@article {1221, title = {Biological, clinical and population relevance of 95 loci for blood lipids.}, journal = {Nature}, volume = {466}, year = {2010}, month = {2010 Aug 05}, pages = {707-13}, abstract = {

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

}, keywords = {African Americans, Animals, Asian Continental Ancestry Group, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Europe, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, Lipids, Liver, Male, Mice, N-Acetylgalactosaminyltransferases, Phenotype, Polymorphism, Single Nucleotide, Protein Phosphatase 1, Reproducibility of Results, Triglycerides}, issn = {1476-4687}, doi = {10.1038/nature09270}, author = {Teslovich, Tanya M and Musunuru, Kiran and Smith, Albert V and Edmondson, Andrew C and Stylianou, Ioannis M and Koseki, Masahiro and Pirruccello, James P and Ripatti, Samuli and Chasman, Daniel I and Willer, Cristen J and Johansen, Christopher T and Fouchier, Sigrid W and Isaacs, Aaron and Peloso, Gina M and Barbalic, Maja and Ricketts, Sally L and Bis, Joshua C and Aulchenko, Yurii S and Thorleifsson, Gudmar and Feitosa, Mary F and Chambers, John and Orho-Melander, Marju and Melander, Olle and Johnson, Toby and Li, Xiaohui and Guo, Xiuqing and Li, Mingyao and Shin Cho, Yoon and Jin Go, Min and Jin Kim, Young and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Twee-Hee Ong, Rick and Croteau-Chonka, Damien C and Lange, Leslie A and Smith, Joshua D and Song, Kijoung and Hua Zhao, Jing and Yuan, Xin and Luan, Jian{\textquoteright}an and Lamina, Claudia and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y L and Wright, Alan F and Witteman, Jacqueline C M and Wilson, James F and Willemsen, Gonneke and Wichmann, H-Erich and Whitfield, John B and Waterworth, Dawn M and Wareham, Nicholas J and Waeber, G{\'e}rard and Vollenweider, Peter and Voight, Benjamin F and Vitart, Veronique and Uitterlinden, Andr{\'e} G and Uda, Manuela and Tuomilehto, Jaakko and Thompson, John R and Tanaka, Toshiko and Surakka, Ida and Stringham, Heather M and Spector, Tim D and Soranzo, Nicole and Smit, Johannes H and Sinisalo, Juha and Silander, Kaisa and Sijbrands, Eric J G and Scuteri, Angelo and Scott, James and Schlessinger, David and Sanna, Serena and Salomaa, Veikko and Saharinen, Juha and Sabatti, Chiara and Ruokonen, Aimo and Rudan, Igor and Rose, Lynda M and Roberts, Robert and Rieder, Mark and Psaty, Bruce M and Pramstaller, Peter P and Pichler, Irene and Perola, Markus and Penninx, Brenda W J H and Pedersen, Nancy L and Pattaro, Cristian and Parker, Alex N and Par{\'e}, Guillaume and Oostra, Ben A and O{\textquoteright}Donnell, Christopher J and Nieminen, Markku S and Nickerson, Deborah A and Montgomery, Grant W and Meitinger, Thomas and McPherson, Ruth and McCarthy, Mark I and McArdle, Wendy and Masson, David and Martin, Nicholas G and Marroni, Fabio and Mangino, Massimo and Magnusson, Patrik K E and Lucas, Gavin and Luben, Robert and Loos, Ruth J F and Lokki, Marja-Liisa and Lettre, Guillaume and Langenberg, Claudia and Launer, Lenore J and Lakatta, Edward G and Laaksonen, Reijo and Kyvik, Kirsten O and Kronenberg, Florian and K{\"o}nig, Inke R and Khaw, Kay-Tee and Kaprio, Jaakko and Kaplan, Lee M and Johansson, Asa and Jarvelin, Marjo-Riitta and Janssens, A Cecile J W and Ingelsson, Erik and Igl, Wilmar and Kees Hovingh, G and Hottenga, Jouke-Jan and Hofman, Albert and Hicks, Andrew A and Hengstenberg, Christian and Heid, Iris M and Hayward, Caroline and Havulinna, Aki S and Hastie, Nicholas D and Harris, Tamara B and Haritunians, Talin and Hall, Alistair S and Gyllensten, Ulf and Guiducci, Candace and Groop, Leif C and Gonzalez, Elena and Gieger, Christian and Freimer, Nelson B and Ferrucci, Luigi and Erdmann, Jeanette and Elliott, Paul