 1. Venn diagrams of causal shared and unique variants.
The polygenic overlap between a) depression (blue) and BMI (green) b) depression (blue) and SBP (purple) and c) depression (blue) and DBP (orange). The numbers is the quantity of causal variants with standard errors in parentheses (numbers in thousand). DEP; depression, BMI; body mass index, SBP; systolic blood pressure, DBP; diastolic blood pressure, rg; genetic correlation.
Fig 2
Fig 2. ConjFDR Manhattan plot.
Common genetic variants both associated with depression (n = 450,619) and a) CAD (n = 502,713), b) SBP (n = 750,000) and c) LDL (n = 297,626) at conjunctional false discovery rate (conjFDR) < 0.05. Manhattan plot showing the–log10 transformed conjFDR values for each SNP on the y axis and the chromosomal positions along the x axis. The dotted horizontal line represents the threshold for significant shared associations (conjFDR < 0.01, i.e. -log10(conjFDR) > 2.0). Independent lead SNPs are encircled in black, and labeled by its nearest gene. The significant shared signal in the major histocompatility complex region (chr6:25119106–33854733) is represented by one independent lead SNP. Further details are available in S8 Table. Dep; depression, CAD; coronary artery disease, SBP; systolic blood pressure, LDL; low-density lipoprotein.
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Grants and funding

KT received founding from the University of Oslo, Research Council of Norway (223273, 248778, 273291, 229129, 213837,), KG Jebsen Stiftelsen, South East Norway Health Authority (2017-112, 2019-108), European Union’s Horizon2020 Research and Innovation Action Grant # 847776 CoMorMent The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.