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. 2021 Jun 17;11(1):368.
doi: 10.1038/s41398-021-01466-9.

Shared genetic architecture between neuroticism, coronary artery disease and cardiovascular risk factors

Kristin Torgersen  1 , Shahram Bahrami  2 , Oleksandr Frei  2   3 , Alexey Shadrin  2 , Kevin S O' Connell  2 , Olav B Smeland  2 , John Munkhaugen  4   5 , Srdjan Djurovic  2   6   7 , Toril Dammen  4 , Ole A Andreassen  8
Affiliations

Shared genetic architecture between neuroticism, coronary artery disease and cardiovascular risk factors

Kristin Torgersen et al. Transl Psychiatry. .

Abstract

Neuroticism is associated with poor health, cardiovascular disease (CVD) risk factors and coronary artery disease (CAD). The conditional/conjunctional false discovery rate method (cond/conjFDR) was applied to genome wide association study (GWAS) summary statistics on neuroticism (n = 432,109), CAD (n = 184,305) and 12 CVD risk factors (n = 188,577-339,224) to investigate genetic overlap between neuroticism and CAD and CVD risk factors. CondFDR analyses identified 729 genomic loci associated with neuroticism after conditioning on CAD and CVD risk factors. The conjFDR analyses revealed 345 loci jointly associated with neuroticism and CAD (n = 30), body mass index (BMI) (n = 96) or another CVD risk factor (n = 1-60). Several loci were jointly associated with neuroticism and multiple CVD risk factors. Seventeen of the shared loci with CAD and 61 of the shared loci with BMI are novel for neuroticism. 21 of 30 (70%) neuroticism risk alleles were associated with higher CAD risk. Functional analyses of the genes mapped to the shared loci implicated cell division, nuclear receptor, elastic fiber formation as well as starch and sucrose metabolism pathways. Our results indicate polygenic overlap between neuroticism and CAD and CVD risk factors, suggesting that genetic factors may partly cause the comorbidity. This gives new insight into the shared molecular genetic basis of these conditions.

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Conflict of interest statement

O.A.A. received speaker’s honorarium from Lundbeck and Sunovion, and is a consultant to HealthLytix. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Polygenic overlap between neuroticism (NEUR) conditioned on CAD (NEUR∣CAD) and CAD conditioned on NEUR (CAD∣NEUR).
Conditional q–q plots of nominal versus empirical –log 10p values (corrected for inflation) in primary trait (NEUR or CAD) below the standard GWAS threshold of P < 5 × 10–8 as a function of significance of association with secondary trait (CAD or NEUR) at the level of P < 0.1, P < 0.01, and P < 0.001, respectively. The blue line indicates all SNPs. The dashed line indicate the null hypothesis.
Fig. 2
Fig. 2. Polygenic overlap between neuroticism (NEUR) conditioned on BMI (NEUR∣BMI) and BMI conditioned on NEUR (BMI∣NEUR).
Conditional q–q plots of nominal versus empirical –log 10p values (corrected for inflation) in primary trait (NEUR or BMI) below the standard GWAS threshold of p < 5 × 10–8 as a function of significance of association with secondary trait (BMI or NEUR) at the level of p < 0.1, p < 0.01, and p < 0.001, respectively. The blue line indicates all SNPs. The dashed line indicate the null hypothesis.
Fig. 3
Fig. 3. Common genetic variants jointly associated with neuroticism (n = 432,109) and CAD (n = 184,305) 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 < 0.05, i.e., −log10(conjFDR) > 2.0). Independent lead SNPs are encircled in black. The significant shared signal in the major histocompatibility complex region (chr6:25119106–33854733) is represented by one independent lead SNP. Further details are available in Supplementary Table 2.
Fig. 4
Fig. 4. Common genetic variants jointly associated with neuroticism (n = 432,109) and BMI (n = 184,305) 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 < 0.05, i.e., −log10(conjFDR) > 2.0). Independent lead SNPs are encircled in black. The significant shared signal in the major histocompatibility complex region (chr6:25119106–33854733) is represented by one independent lead SNP. Further details are available in Supplementary Table 3.
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