and Ejebe, Kenechi G and D{\"o}ring, Angela and Dominiczak, Anna F and Demissie, Serkalem and Deloukas, Panagiotis and de Geus, Eco J C and de Faire, Ulf and Crawford, Gabriel and Collins, Francis S and Chen, Yii-der I and Caulfield, Mark J and Campbell, Harry and Burtt, Noel P and Bonnycastle, Lori L and Boomsma, Dorret I and Boekholdt, S Matthijs and Bergman, Richard N and Barroso, In{\^e}s and Bandinelli, Stefania and Ballantyne, Christie M and Assimes, Themistocles L and Quertermous, Thomas and Altshuler, David and Seielstad, Mark and Wong, Tien Y and Tai, E-Shyong and Feranil, Alan B and Kuzawa, Christopher W and Adair, Linda S and Taylor, Herman A and Borecki, Ingrid B and Gabriel, Stacey B and Wilson, James G and Holm, Hilma and Thorsteinsdottir, Unnur and Gudnason, Vilmundur and Krauss, Ronald M and Mohlke, Karen L and Ordovas, Jose M and Munroe, Patricia B and Kooner, Jaspal S and Tall, Alan R and Hegele, Robert A and Kastelein, John J P and Schadt, Eric E and Rotter, Jerome I and Boerwinkle, Eric and Strachan, David P and Mooser, Vincent and Stefansson, Kari and Reilly, Muredach P and Samani, Nilesh J and Schunkert, Heribert and Cupples, L Adrienne and Sandhu, Manjinder S and Ridker, Paul M and Rader, Daniel J and van Duijn, Cornelia M and Peltonen, Leena and Abecasis, Goncalo R and Boehnke, Michael and Kathiresan, Sekar} } @article {1188, title = {Candidate gene association resource (CARe): design, methods, and proof of concept.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Jun}, pages = {267-75}, abstract = {

BACKGROUND: The National Heart, Lung, and Blood Institute{\textquoteright}s Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

}, keywords = {African Americans, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Databases, Genetic, European Continental Ancestry Group, Genetic Association Studies, Genotype, Humans, Phenotype, Pilot Projects, Polymorphism, Single Nucleotide, Research Design, Triglycerides}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.882696}, author = {Musunuru, Kiran and Lettre, Guillaume and Young, Taylor and Farlow, Deborah N and Pirruccello, James P and Ejebe, Kenechi G and Keating, Brendan J and Yang, Qiong and Chen, Ming-Huei and Lapchyk, Nina and Crenshaw, Andrew and Ziaugra, Liuda and Rachupka, Anthony and Benjamin, Emelia J and Cupples, L Adrienne and Fornage, Myriam and Fox, Ervin R and Heckbert, Susan R and Hirschhorn, Joel N and Newton-Cheh, Christopher and Nizzari, Marcia M and Paltoo, Dina N and Papanicolaou, George J and Patel, Sanjay R and Psaty, Bruce M and Rader, Daniel J and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Taylor, Herman A and Tracy, Russell P and Vasan, Ramachandran S and Wilson, James G and Kathiresan, Sekar and Fabsitz, Richard R and Boerwinkle, Eric and Gabriel, Stacey B} } @article {1378, title = {Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1002607}, abstract = {

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5{\texttimes}10(-8)-1.2{\texttimes}10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3{\texttimes}10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3{\texttimes}10(-3), n = 22,044), increased triglycerides (p = 2.6{\texttimes}10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8{\texttimes}10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4{\texttimes}10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5{\texttimes}10(-13), n = 96,748) and decreased BMI (p = 1.4{\texttimes}10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

