@article {6590, title = {Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {223-32}, abstract = {

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1\% and 2\%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Adult, African Continental Ancestry Group, Aged, Alleles, Animals, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Coronary Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Association Studies, Genetic Code, Genetic Variation, Humans, Linear Models, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins, Middle Aged, Phenotype, Sequence Analysis, DNA, Subtilisins, Triglycerides}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.009}, author = {Peloso, Gina M and Auer, Paul L and Bis, Joshua C and Voorman, Arend and Morrison, Alanna C and Stitziel, Nathan O and Brody, Jennifer A and Khetarpal, Sumeet A and Crosby, Jacy R and Fornage, Myriam and Isaacs, Aaron and Jakobsdottir, Johanna and Feitosa, Mary F and Davies, Gail and Huffman, Jennifer E and Manichaikul, Ani and Davis, Brian and Lohman, Kurt and Joon, Aron Y and Smith, Albert V and Grove, Megan L and Zanoni, Paolo and Redon, Valeska and Demissie, Serkalem and Lawson, Kim and Peters, Ulrike and Carlson, Christopher and Jackson, Rebecca D and Ryckman, Kelli K and Mackey, Rachel H and Robinson, Jennifer G and Siscovick, David S and Schreiner, Pamela J and Mychaleckyj, Josyf C and Pankow, James S and Hofman, Albert and Uitterlinden, Andr{\'e} G and Harris, Tamara B and Taylor, Kent D and Stafford, Jeanette M and Reynolds, Lindsay M and Marioni, Riccardo E and Dehghan, Abbas and Franco, Oscar H and Patel, Aniruddh P and Lu, Yingchang and Hindy, George and Gottesman, Omri and Bottinger, Erwin P and Melander, Olle and Orho-Melander, Marju and Loos, Ruth J F and Duga, Stefano and Merlini, Piera Angelica and Farrall, Martin and Goel, Anuj and Asselta, Rosanna and Girelli, Domenico and Martinelli, Nicola and Shah, Svati H and Kraus, William E and Li, Mingyao and Rader, Daniel J and Reilly, Muredach P and McPherson, Ruth and Watkins, Hugh and Ardissino, Diego and Zhang, Qunyuan and Wang, Judy and Tsai, Michael Y and Taylor, Herman A and Correa, Adolfo and Griswold, Michael E and Lange, Leslie A and Starr, John M and Rudan, Igor and Eiriksdottir, Gudny and Launer, Lenore J and Ordovas, Jose M and Levy, Daniel and Chen, Y-D Ida and Reiner, Alexander P and Hayward, Caroline and Polasek, Ozren and Deary, Ian J and Borecki, Ingrid B and Liu, Yongmei and Gudnason, Vilmundur and Wilson, James G and van Duijn, Cornelia M and Kooperberg, Charles and Rich, Stephen S and Psaty, Bruce M and Rotter, Jerome I and O{\textquoteright}Donnell, Christopher J and Rice, Kenneth and Boerwinkle, Eric and Kathiresan, Sekar and Cupples, L Adrienne} } @article {6597, title = {Association of exome sequences with plasma C-reactive protein levels in >9000 participants.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jan 15}, pages = {559-71}, abstract = {

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in \~{}25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16\%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53\% lower mean CRP levels (P = 2.9 {\texttimes} 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 {\texttimes} 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 {\texttimes} 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P <= 6.8 {\texttimes} 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 {\texttimes} 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 {\texttimes} 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

