@article {9176, title = {Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.}, journal = {Nat Med}, volume = {28}, year = {2022}, month = {2022 08}, pages = {1679-1692}, abstract = {

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

}, keywords = {Coronary Artery Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-170X}, doi = {10.1038/s41591-022-01891-3}, author = {Tcheandjieu, Catherine and Zhu, Xiang and Hilliard, Austin T and Clarke, Shoa L and Napolioni, Valerio and Ma, Shining and Lee, Kyung Min and Fang, Huaying and Chen, Fei and Lu, Yingchang and Tsao, Noah L and Raghavan, Sridharan and Koyama, Satoshi and Gorman, Bryan R and Vujkovic, Marijana and Klarin, Derek and Levin, Michael G and Sinnott-Armstrong, Nasa and Wojcik, Genevieve L and Plomondon, Mary E and Maddox, Thomas M and Waldo, Stephen W and Bick, Alexander G and Pyarajan, Saiju and Huang, Jie and Song, Rebecca and Ho, Yuk-Lam and Buyske, Steven and Kooperberg, Charles and Haessler, Jeffrey and Loos, Ruth J F and Do, Ron and Verbanck, Marie and Chaudhary, Kumardeep and North, Kari E and Avery, Christy L and Graff, Mariaelisa and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Wilkens, Lynne R and Bis, Joshua C and Leonard, Hampton and Shen, Botong and Lange, Leslie A and Giri, Ayush and Dikilitas, Ozan and Kullo, Iftikhar J and Stanaway, Ian B and Jarvik, Gail P and Gordon, Adam S and Hebbring, Scott and Namjou, Bahram and Kaufman, Kenneth M and Ito, Kaoru and Ishigaki, Kazuyoshi and Kamatani, Yoichiro and Verma, Shefali S and Ritchie, Marylyn D and Kember, Rachel L and Baras, Aris and Lotta, Luca A and Kathiresan, Sekar and Hauser, Elizabeth R and Miller, Donald R and Lee, Jennifer S and Saleheen, Danish and Reaven, Peter D and Cho, Kelly and Gaziano, J Michael and Natarajan, Pradeep and Huffman, Jennifer E and Voight, Benjamin F and Rader, Daniel J and Chang, Kyong-Mi and Lynch, Julie A and Damrauer, Scott M and Wilson, Peter W F and Tang, Hua and Sun, Yan V and Tsao, Philip S and O{\textquoteright}Donnell, Christopher J and Assimes, Themistocles L} } @article {9501, title = {Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Oct}, pages = {1651-1664}, abstract = {

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

}, issn = {1546-1718}, doi = {10.1038/s41588-023-01518-4}, author = {Kavousi, Maryam and Bos, Maxime M and Barnes, Hanna J and Lino Cardenas, Christian L and Wong, Doris and Lu, Haojie and Hodonsky, Chani J and Landsmeer, Lennart P L and Turner, Adam W and Kho, Minjung and Hasbani, Natalie R and de Vries, Paul S and Bowden, Donald W and Chopade, Sandesh and Deelen, Joris and Benavente, Ernest Diez and Guo, Xiuqing and Hofer, Edith and Hwang, Shih-Jen and Lutz, Sharon M and Lyytik{\"a}inen, Leo-Pekka and Slenders, Lotte and Smith, Albert V and Stanislawski, Maggie A and van Setten, Jessica and Wong, Quenna and Yanek, Lisa R and Becker, Diane M and Beekman, Marian and Budoff, Matthew J and Feitosa, Mary F and Finan, Chris and Hilliard, Austin T and Kardia, Sharon L R and Kovacic, Jason C and Kral, Brian G and Langefeld, Carl D and Launer, Lenore J and Malik, Shaista and Hoesein, Firdaus A A Mohamed and Mokry, Michal and Schmidt, Reinhold and Smith, Jennifer A and Taylor, Kent D and Terry, James G and van der Grond, Jeroen and van Meurs, Joyce and Vliegenthart, Rozemarijn and Xu, Jianzhao and Young, Kendra A and Zilh{\~a}o, Nuno R and Zweiker, Robert and Assimes, Themistocles L and Becker, Lewis C and Bos, Daniel and Carr, J Jeffrey and Cupples, L Adrienne and de Kleijn, Dominique P V and de Winther, Menno and den Ruijter, Hester M and Fornage, Myriam and Freedman, Barry I and Gudnason, Vilmundur and Hingorani, Aroon D and Hokanson, John E and Ikram, M Arfan and I{\v s}gum, Ivana and Jacobs, David R and K{\"a}h{\"o}nen, Mika and Lange, Leslie A and Lehtim{\"a}ki, Terho and Pasterkamp, Gerard and Raitakari, Olli T and Schmidt, Helena and Slagboom, P Eline and Uitterlinden, Andr{\'e} G and Vernooij, Meike W and Bis, Joshua C and Franceschini, Nora and Psaty, Bruce M and Post, Wendy S and Rotter, Jerome I and Bj{\"o}rkegren, Johan L M and O{\textquoteright}Donnell, Christopher J and Bielak, Lawrence F and Peyser, Patricia A and Malhotra, Rajeev and van der Laan, Sander W and Miller, Clint L} } @article {9707, title = {Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.}, journal = {Nat Cardiovasc Res}, volume = {2}, year = {2023}, month = {2023 Dec}, pages = {1159-1172}, abstract = {

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( and ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of and in human vascular smooth muscle cells (VSMCs) demonstrate that is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near with reduced CAC is likely explained by reduced expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.