}, keywords = {Adiponectin, African Americans, Asian Continental Ancestry Group, Cholesterol, HDL, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002607}, author = {Dastani, Zari and Hivert, Marie-France and Timpson, Nicholas and Perry, John R B and Yuan, Xin and Scott, Robert A and Henneman, Peter and Heid, Iris M and Kizer, Jorge R and Lyytik{\"a}inen, Leo-Pekka and Fuchsberger, Christian and Tanaka, Toshiko and Morris, Andrew P and Small, Kerrin and Isaacs, Aaron and Beekman, Marian and Coassin, Stefan and Lohman, Kurt and Qi, Lu and Kanoni, Stavroula and Pankow, James S and Uh, Hae-Won and Wu, Ying and Bidulescu, Aurelian and Rasmussen-Torvik, Laura J and Greenwood, Celia M T and Ladouceur, Martin and Grimsby, Jonna and Manning, Alisa K and Liu, Ching-Ti and Kooner, Jaspal and Mooser, Vincent E and Vollenweider, Peter and Kapur, Karen A and Chambers, John and Wareham, Nicholas J and Langenberg, Claudia and Frants, Rune and Willems-Vandijk, Ko and Oostra, Ben A and Willems, Sara M and Lamina, Claudia and Winkler, Thomas W and Psaty, Bruce M and Tracy, Russell P and Brody, Jennifer and Chen, Ida and Viikari, Jorma and K{\"a}h{\"o}nen, Mika and Pramstaller, Peter P and Evans, David M and St Pourcain, Beate and Sattar, Naveed and Wood, Andrew R and Bandinelli, Stefania and Carlson, Olga D and Egan, Josephine M and B{\"o}hringer, Stefan and van Heemst, Diana and Kedenko, Lyudmyla and Kristiansson, Kati and Nuotio, Marja-Liisa and Loo, Britt-Marie and Harris, Tamara and Garcia, Melissa and Kanaya, Alka and Haun, Margot and Klopp, Norman and Wichmann, H-Erich and Deloukas, Panos and Katsareli, Efi and Couper, David J and Duncan, Bruce B and Kloppenburg, Margreet and Adair, Linda S and Borja, Judith B and Wilson, James G and Musani, Solomon and Guo, Xiuqing and Johnson, Toby and Semple, Robert and Teslovich, Tanya M and Allison, Matthew A and Redline, Susan and Buxbaum, Sarah G and Mohlke, Karen L and Meulenbelt, Ingrid and Ballantyne, Christie M and Dedoussis, George V and Hu, Frank B and Liu, Yongmei and Paulweber, Bernhard and Spector, Timothy D and Slagboom, P Eline and Ferrucci, Luigi and Jula, Antti and Perola, Markus and Raitakari, Olli and Florez, Jose C and Salomaa, Veikko and Eriksson, Johan G and Frayling, Timothy M and Hicks, Andrew A and Lehtim{\"a}ki, Terho and Smith, George Davey and Siscovick, David S and Kronenberg, Florian and van Duijn, Cornelia and Loos, Ruth J F and Waterworth, Dawn M and Meigs, James B and Dupuis, Jos{\'e}e and Richards, J Brent and Voight, Benjamin F and Scott, Laura J and Steinthorsdottir, Valgerdur and Dina, Christian and Welch, Ryan P and Zeggini, Eleftheria and Huth, Cornelia and Aulchenko, Yurii S and Thorleifsson, Gudmar and McCulloch, Laura J and Ferreira, Teresa and Grallert, Harald and Amin, Najaf and Wu, Guanming and Willer, Cristen J and Raychaudhuri, Soumya and McCarroll, Steve A and Hofmann, Oliver M and Segr{\`e}, Ayellet V and van Hoek, Mandy and Navarro, Pau and Ardlie, Kristin and Balkau, Beverley and Benediktsson, Rafn and Bennett, Amanda J and Blagieva, Roza and Boerwinkle, Eric and Bonnycastle, Lori L and Bostr{\"o}m, Kristina Bengtsson and Bravenboer, Bert and Bumpstead, Suzannah and Burtt, Noel P and Charpentier, Guillaume and Chines, Peter S and Cornelis, Marilyn and Crawford, Gabe and Doney, Alex S F and Elliott, Katherine S and Elliott, Amanda L and Erdos, Michael R and Fox, Caroline S and Franklin, Christopher S and Ganser, Martha and Gieger, Christian and Grarup, Niels and Green, Todd and Griffin, Simon and Groves, Christopher J and Guiducci, Candace and Hadjadj, Samy and Hassanali, Neelam and Herder, Christian and Isomaa, Bo and Jackson, Anne U and Johnson, Paul R V and J{\o}rgensen, Torben and Kao, Wen H L and Kong, Augustine and Kraft, Peter and Kuusisto, Johanna and Lauritzen, Torsten and Li, Man and Lieverse, Aloysius and Lindgren, Cecilia M and Lyssenko, Valeriya and Marre, Michel and Meitinger, Thomas and Midthjell, Kristian and Morken, Mario A and