}, keywords = {Adult, African Americans, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-alpha, Humans, Male, Plasma, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Risk Factors}, issn = {1460-2083}, doi = {10.1093/hmg/ddu450}, author = {Schick, Ursula M and Auer, Paul L and Bis, Joshua C and Lin, Honghuang and Wei, Peng and Pankratz, Nathan and Lange, Leslie A and Brody, Jennifer and Stitziel, Nathan O and Kim, Daniel S and Carlson, Christopher S and Fornage, Myriam and Haessler, Jeffery and Hsu, Li and Jackson, Rebecca D and Kooperberg, Charles and Leal, Suzanne M and Psaty, Bruce M and Boerwinkle, Eric and Tracy, Russell and Ardissino, Diego and Shah, Svati and Willer, Cristen and Loos, Ruth and Melander, Olle and McPherson, Ruth and Hovingh, Kees and Reilly, Muredach and Watkins, Hugh and Girelli, Domenico and Fontanillas, Pierre and Chasman, Daniel I and Gabriel, Stacey B and Gibbs, Richard and Nickerson, Deborah A and Kathiresan, Sekar and Peters, Ulrike and Dupuis, Jos{\'e}e and Wilson, James G and Rich, Stephen S and Morrison, Alanna C and Benjamin, Emelia J and Gross, Myron D and Reiner, Alex P} } @article {6691, title = {Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 5}, pages = {102-6}, abstract = {

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (<=50 years in males and <=60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2\% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190~mg~dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

}, keywords = {Age Factors, Age of Onset, Alleles, Apolipoproteins A, Case-Control Studies, Cholesterol, LDL, Coronary Artery Disease, Exome, Female, Genetic Predisposition to Disease, Genetics, Population, Heterozygote, Humans, Male, Middle Aged, Mutation, Myocardial Infarction, National Heart, Lung, and Blood Institute (U.S.), Receptors, LDL, Triglycerides, United States}, issn = {1476-4687}, doi = {10.1038/nature13917}, author = {Do, Ron and Stitziel, Nathan O and Won, Hong-Hee and J{\o}rgensen, Anders Berg and Duga, Stefano and Angelica Merlini, Pier and Kiezun, Adam and Farrall, Martin and Goel, Anuj and Zuk, Or and Guella, Illaria and Asselta, Rosanna and Lange, Leslie A and Peloso, Gina M and Auer, Paul L and Girelli, Domenico and Martinelli, Nicola and Farlow, Deborah N and DePristo, Mark A and Roberts, Robert and Stewart, Alexander F R and Saleheen, Danish and Danesh, John and Epstein, Stephen E and Sivapalaratnam, Suthesh and Hovingh, G Kees and Kastelein, John J and Samani, Nilesh J and Schunkert, Heribert and Erdmann, Jeanette and Shah, Svati H and Kraus, William E and Davies, Robert and Nikpay, Majid and Johansen, Christopher T and Wang, Jian and Hegele, Robert A and Hechter, Eliana and M{\"a}rz, Winfried and Kleber, Marcus E and Huang, Jie and Johnson, Andrew D and Li, Mingyao and Burke, Greg L and Gross, Myron and Liu, Yongmei and Assimes, Themistocles L and Heiss, Gerardo and Lange, Ethan M and Folsom, Aaron R and Taylor, Herman A and Olivieri, Oliviero and Hamsten, Anders and Clarke, Robert and Reilly, Dermot F and Yin, Wu and Rivas, Manuel A and Donnelly, Peter and Rossouw, Jacques E and Psaty, Bruce M and Herrington, David M and Wilson, James G and Rich, Stephen S and Bamshad, Michael J and Tracy, Russell P and Cupples, L Adrienne and Rader, Daniel J and Reilly, Muredach P and Spertus, John A and Cresci, Sharon and Hartiala, Jaana and Tang, W H Wilson and Hazen, Stanley L and Allayee, Hooman and Reiner, Alex P and Carlson, Christopher S and Kooperberg, Charles and Jackson, Rebecca D and Boerwinkle, Eric and Lander, Eric S and Schwartz, Stephen M and Siscovick, David S and McPherson, Ruth and Tybjaerg-Hansen, Anne and Abecasis, Goncalo R and Watkins, Hugh and Nickerson, Deborah A and Ardissino, Diego and Sunyaev, Shamil R and O{\textquoteright}Donnell, Christopher J and Altshuler, David and Gabriel, Stacey and Kathiresan, Sekar} } @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} }