%0 Journal Article %J Nat Genet %D 2022 %T Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. %A Aragam, Krishna G %A Jiang, Tao %A Goel, Anuj %A Kanoni, Stavroula %A Wolford, Brooke N %A Atri, Deepak S %A Weeks, Elle M %A Wang, Minxian %A Hindy, George %A Zhou, Wei %A Grace, Christopher %A Roselli, Carolina %A Marston, Nicholas A %A Kamanu, Frederick K %A Surakka, Ida %A Venegas, Loreto Muñoz %A Sherliker, Paul %A Koyama, Satoshi %A Ishigaki, Kazuyoshi %A Åsvold, Bjørn O %A Brown, Michael R %A Brumpton, Ben %A de Vries, Paul S %A Giannakopoulou, Olga %A Giardoglou, Panagiota %A Gudbjartsson, Daniel F %A Güldener, Ulrich %A Haider, Syed M Ijlal %A Helgadottir, Anna %A Ibrahim, Maysson %A Kastrati, Adnan %A Kessler, Thorsten %A Kyriakou, Theodosios %A Konopka, Tomasz %A Li, Ling %A Ma, Lijiang %A Meitinger, Thomas %A Mucha, Sören %A Munz, Matthias %A Murgia, Federico %A Nielsen, Jonas B %A Nöthen, Markus M %A Pang, Shichao %A Reinberger, Tobias %A Schnitzler, Gavin %A Smedley, Damian %A Thorleifsson, Gudmar %A von Scheidt, Moritz %A Ulirsch, Jacob C %A Arnar, David O %A Burtt, Noël P %A Costanzo, Maria C %A Flannick, Jason %A Ito, Kaoru %A Jang, Dong-Keun %A Kamatani, Yoichiro %A Khera, Amit V %A Komuro, Issei %A Kullo, Iftikhar J %A Lotta, Luca A %A Nelson, Christopher P %A Roberts, Robert %A Thorgeirsson, Gudmundur %A Thorsteinsdottir, Unnur %A Webb, Thomas R %A Baras, Aris %A Björkegren, Johan L M %A Eric Boerwinkle %A Dedoussis, George %A Holm, Hilma %A Hveem, Kristian %A Melander, Olle %A Morrison, Alanna C %A Orho-Melander, Marju %A Rallidis, Loukianos S %A Ruusalepp, Arno %A Sabatine, Marc S %A Stefansson, Kari %A Zalloua, Pierre %A Ellinor, Patrick T %A Farrall, Martin %A Danesh, John %A Ruff, Christian T %A Finucane, Hilary K %A Hopewell, Jemma C %A Clarke, Robert %A Gupta, Rajat M %A Erdmann, Jeanette %A Samani, Nilesh J %A Schunkert, Heribert %A Watkins, Hugh %A Willer, Cristen J %A Deloukas, Panos %A Kathiresan, Sekar %A Butterworth, Adam S %K Coronary Artery Disease %K Genome-Wide Association Study %K Humans %X

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

%B Nat Genet %V 54 %P 1803-1815 %8 2022 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/36474045?dopt=Abstract %R 10.1038/s41588-022-01233-6 %0 Journal Article %J Mol Psychiatry %D 2022 %T Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. %A Lahti, Jari %A Tuominen, Samuli %A Yang, Qiong %A Pergola, Giulio %A Ahmad, Shahzad %A Amin, Najaf %A Armstrong, Nicola J %A Beiser, Alexa %A Bey, Katharina %A Bis, Joshua C %A Eric Boerwinkle %A Bressler, Jan %A Campbell, Archie %A Campbell, Harry %A Chen, Qiang %A Corley, Janie %A Cox, Simon R %A Davies, Gail %A De Jager, Philip L %A Derks, Eske M %A Faul, Jessica D %A Fitzpatrick, Annette L %A Fohner, Alison E %A Ford, Ian %A Fornage, Myriam %A Gerring, Zachary %A Grabe, Hans J %A Grodstein, Francine %A Gudnason, Vilmundur %A Simonsick, Eleanor %A Holliday, Elizabeth G %A Joshi, Peter K %A Kajantie, Eero %A Kaprio, Jaakko %A Karell, Pauliina %A Kleineidam, Luca %A Knol, Maria J %A Kochan, Nicole A %A Kwok, John B %A Leber, Markus %A Lam, Max %A Lee, Teresa %A Li, Shuo %A Loukola, Anu %A Luck, Tobias %A Marioni, Riccardo E %A Mather, Karen A %A Medland, Sarah %A Mirza, Saira S %A Nalls, Mike A %A Nho, Kwangsik %A O'Donnell, Adrienne %A Oldmeadow, Christopher %A Painter, Jodie %A Pattie, Alison %A Reppermund, Simone %A Risacher, Shannon L %A Rose, Richard J %A Sadashivaiah, Vijay %A Scholz, Markus %A Satizabal, Claudia L %A Schofield, Peter W %A Schraut, Katharina E %A Scott, Rodney J %A Simino, Jeannette %A Smith, Albert V %A Smith, Jennifer A %A Stott, David J %A Surakka, Ida %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Trompet, Stella %A Turner, Stephen T %A van der Lee, Sven J %A Villringer, Arno %A Völker, Uwe %A Wilson, Robert S %A Wittfeld, Katharina %A Vuoksimaa, Eero %A Xia, Rui %A Yaffe, Kristine %A Yu, Lei %A Zare, Habil %A Zhao, Wei %A Ames, David %A Attia, John %A Bennett, David A %A Brodaty, Henry %A Chasman, Daniel I %A Goldman, Aaron L %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon L R %A Lencz, Todd %A Loeffler, Markus %A Mattay, Venkata S %A Palotie, Aarno %A Psaty, Bruce M %A Ramirez, Alfredo %A Ridker, Paul M %A Riedel-Heller, Steffi G %A Sachdev, Perminder S %A Saykin, Andrew J %A Scherer, Martin %A Schofield, Peter R %A Sidney, Stephen %A Starr, John M %A Trollor, Julian %A Ulrich, William %A Wagner, Michael %A Weir, David R %A Wilson, James F %A Wright, Margaret J %A Weinberger, Daniel R %A Debette, Stephanie %A Eriksson, Johan G %A Mosley, Thomas H %A Launer, Lenore J %A van Duijn, Cornelia M %A Deary, Ian J %A Seshadri, Sudha %A Räikkönen, Katri %K Brain %K Learning %K Memory, Short-Term %K Multifactorial Inheritance %K Verbal Learning %X