Narisu, Narisu and Nilsson, Peter and Owen, Katharine R and Payne, Felicity and Petersen, Ann-Kristin and Platou, Carl and Proen{\c c}a, Christine and Prokopenko, Inga and Rathmann, Wolfgang and Rayner, N William and Robertson, Neil R and Rocheleau, Ghislain and Roden, Michael and Sampson, Michael J and Saxena, Richa and Shields, Beverley M and Shrader, Peter and Sigurdsson, Gunnar and Spars{\o}, Thomas and Strassburger, Klaus and Stringham, Heather M and Sun, Qi and Swift, Amy J and Thorand, Barbara and Tichet, Jean and Tuomi, Tiinamaija and van Dam, Rob M and van Haeften, Timon W and van Herpt, Thijs and van Vliet-Ostaptchouk, Jana V and Walters, G Bragi and Weedon, Michael N and Wijmenga, Cisca and Witteman, Jacqueline and Bergman, Richard N and Cauchi, Stephane and Collins, Francis S and Gloyn, Anna L and Gyllensten, Ulf and Hansen, Torben and Hide, Winston A and Hitman, Graham A and Hofman, Albert and Hunter, David J and Hveem, Kristian and Laakso, Markku and Morris, Andrew D and Palmer, Colin N A and Rudan, Igor and Sijbrands, Eric and Stein, Lincoln D and Tuomilehto, Jaakko and Uitterlinden, Andre and Walker, Mark and Watanabe, Richard M and Abecasis, Goncalo R and Boehm, Bernhard O and Campbell, Harry and Daly, Mark J and Hattersley, Andrew T and Pedersen, Oluf and Barroso, In{\^e}s and Groop, Leif and Sladek, Rob and Thorsteinsdottir, Unnur and Wilson, James F and Illig, Thomas and Froguel, Philippe and van Duijn, Cornelia M and Stefansson, Kari and Altshuler, David and Boehnke, Michael and McCarthy, Mark I and Soranzo, Nicole and Wheeler, Eleanor and Glazer, Nicole L and Bouatia-Naji, Nabila and M{\"a}gi, Reedik and Randall, Joshua and Elliott, Paul and Rybin, Denis and Dehghan, Abbas and Hottenga, Jouke Jan and Song, Kijoung and Goel, Anuj and Lajunen, Taina and Doney, Alex and Cavalcanti-Proen{\c c}a, Christine and Kumari, Meena and Timpson, Nicholas J and Zabena, Carina and Ingelsson, Erik and An, Ping and O{\textquoteright}Connell, Jeffrey and Luan, Jian{\textquoteright}an and Elliott, Amanda and McCarroll, Steven A and Roccasecca, Rosa Maria and Pattou, Fran{\c c}ois and Sethupathy, Praveen and Ariyurek, Yavuz and Barter, Philip and Beilby, John P and Ben-Shlomo, Yoav and Bergmann, Sven and Bochud, Murielle and Bonnefond, Am{\'e}lie and Borch-Johnsen, Knut and B{\"o}ttcher, Yvonne and Brunner, Eric and Bumpstead, Suzannah J and Chen, Yii-Der Ida and Chines, Peter and Clarke, Robert and Coin, Lachlan J M and Cooper, Matthew N and Crisponi, Laura and Day, Ian N M and de Geus, Eco J C and Delplanque, Jerome and Fedson, Annette C and Fischer-Rosinsky, Antje and Forouhi, Nita G and Franzosi, Maria Grazia and Galan, Pilar and Goodarzi, Mark O and Graessler, J{\"u}rgen and Grundy, Scott and Gwilliam, Rhian and Hallmans, G{\"o}ran and Hammond, Naomi and Han, Xijing and Hartikainen, Anna-Liisa and Hayward, Caroline and Heath, Simon C and Hercberg, Serge and Hillman, David R and Hingorani, Aroon D and Hui, Jennie and Hung, Joe and Kaakinen, Marika and Kaprio, Jaakko and Kesaniemi, Y Antero and Kivimaki, Mika and Knight, Beatrice and Koskinen, Seppo and Kovacs, Peter and Kyvik, Kirsten Ohm and Lathrop, G Mark and Lawlor, Debbie A and Le Bacquer, Olivier and Lecoeur, C{\'e}cile and Li, Yun and Mahley, Robert and Mangino, Massimo and Mart{\'\i}nez-Larrad, Mar{\'\i}a Teresa and McAteer, Jarred B and McPherson, Ruth and Meisinger, Christa and Melzer, David and Meyre, David and Mitchell, Braxton D and Mukherjee, Sutapa and Naitza, Silvia and Neville, Matthew J and Orr{\`u}, Marco and Pakyz, Ruth and Paolisso, Giuseppe and Pattaro, Cristian and Pearson, Daniel and Peden, John F and Pedersen, Nancy L and Pfeiffer, Andreas F H and Pichler, Irene and Polasek, Ozren and Posthuma, Danielle and Potter, Simon