@article {1274, title = {A bivariate genome-wide approach to metabolic syndrome: STAMPEED consortium.}, journal = {Diabetes}, volume = {60}, year = {2011}, month = {2011 Apr}, pages = {1329-39}, abstract = {

OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of \~{}2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from \~{}9\% of the variance in triglycerides, 5.8\% of high-density lipoprotein cholesterol, 3.6\% of fasting glucose, and 1.4\% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.

}, keywords = {Adult, Aged, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Meta-Analysis as Topic, Metabolic Syndrome, Middle Aged, Phenotype, Polymorphism, Single Nucleotide}, issn = {1939-327X}, doi = {10.2337/db10-1011}, author = {Kraja, Aldi T and Vaidya, Dhananjay and Pankow, James S and Goodarzi, Mark O and Assimes, Themistocles L and Kullo, Iftikhar J and Sovio, Ulla and Mathias, Rasika A and Sun, Yan V and Franceschini, Nora and Absher, Devin and Li, Guo and Zhang, Qunyuan and Feitosa, Mary F and Glazer, Nicole L and Haritunians, Talin and Hartikainen, Anna-Liisa and Knowles, Joshua W and North, Kari E and Iribarren, Carlos and Kral, Brian and Yanek, Lisa and O{\textquoteright}Reilly, Paul F and McCarthy, Mark I and Jaquish, Cashell and Couper, David J and Chakravarti, Aravinda and Psaty, Bruce M and Becker, Lewis C and Province, Michael A and Boerwinkle, Eric and Quertermous, Thomas and Palotie, Leena and Jarvelin, Marjo-Riitta and Becker, Diane M and Kardia, Sharon L R and Rotter, Jerome I and Chen, Yii-Der Ida and Borecki, Ingrid B} } @article {1359, title = {Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Feb 01}, pages = {100-12}, abstract = {

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI <=0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60\% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46{\texttimes}10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65{\texttimes}10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6{\texttimes}10(-5)), CYBA (rs3794624, P=6.3{\texttimes}10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Alleles, Ankle Brachial Index, Chromosomes, Human, Pair 9, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p15, Female, Genome-Wide Association Study, Genotype, HapMap Project, Humans, Logistic Models, Male, Middle Aged, Peripheral Vascular Diseases, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sex Factors}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.961292}, author = {Murabito, Joanne M and White, Charles C and Kavousi, Maryam and Sun, Yan V and Feitosa, Mary F and Nambi, Vijay and Lamina, Claudia and Schillert, Arne and Coassin, Stefan and Bis, Joshua C and Broer, Linda and Crawford, Dana C and Franceschini, Nora and Frikke-Schmidt, Ruth and Haun, Margot and Holewijn, Suzanne and Huffman, Jennifer E and Hwang, Shih-Jen and Kiechl, Stefan and Kollerits, Barbara and Montasser, May E and Nolte, Ilja M and Rudock, Megan E and Senft, Andrea and Teumer, Alexander and van der Harst, Pim and Vitart, Veronique and Waite, Lindsay L and Wood, Andrew R and Wassel, Christina L and Absher, Devin M and Allison, Matthew A and Amin, Najaf and Arnold, Alice and Asselbergs, Folkert W and Aulchenko, Yurii and Bandinelli, Stefania and Barbalic, Maja and Boban, Mladen and Brown-Gentry, Kristin and Couper, David J and Criqui, Michael H and Dehghan, Abbas and den Heijer, Martin and Dieplinger, Benjamin and Ding, Jingzhong and D{\"o}rr, Marcus and Espinola-Klein, Christine and Felix, Stephan B and Ferrucci, Luigi and Folsom, Aaron R and Fraedrich, Gustav and Gibson, Quince and Goodloe, Robert and Gunjaca, Grgo and Haltmayer, Meinhard and Heiss, Gerardo and Hofman, Albert and Kieback, Arne and Kiemeney, Lambertus A and Kolcic, Ivana and Kullo, Iftikhar J and Kritchevsky, Stephen B and Lackner, Karl J and Li, Xiaohui and Lieb, Wolfgang and Lohman, Kurt and Meisinger, Christa and Melzer, David and Mohler, Emile R and Mudnic, Ivana and Mueller, Thomas and Navis, Gerjan and Oberhollenzer, Friedrich and Olin, Jeffrey W and O{\textquoteright}Connell, Jeff and O{\textquoteright}Donnell, Christopher J and Palmas, Walter and Penninx, Brenda W and Petersmann, Astrid and Polasek, Ozren and Psaty, Bruce M and Rantner, Barbara and Rice, Ken and Rivadeneira, Fernando and Rotter, Jerome I and Seldenrijk, Adrie and Stadler, Marietta and Summerer, Monika and Tanaka, Toshiko and Tybjaerg-Hansen, Anne and Uitterlinden, Andr{\'e} G and van Gilst, Wiek H and Vermeulen, Sita H and Wild, Sarah H and Wild, Philipp S and Willeit, Johann and Zeller, Tanja and Zemunik, Tatijana and Zgaga, Lina and Assimes, Themistocles L and Blankenberg, Stefan and Boerwinkle, Eric and Campbell, Harry and Cooke, John P and de Graaf, Jacqueline and Herrington, David and Kardia, Sharon L R and Mitchell, Braxton D and Murray, Anna and M{\"u}nzel, Thomas and Newman, Anne B and Oostra, Ben A and Rudan, Igor and Shuldiner, Alan R and Snieder, Harold and van Duijn, Cornelia M and V{\"o}lker, Uwe and Wright, Alan F and Wichmann, H-Erich and Wilson, James F and Witteman, Jacqueline C M and Liu, Yongmei and Hayward, Caroline and Borecki, Ingrid B and Ziegler, Andreas and North, Kari E and Cupples, L Adrienne and Kronenberg, Florian} } @article {7566, title = {Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.}, journal = {BioData Min}, volume = {10}, year = {2017}, month = {2017}, pages = {25}, abstract = {

BACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).

RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n~=~12,853 to n~=~16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p~<~0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p~<~0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.

CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

}, issn = {1756-0381}, doi = {10.1186/s13040-017-0145-5}, author = {Holzinger, Emily R and Verma, Shefali S and Moore, Carrie B and Hall, Molly and De, Rishika and Gilbert-Diamond, Diane and Lanktree, Matthew B and Pankratz, Nathan and Amuzu, Antoinette and Burt, Amber and Dale, Caroline and Dudek, Scott and Furlong, Clement E and Gaunt, Tom R and Kim, Daniel Seung and Riess, Helene and Sivapalaratnam, Suthesh and Tragante, Vinicius and van Iperen, Erik P A and Brautbar, Ariel and Carrell, David S and Crosslin, David R and Jarvik, Gail P and Kuivaniemi, Helena and Kullo, Iftikhar J and Larson, Eric B and Rasmussen-Torvik, Laura J and Tromp, Gerard and Baumert, Jens and Cruickshanks, Karen J and Farrall, Martin and Hingorani, Aroon D and Hovingh, G K and Kleber, Marcus E and Klein, Barbara E and Klein, Ronald and Koenig, Wolfgang and Lange, Leslie A and Mӓrz, Winfried and North, Kari E and Charlotte Onland-Moret, N and Reiner, Alex P and Talmud, Philippa J and van der Schouw, Yvonne T and Wilson, James G and Kivimaki, Mika and Kumari, Meena and Moore, Jason H and Drenos, Fotios and Asselbergs, Folkert W and Keating, Brendan J and Ritchie, Marylyn D} } @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} }