Title |
Genetic Regulation of SMC Gene Expression and Splicing Predict Causal CAD Genes
|
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Published in |
Circulation Research, January 2023
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DOI | 10.1161/circresaha.122.321586 |
Pubmed ID | |
Authors |
Rédouane Aherrahrou, Dillon Lue, R. Noah Perry, Yonathan Tamrat Aberra, Mohammad Daud Khan, Joon Yuhl Soh, Tiit Örd, Prosanta Singha, Qianyi Yang, Huda Gilani, Ernest Diez Benavente, Doris Wong, Jameson Hinkle, Lijiang Ma, Gloria M. Sheynkman, Hester M. den Ruijter, Clint L. Miller, Johan L.M. Björkegren, Minna U. Kaikkonen, Mete Civelek |
Abstract |
Coronary artery disease (CAD) is the leading cause of death worldwide. Recent meta-analyses of genome-wide association studies have identified over 175 loci associated with CAD. The majority of these loci are in noncoding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we aimed to identify the subset of the CAD genome-wide association studies risk loci associated with the regulation of transcription in distinct SMC phenotypes. Here, we measured gene expression in SMCs isolated from the ascending aortas of 151 heart transplant donors of various genetic ancestries in quiescent or proliferative conditions and calculated the association of their expression and splicing with ~6.3 million imputed single-nucleotide polymorphism markers across the genome. We identified 4910 expression and 4412 splice quantitative trait loci representing regions of the genome associated with transcript abundance and splicing. A total of 3660 expression quantitative trait locus (eQTLs) had not been observed in the publicly available Genotype-Tissue Expression dataset. Further, 29 and 880 eQTLs were SMC- and sex-specific, respectively. We made these results available for public query on a user-friendly website. To identify the effector transcript(s) regulated by CAD genome-wide association studies loci, we used 4 distinct colocalization approaches. We identified 84 eQTL and 164 splice quantitative trait loci that colocalized with CAD loci, highlighting the importance of genetic regulation of mRNA splicing as a molecular mechanism for CAD genetic risk. Notably, 20% and 35% of the eQTLs were unique to quiescent or proliferative SMCs, respectively. One CAD locus colocalized with an SMC sex-specific eQTL (TERF2IP), and another locus colocalized with SMC-specific eQTL (ALKBH8). The most significantly associated CAD locus, 9p21, was an splice quantitative trait loci for the long noncoding RNA CDKN2B-AS1, also known as ANRIL, in proliferative SMCs. Collectively, our results provide evidence for the molecular mechanisms of genetic susceptibility to CAD in distinct SMC phenotypes. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 17 | 36% |
India | 1 | 2% |
Thailand | 1 | 2% |
Netherlands | 1 | 2% |
Canada | 1 | 2% |
Finland | 1 | 2% |
Qatar | 1 | 2% |
Belgium | 1 | 2% |
Unknown | 23 | 49% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 24 | 51% |
Members of the public | 17 | 36% |
Science communicators (journalists, bloggers, editors) | 4 | 9% |
Practitioners (doctors, other healthcare professionals) | 2 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 22 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Postgraduate | 3 | 14% |
Researcher | 3 | 14% |
Unspecified | 1 | 5% |
Student > Bachelor | 1 | 5% |
Other | 1 | 5% |
Other | 2 | 9% |
Unknown | 11 | 50% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 7 | 32% |
Unspecified | 1 | 5% |
Nursing and Health Professions | 1 | 5% |
Medicine and Dentistry | 1 | 5% |
Unknown | 12 | 55% |