C and Pouta, Anneli and Province, Michael A and Rayner, Nigel W and Rice, Kenneth and Ripatti, Samuli and Rivadeneira, Fernando and Rolandsson, Olov and Sandbaek, Annelli and Sandhu, Manjinder and Sanna, Serena and Sayer, Avan Aihie and Scheet, Paul and Seedorf, Udo and Sharp, Stephen J and Shields, Beverley and Sigur{\dh}sson, Gunnar and Sijbrands, Eric J G and Silveira, Angela and Simpson, Laila and Singleton, Andrew and Smith, Nicholas L and Sovio, Ulla and Swift, Amy and Syddall, Holly and Syv{\"a}nen, Ann-Christine and T{\"o}njes, Anke and Uitterlinden, Andr{\'e} G and van Dijk, Ko Willems and Varma, Dhiraj and Visvikis-Siest, Sophie and Vitart, Veronique and Vogelzangs, Nicole and Waeber, G{\'e}rard and Wagner, Peter J and Walley, Andrew and Ward, Kim L and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Witteman, Jaqueline C M and Yarnell, John W G and Zelenika, Diana and Zethelius, Bj{\"o}rn and Zhai, Guangju and Zhao, Jing Hua and Zillikens, M Carola and Borecki, Ingrid B and Meneton, Pierre and Magnusson, Patrik K E and Nathan, David M and Williams, Gordon H and Silander, Kaisa and Bornstein, Stefan R and Schwarz, Peter and Spranger, Joachim and Karpe, Fredrik and Shuldiner, Alan R and Cooper, Cyrus and Serrano-R{\'\i}os, Manuel and Lind, Lars and Palmer, Lyle J and Hu, Frank B and Franks, Paul W and Ebrahim, Shah and Marmot, Michael and Kao, W H Linda and Pramstaller, Peter Paul and Wright, Alan F and Stumvoll, Michael and Hamsten, Anders and Buchanan, Thomas A and Valle, Timo T and Rotter, Jerome I and Penninx, Brenda W J H and Boomsma, Dorret I and Cao, Antonio and Scuteri, Angelo and Schlessinger, David and Uda, Manuela and Ruokonen, Aimo and Jarvelin, Marjo-Riitta and Peltonen, Leena and Mooser, Vincent and Sladek, Robert and Musunuru, Kiran and Smith, Albert V and Edmondson, Andrew C and Stylianou, Ioannis M and Koseki, Masahiro and Pirruccello, James P and Chasman, Daniel I and Johansen, Christopher T and Fouchier, Sigrid W and Peloso, Gina M and Barbalic, Maja and Ricketts, Sally L and Bis, Joshua C and Feitosa, Mary F and Orho-Melander, Marju and Melander, Olle and Li, Xiaohui and Li, Mingyao and Cho, Yoon Shin and Go, Min Jin and Kim, Young Jin and Lee, Jong-Young and Park, Taesung and Kim, Kyunga and Sim, Xueling and Ong, Rick Twee-Hee and Croteau-Chonka, Damien C and Lange, Leslie A and Smith, Joshua D and Ziegler, Andreas and Zhang, Weihua and Zee, Robert Y L and Whitfield, John B and Thompson, John R and Surakka, Ida and Spector, Tim D and Smit, Johannes H and Sinisalo, Juha and Scott, James and Saharinen, Juha and Sabatti, Chiara and Rose, Lynda M and Roberts, Robert and Rieder, Mark and Parker, Alex N and Par{\'e}, Guillaume and O{\textquoteright}Donnell, Christopher J and Nieminen, Markku S and Nickerson, Deborah A and Montgomery, Grant W and McArdle, Wendy and Masson, David and Martin, Nicholas G and Marroni, Fabio and Lucas, Gavin and Luben, Robert and Lokki, Marja-Liisa and Lettre, Guillaume and Launer, Lenore J and Lakatta, Edward G and Laaksonen, Reijo and Kyvik, Kirsten O and K{\"o}nig, Inke R and Khaw, Kay-Tee and Kaplan, Lee M and Johansson, Asa and Janssens, A Cecile J W and Igl, Wilmar and Hovingh, G Kees and Hengstenberg, Christian and Havulinna, Aki S and Hastie, Nicholas D and Harris, Tamara B and Haritunians, Talin and Hall, Alistair S and Groop, Leif C and Gonzalez, Elena and Freimer, Nelson B and Erdmann, Jeanette and Ejebe, Kenechi G and D{\"o}ring, Angela and Dominiczak, Anna F and Demissie, Serkalem and Deloukas, Panagiotis and de Faire, Ulf and Crawford, Gabriel and Chen, Yii-der I and Caulfield, Mark J and Boekholdt, S Matthijs and Assimes, Themistocles L and Quertermous, Thomas and Seielstad, Mark and Wong, Tien Y and Tai, E-Shyong and Feranil, Alan