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Genome-Wide and Exome-Wide Association Study Identifies Genetic Underpinning of Comorbidity between Myocardial
Bixuan Jiang1, Xiangyi Li1, Mo Li2,3,4
1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
Insights
This study identified shared genetic factors underlying myocardial infarction (MI) and severe mental disorders (SMDs). Findings reveal common and rare genetic variants contributing to the comorbidity of these prevalent conditions.
Area of Science:
- Genetics
- Cardiology
- Psychiatry
Background:
- Myocardial Infarction (MI) and severe mental disorders (SMDs) are prevalent, complex conditions with high mortality.
- The genetic basis of their comorbidity remains largely unknown.
Purpose of the Study:
- To investigate the common and rare genetic variants contributing to the comorbidity of MI and SMDs.
- To identify shared genetic underpinnings and potential causal genes for both conditions.
Main Methods:
- Combined genome-wide association study (GWAS) and exome-wide association study (EWAS).
- Gene-based, gene-set, and Mendelian randomization analyses were performed.
- UK Biobank exome sequencing data was utilized.
Main Results:
- Identified nine common genes (e.g., GIGYF2, HLA-C) and nine pathways shared between MI and SMDs.
- Discovered MUC2 as exome-wide significant for both diseases.
- Found pathways related to insulin processing, androgen catabolism, and angiotensin receptor binding implicated in comorbidity.
- Identified six candidate genes interacting with therapeutic drugs.
Conclusions:
- This study elucidates the shared genetic architecture of MI and SMDs, encompassing both common and rare variants.
- Findings offer valuable insights into the mechanisms and potential therapeutic targets for these interconnected disorders.
Background:
Myocardial Infarction (MI) and severe mental disorders (SMDs) are two types of highly prevalent and complex disorders and seem to have a relatively high possibility of mortality. However, the contributions of common and rare genetic variants to their comorbidity arestill unclear.
Methods:
We conducted a combined genome-wide association study (GWAS) and exome-wide association study (EWAS) approach.
Results:
Using gene-based and gene-set association analyses based on the results of GWAS, we found the common genetic underpinnings of nine genes (GIGYF2, KCNJ13, PCCB, STAG1, HLA-C, HLA-B, FURIN, FES, and SMG6) and nine pathways significantly shared between MI and SMDs. Through Mendelian randomization analysis, we found that twenty-seven genes were potential causal genes for SMDs and MI. Based on the exome sequencing data of MI and SMDs patients from the UK Biobank, we found that MUC2 was exome-wide significant in the two diseases. The gene-set analyses of the exome-wide association study indicated that pathways related to insulin processing androgen catabolic process and angiotensin receptor binding may be involved in the comorbidity between SMDs and MI. We also found that six candidate genes were reported to interact with known therapeutic drugs based on the drug-gene interaction information in DGIdb.
Conclusions:
Altogether, this study revealed the overlap of common and rare genetic underpinning between SMDs and MI and may provide useful insights for their mechanism study and therapeutic investigations.
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