Understanding the genomic basis of memory processes may help in combating neurodegenerative disorders. Hence, we examined the associations of common genetic variants with verbal short-term memory and verbal learning in adults without dementia or stroke (N = 53,637). We identified novel loci in the intronic region of CDH18, and at 13q21 and 3p21.1, as well as an expected signal in the APOE/APOC1/TOMM40 region. These results replicated in an independent sample. Functional and bioinformatic analyses supported many of these loci and further implicated POC1. We showed that polygenic score for verbal learning associated with brain activation in right parieto-occipital region during working memory task. Finally, we showed genetic correlations of these memory traits with several neurocognitive and health outcomes. Our findings suggest a role of several genomic loci in verbal memory processes.

%B Mol Psychiatry %V 27 %P 4419-4431 %8 2022 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/35974141?dopt=Abstract %R 10.1038/s41380-022-01710-8 %0 Journal Article %J J Med Genet %D 2016 %T Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. %A van Leeuwen, Elisabeth M %A Sabo, Aniko %A Bis, Joshua C %A Huffman, Jennifer E %A Manichaikul, Ani %A Smith, Albert V %A Feitosa, Mary F %A Demissie, Serkalem %A Joshi, Peter K %A Duan, Qing %A Marten, Jonathan %A van Klinken, Jan B %A Surakka, Ida %A Nolte, Ilja M %A Zhang, Weihua %A Mbarek, Hamdi %A Li-Gao, Ruifang %A Trompet, Stella %A Verweij, Niek %A Evangelou, Evangelos %A Lyytikäinen, Leo-Pekka %A Tayo, Bamidele O %A Deelen, Joris %A van der Most, Peter J %A van der Laan, Sander W %A Arking, Dan E %A Morrison, Alanna %A Dehghan, Abbas %A Franco, Oscar H %A Hofman, Albert %A Rivadeneira, Fernando %A Sijbrands, Eric J %A Uitterlinden, André G %A Mychaleckyj, Josyf C %A Campbell, Archie %A Hocking, Lynne J %A Padmanabhan, Sandosh %A Brody, Jennifer A %A Rice, Kenneth M %A White, Charles C %A Harris, Tamara %A Isaacs, Aaron %A Campbell, Harry %A Lange, Leslie A %A Rudan, Igor %A Kolcic, Ivana %A Navarro, Pau %A Zemunik, Tatijana %A Salomaa, Veikko %A Kooner, Angad S %A Kooner, Jaspal S %A Lehne, Benjamin %A Scott, William R %A Tan, Sian-Tsung %A de Geus, Eco J %A Milaneschi, Yuri %A Penninx, Brenda W J H %A Willemsen, Gonneke %A de Mutsert, Renée %A Ford, Ian %A Gansevoort, Ron T %A Segura-Lepe, Marcelo P %A Raitakari, Olli T %A Viikari, Jorma S %A Nikus, Kjell %A Forrester, Terrence %A McKenzie, Colin A %A de Craen, Anton J M %A de Ruijter, Hester M %A Pasterkamp, Gerard %A Snieder, Harold %A Oldehinkel, Albertine J %A Slagboom, P Eline %A Cooper, Richard S %A Kähönen, Mika %A Lehtimäki, Terho %A Elliott, Paul %A van der Harst, Pim %A Jukema, J Wouter %A Mook-Kanamori, Dennis O %A Boomsma, Dorret I %A Chambers, John C %A Swertz, Morris %A Ripatti, Samuli %A Willems van Dijk, Ko %A Vitart, Veronique %A Polasek, Ozren %A Hayward, Caroline %A Wilson, James G %A Wilson, James F %A Gudnason, Vilmundur %A Rich, Stephen S %A Psaty, Bruce M %A Borecki, Ingrid B %A Boerwinkle, Eric %A Rotter, Jerome I %A Cupples, L Adrienne %A van Duijn, Cornelia M %K Angiopoietin-Like Protein 4 %K Angiopoietins %K Exons %K Fasting %K Female %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

%B J Med Genet %V 53 %P 441-9 %8 2016 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/27036123?dopt=Abstract %R 10.1136/jmedgenet-2015-103439