B and Kuzawa, Christopher W and Taylor, Herman A and Gabriel, Stacey B and Holm, Hilma and Gudnason, Vilmundur and Krauss, Ronald M and Ordovas, Jose M and Munroe, Patricia B and Kooner, Jaspal S and Tall, Alan R and Hegele, Robert A and Kastelein, John J P and Schadt, Eric E and Strachan, David P and Reilly, Muredach P and Samani, Nilesh J and Schunkert, Heribert and Cupples, L Adrienne and Sandhu, Manjinder S and Ridker, Paul M and Rader, Daniel J and Kathiresan, Sekar} } @article {8711, title = {Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 12}, pages = {2182}, abstract = {

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 {\texttimes} 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 {\texttimes} 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 {\texttimes} 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

}, issn = {2041-1723}, doi = {10.1038/s41467-021-22339-1}, author = {Natarajan, Pradeep and Pampana, Akhil and Graham, Sarah E and Ruotsalainen, Sanni E and Perry, James A and de Vries, Paul S and Broome, Jai G and Pirruccello, James P and Honigberg, Michael C and Aragam, Krishna and Wolford, Brooke and Brody, Jennifer A and Antonacci-Fulton, Lucinda and Arden, Moscati and Aslibekyan, Stella and Assimes, Themistocles L and Ballantyne, Christie M and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Do, Ron and Doddapaneni, Harsha and Emery, Leslie S and Hung, Yi-Jen and Irvin, Marguerite R and Khan, Alyna T and Lange, Leslie and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Metcalf, Ginger and Montasser, May E and Moon, Jee-Young and Muzny, Donna and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peralta, Juan M and Peyser, Patricia A and Stilp, Adrienne M and Tsai, Michael and Wang, Fei Fei and Weeks, Daniel E and Yanek, Lisa R and Wilson, James G and Abecasis, Goncalo and Arnett, Donna K and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Chang, Yi-Cheng and Chen, Yii-der I and Choi, Won Jung and Correa, Adolfo and Curran, Joanne E and Daly, Mark J and Dutcher, Susan K and Ellinor, Patrick T and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and He, Jiang and Hveem, Kristian and Jarvik, Gail P and Kaplan, Robert C and Kardia, Sharon L R and Kenny, Eimear and Kim, Ryan W and Kooperberg, Charles and Laurie, Cathy C and Lee, Seonwook and Lloyd-Jones, Don M and Loos, Ruth J F and Lubitz, Steven A and Mathias, Rasika A and Martinez, Karine A Viaud and McGarvey, Stephen T and Mitchell, Braxton D and Nickerson, Deborah A and North, Kari E and Palotie, Aarno and Park, Cheol Joo and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Seo, Daekwan and Seo, Jeong-Sun and Smith, Albert V and Tracy, Russell P and Vasan, Ramachandran S and Kathiresan, Sekar and Cupples, L Adrienne and Rotter, Jerome I and Morrison, Alanna C and Rich, Stephen S and Ripatti, Samuli and Willer, Cristen and Peloso, Gina M} } @article {9167, title = {Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 08 30}, pages = {5106}, abstract = {

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of >= 0.5 times the endophenotype standard deviation nominates up to 35\% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