}, issn = {2731-0590}, doi = {10.1038/s44161-023-00375-y}, author = {de Vries, Paul S and Conomos, Matthew P and Singh, Kuldeep and Nicholson, Christopher J and Jain, Deepti and Hasbani, Natalie R and Jiang, Wanlin and Lee, Sujin and Lino Cardenas, Christian L and Lutz, Sharon M and Wong, Doris and Guo, Xiuqing and Yao, Jie and Young, Erica P and Tcheandjieu, Catherine and Hilliard, Austin T and Bis, Joshua C and Bielak, Lawrence F and Brown, Michael R and Musharoff, Shaila and Clarke, Shoa L and Terry, James G and Palmer, Nicholette D and Yanek, Lisa R and Xu, Huichun and Heard-Costa, Nancy and Wessel, Jennifer and Selvaraj, Margaret Sunitha and Li, Rebecca H and Sun, Xiao and Turner, Adam W and Stilp, Adrienne M and Khan, Alyna and Newman, Anne B and Rasheed, Asif and Freedman, Barry I and Kral, Brian G and McHugh, Caitlin P and Hodonsky, Chani and Saleheen, Danish and Herrington, David M and Jacobs, David R and Nickerson, Deborah A and Boerwinkle, Eric and Wang, Fei Fei and Heiss, Gerardo and Jun, Goo and Kinney, Greg L and Sigurslid, Haakon H and Doddapaneni, Harshavardhan and Hall, Ira M and Bensenor, Isabela M and Broome, Jai and Crapo, James D and Wilson, James G and Smith, Jennifer A and Blangero, John and Vargas, Jose D and Mosquera, Jose Verdezoto and Smith, Joshua D and Viaud-Martinez, Karine A and Ryan, Kathleen A and Young, Kendra A and Taylor, Kent D and Lange, Leslie A and Emery, Leslie S and Bittencourt, Marcio S and Budoff, Matthew J and Montasser, May E and Yu, Miao and Mahaney, Michael C and Mahamdeh, Mohammed S and Fornage, Myriam and Franceschini, Nora and Lotufo, Paulo A and Natarajan, Pradeep and Wong, Quenna and Mathias, Rasika A and Gibbs, Richard A and Do, Ron and Mehran, Roxana and Tracy, Russell P and Kim, Ryan W and Nelson, Sarah C and Damrauer, Scott M and Kardia, Sharon L R and Rich, Stephen S and Fuster, Valentin and Napolioni, Valerio and Zhao, Wei and Tian, Wenjie and Yin, Xianyong and Min, Yuan-I and Manning, Alisa K and Peloso, Gina and Kelly, Tanika N and O{\textquoteright}Donnell, Christopher J and Morrison, Alanna C and Curran, Joanne E and Zapol, Warren M and Bowden, Donald W and Becker, Lewis C and Correa, Adolfo and Mitchell, Braxton D and Psaty, Bruce M and Carr, John Jeffrey and Pereira, Alexandre C and Assimes, Themistocles L and Stitziel, Nathan O and Hokanson, John E and Laurie, Cecelia A and Rotter, Jerome I and Vasan, Ramachandran S and Post, Wendy S and Peyser, Patricia A and Miller, Clint L and Malhotra, Rajeev} } @article {9787, title = {Rare variant contribution to the heritability of coronary artery disease.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Oct 09}, pages = {8741}, abstract = {

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3\% assuming a prevalence of 8.2\%. Ultra-rare (minor allele frequency <= 0.1\%) variants with low linkage disequilibrium (LD) score contribute ~50\% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

}, keywords = {Case-Control Studies, Coronary Artery Disease, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-024-52939-6}, author = {Rocheleau, Ghislain and Clarke, Shoa L and Auguste, Ga{\"e}lle and Hasbani, Natalie R and Morrison, Alanna C and Heath, Adam S and Bielak, Lawrence F and Iyer, Kruthika R and Young, Erica P and Stitziel, Nathan O and Jun, Goo and Laurie, Cecelia and Broome, Jai G and Khan, Alyna T and Arnett, Donna K and Becker, Lewis C and Bis, Joshua C and Boerwinkle, Eric and Bowden, Donald W and Carson, April P and Ellinor, Patrick T and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Heard-Costa, Nancy L and Hou, Lifang and Chen, Yii-Der Ida and Kenny, Eimear E and Kooperberg, Charles and Kral, Brian G and Loos, Ruth J F and Lutz, Sharon M and Manson, JoAnn E and Martin, Lisa W and Mitchell, Braxton D and Nassir, Rami and Palmer, Nicholette D and Post, Wendy S and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Regan, Elizabeth A and Rich, Stephen S and Smith, Jennifer A and Taylor, Kent D and Yanek, Lisa R and Young, Kendra A and Hilliard, Austin T and Tcheandjieu, Catherine and Peyser, Patricia A and Vasan, Ramachandran S and Rotter, Jerome I and Miller, Clint L and Assimes, Themistocles L and de Vries, Paul S and Do, Ron} }