}, keywords = {Disease Susceptibility, Endophenotypes, Humans, Long QT Syndrome, Virulence}, issn = {2041-1723}, doi = {10.1038/s41467-022-32009-5}, author = {Halford, Jennifer L and Morrill, Valerie N and Choi, Seung Hoan and Jurgens, Sean J and Melloni, Giorgio and Marston, Nicholas A and Weng, Lu-Chen and Nauffal, Victor and Hall, Amelia W and Gunn, Sophia and Austin-Tse, Christina A and Pirruccello, James P and Khurshid, Shaan and Rehm, Heidi L and Benjamin, Emelia J and Boerwinkle, Eric and Brody, Jennifer A and Correa, Adolfo and Fornwalt, Brandon K and Gupta, Namrata and Haggerty, Christopher M and Harris, Stephanie and Heckbert, Susan R and Hong, Charles C and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Post, Wendy and Psaty, Bruce M and Redline, Susan and Rice, Kenneth M and Rich, Stephen S and Rotter, Jerome I and Schnatz, Peter F and Soliman, Elsayed Z and Sotoodehnia, Nona and Wong, Eugene K and Sabatine, Marc S and Ruff, Christian T and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} } @article {9914, title = {Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {539-547}, abstract = {

Atrial fibrillation (AF) is the most common heart rhythm abnormality and is a leading cause of heart failure and stroke. This large-scale meta-analysis of genome-wide association studies increased the power to detect single-nucleotide variant associations and found more than 350 AF-associated genetic loci. We identified candidate genes related to muscle contractility, cardiac muscle development and cell-cell communication at 139 loci. Furthermore, we assayed chromatin accessibility using assay for transposase-accessible chromatin with sequencing and histone H3 lysine 4 trimethylation in stem cell-derived atrial cardiomyocytes. We observed a marked increase in chromatin accessibility for our sentinel variants and prioritized genes in atrial cardiomyocytes. Finally, a polygenic risk score (PRS) based on our updated effect estimates improved AF risk prediction compared to the CHARGE-AF clinical risk score and a previously reported PRS for AF. The doubling of known risk loci will facilitate a greater understanding of the pathways underlying AF.

}, keywords = {Atrial Fibrillation, Chromatin, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-024-02072-3}, author = {Roselli, Carolina and Surakka, Ida and Olesen, Morten S and Sveinbjornsson, Gardar and Marston, Nicholas A and Choi, Seung Hoan and Holm, Hilma and Chaffin, Mark and Gudbjartsson, Daniel and Hill, Matthew C and Aegisdottir, Hildur and Albert, Christine M and Alonso, Alvaro and Anderson, Christopher D and Arking, Dan E and Arnar, David O and Barnard, John and Benjamin, Emelia J and Braunwald, Eugene and Brumpton, Ben and Campbell, Archie and Chami, Nathalie and Chasman, Daniel I and Cho, Kelly and Choi, Eue-Keun and Christophersen, Ingrid E and Chung, Mina K and Conen, David and Crijns, Harry J and Cutler, Michael J and Czuba, Tomasz and Damrauer, Scott M and Dichgans, Martin and D{\"o}rr, Marcus and Dudink, Elton and Duong, ThuyVy and Erikstrup, Christian and Esko, T{\~o}nu and Fatkin, Diane and Faul, Jessica D and Ferreira, Manuel and Freitag, Daniel F and Ganesh, Santhi K and Gaziano, J Michael and Geelhoed, Bastiaan and Ghouse, Jonas and Gieger, Christian and Giulianini, Franco and Graham, Sarah E and Gudnason, Vilmundur and Guo, Xiuqing and Haggerty, Christopher and Hayward, Caroline and Heckbert, Susan R and Hveem, Kristian and Ito, Kaoru and Johnson, Renee and Jukema, J Wouter and Jurgens, Sean J and K{\"a}{\"a}b, Stefan and Kane, John P and Kany, Shinwan and Kardia, Sharon L R and Kavousi, Maryam and Khurshid, Shaan and Kamanu, Frederick K and Kirchhof, Paulus and Kleber, Marcus E and Knight, Stacey and Komuro, Issei and Krieger, Jose E and Launer, Lenore J and Li, Dadong and Lin, Honghuang and Lin, Henry J and Loos, Ruth J F and Lotta, Luca and Lubitz, Steven A and Lunetta, Kathryn L and Macfarlane, Peter W and Magnusson, Patrik K E and Malik, Rainer and Mantineo, Helene and Marcus, Gregory M and M{\"a}rz, Winfried and McManus, David D and Melander, Olle and Melloni, Giorgio E M and Meyre, Pascal B and Miyazawa, Kazuo and Mohanty, Sanghamitra and Monfort, Laia M and M{\"u}ller-Nurasyid, Martina and Nafissi, Navid A and Natale, Andrea and Nazarian, Saman and Ostrowski, Sisse R and Pak, Hui-Nam and Pang, Shichao and Pedersen, Ole B and Pedersen, Nancy L and Pereira, Alexandre C and Pirruccello, James P and Preuss, Michael and Psaty, Bruce M and Pullinger, Clive R and Rader, Daniel J and R{\"a}m{\"o}, Joel T and Ridker, Paul M and Rienstra, Michiel and Risch, Lorenz and Roden, Dan M and Rotter, Jerome I and Sabatine, Marc S and Schunkert, Heribert and Shah, Svati H and Shim, Jaemin and Shoemaker, M Benjamin and Simonson, Bridget and Sinner, Moritz F and Smit, Roelof A J and Smith, Jennifer A and Smith, Nicholas L and Smith, J Gustav and Soliman, Elsayed Z and S{\o}rensen, Erik and Sotoodehnia, Nona and Strbian, Daniel and Stricker, Bruno H and Teder-Laving, Maris and Sun, Yan V and Th{\'e}riault, S{\'e}bastien and Thorolfsdottir, Rosa B and Thorsteinsdottir, Unnur and Tveit, Arnljot and van der Harst, Pim and van Meurs, Joyce and Wang, Biqi and Weiss, Stefan and Wells, Quinn S and Weng, Lu-Chen and Wilson, Peter W and Xiao, Ling and Yang, Pil-Sung and Yao, Jie and Yoneda, Zachary T and Zeller, Tanja and Zeng, Lingyao and Zhao, Wei and Zhou, Xiang and Z{\"o}llner, Sebastian and Ruff, Christian T and Bundgaard, Henning and Willer, Cristen and Stefansson, Kari and Ellinor, Patrick T} } @article {9907, title = {Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {548-562}, abstract = {

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

}, keywords = {Atrial Fibrillation, Case-Control Studies, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Myocytes, Cardiac, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-025-02074-9}, author = {Choi, Seung Hoan and Jurgens, Sean J and Xiao, Ling and Hill, Matthew C and Haggerty, Christopher M and Sveinbj{\"o}rnsson, Gar{\dh}ar and Morrill, Valerie N and Marston, Nicholas A and Weng, Lu-Chen and Pirruccello, James P and Arnar, David O and Gudbjartsson, Daniel Fannar and Mantineo, Helene and von Falkenhausen, Aenne S and Natale, Andrea and Tveit, Arnljot and Geelhoed, Bastiaan and Roselli, Carolina and Van Wagoner, David R and Darbar, Dawood and Haase, Doreen and Soliman, Elsayed Z and Davogustto, Giovanni E and Jun, Goo and Calkins, Hugh and Anderson, Jeffrey L and Brody, Jennifer A and Halford, Jennifer L and Barnard, John and Hokanson, John E and Smith, Jonathan D and Bis, Joshua C and Young, Kendra and Johnson, Linda S B and Risch, Lorenz and Gula, Lorne J and Kwee, Lydia Coulter and Chaffin, Mark D and K{\"u}hne, Michael and Preuss, Michael and Gupta, Namrata and Nafissi, Navid A and Smith, Nicholas L and Nilsson, Peter M and van der Harst, Pim and Wells, Quinn S and Judy, Renae L and Schnabel, Renate B and Johnson, Renee and Smit, Roelof A J and Gabriel, Stacey and Knight, Stacey and Furukawa, Tetsushi and Blackwell, Thomas W and Nauffal, Victor and Wang, Xin and Min, Yuan-I and Yoneda, Zachary T and Laksman, Zachary W M and Bezzina, Connie R and Alonso, Alvaro and Psaty, Bruce M and Albert, Christine M and Arking, Dan E and Roden, Dan M and Chasman, Daniel I and Rader, Daniel J and Conen, David and McManus, David D and Fatkin, Diane and Benjamin, Emelia J and Boerwinkle, Eric and Marcus, Gregory M and Christophersen, Ingrid E and Smith, J Gustav and Roberts, Jason D and Raffield, Laura M and Shoemaker, M Benjamin and Cho, Michael H and Cutler, Michael J and Rienstra, Michiel and Chung, Mina K and S Olesen, Morten and Sinner, Moritz F and Sotoodehnia, Nona and Kirchhof, Paulus and Loos, Ruth J F and Nazarian, Saman and Mohanty, Sanghamitra and Damrauer, Scott M and K{\"a}{\"a}b, Stefan and Heckbert, Susan R and Redline, Susan and Shah, Svati H and Tanaka, Toshihiro and Ebana, Yusuke and Holm, Hilma and Stefansson, Kari and Ruff, Christian T and Sabatine, Marc S and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} }