%0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. %A Murabito, Joanne M %A White, Charles C %A Kavousi, Maryam %A Sun, Yan V %A Feitosa, Mary F %A Nambi, Vijay %A Lamina, Claudia %A Schillert, Arne %A Coassin, Stefan %A Bis, Joshua C %A Broer, Linda %A Crawford, Dana C %A Franceschini, Nora %A Frikke-Schmidt, Ruth %A Haun, Margot %A Holewijn, Suzanne %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Kiechl, Stefan %A Kollerits, Barbara %A Montasser, May E %A Nolte, Ilja M %A Rudock, Megan E %A Senft, Andrea %A Teumer, Alexander %A van der Harst, Pim %A Vitart, Veronique %A Waite, Lindsay L %A Wood, Andrew R %A Wassel, Christina L %A Absher, Devin M %A Allison, Matthew A %A Amin, Najaf %A Arnold, Alice %A Asselbergs, Folkert W %A Aulchenko, Yurii %A Bandinelli, Stefania %A Barbalic, Maja %A Boban, Mladen %A Brown-Gentry, Kristin %A Couper, David J %A Criqui, Michael H %A Dehghan, Abbas %A den Heijer, Martin %A Dieplinger, Benjamin %A Ding, Jingzhong %A Dörr, Marcus %A Espinola-Klein, Christine %A Felix, Stephan B %A Ferrucci, Luigi %A Folsom, Aaron R %A Fraedrich, Gustav %A Gibson, Quince %A Goodloe, Robert %A Gunjaca, Grgo %A Haltmayer, Meinhard %A Heiss, Gerardo %A Hofman, Albert %A Kieback, Arne %A Kiemeney, Lambertus A %A Kolcic, Ivana %A Kullo, Iftikhar J %A Kritchevsky, Stephen B %A Lackner, Karl J %A Li, Xiaohui %A Lieb, Wolfgang %A Lohman, Kurt %A Meisinger, Christa %A Melzer, David %A Mohler, Emile R %A Mudnic, Ivana %A Mueller, Thomas %A Navis, Gerjan %A Oberhollenzer, Friedrich %A Olin, Jeffrey W %A O'Connell, Jeff %A O'Donnell, Christopher J %A Palmas, Walter %A Penninx, Brenda W %A Petersmann, Astrid %A Polasek, Ozren %A Psaty, Bruce M %A Rantner, Barbara %A Rice, Ken %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seldenrijk, Adrie %A Stadler, Marietta %A Summerer, Monika %A Tanaka, Toshiko %A Tybjaerg-Hansen, Anne %A Uitterlinden, André G %A van Gilst, Wiek H %A Vermeulen, Sita H %A Wild, Sarah H %A Wild, Philipp S %A Willeit, Johann %A Zeller, Tanja %A Zemunik, Tatijana %A Zgaga, Lina %A Assimes, Themistocles L %A Blankenberg, Stefan %A Boerwinkle, Eric %A Campbell, Harry %A Cooke, John P %A de Graaf, Jacqueline %A Herrington, David %A Kardia, Sharon L R %A Mitchell, Braxton D %A Murray, Anna %A Münzel, Thomas %A Newman, Anne B %A Oostra, Ben A %A Rudan, Igor %A Shuldiner, Alan R %A Snieder, Harold %A van Duijn, Cornelia M %A Völker, Uwe %A Wright, Alan F %A Wichmann, H-Erich %A Wilson, James F %A Witteman, Jacqueline C M %A Liu, Yongmei %A Hayward, Caroline %A Borecki, Ingrid B %A Ziegler, Andreas %A North, Kari E %A Cupples, L Adrienne %A Kronenberg, Florian %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alleles %K Ankle Brachial Index %K Chromosomes, Human, Pair 9 %K Cohort Studies %K Cyclin-Dependent Kinase Inhibitor p15 %K Female %K Genome-Wide Association Study %K Genotype %K HapMap Project %K Humans %K Logistic Models %K Male %K Middle Aged %K Peripheral Vascular Diseases %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Sex Factors %X

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=2.46×10(-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=2.65×10(-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=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-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.

%B Circ Cardiovasc Genet %V 5 %P 100-12 %8 2012 Feb 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract %R 10.1161/CIRCGENETICS.111.961292 %0 Journal Article %J Nat Genet %D 2012 %T Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. %A Scott, Robert A %A Lagou, Vasiliki %A Welch, Ryan P %A Wheeler, Eleanor %A Montasser, May E %A Luan, Jian'an %A Mägi, Reedik %A Strawbridge, Rona J %A Rehnberg, Emil %A Gustafsson, Stefan %A Kanoni, Stavroula %A Rasmussen-Torvik, Laura J %A Yengo, Loic %A Lecoeur, Cécile %A Shungin, Dmitry %A Sanna, Serena %A Sidore, Carlo %A Johnson, Paul C D %A Jukema, J Wouter %A Johnson, Toby %A Mahajan, Anubha %A Verweij, Niek %A Thorleifsson, Gudmar %A Hottenga, Jouke-Jan %A Shah, Sonia %A Smith, Albert V %A Sennblad, Bengt %A Gieger, Christian %A Salo, Perttu %A Perola, Markus %A Timpson, Nicholas J %A Evans, David M %A Pourcain, Beate St %A Wu, Ying %A Andrews, Jeanette S %A Hui, Jennie %A Bielak, Lawrence F %A Zhao, Wei %A Horikoshi, Momoko %A Navarro, Pau %A Isaacs, Aaron %A O'Connell, Jeffrey R %A Stirrups, Kathleen %A Vitart, Veronique %A Hayward, Caroline %A Esko, Tõnu %A Mihailov, Evelin %A Fraser, Ross M %A Fall, Tove %A Voight, Benjamin F %A Raychaudhuri, Soumya %A Chen, Han %A Lindgren, Cecilia M %A Morris, Andrew P %A Rayner, Nigel W %A Robertson, Neil %A Rybin, Denis %A Liu, Ching-Ti %A Beckmann, Jacques S %A Willems, Sara M %A Chines, Peter S %A Jackson, Anne U %A Kang, Hyun Min %A Stringham, Heather M %A Song, Kijoung %A Tanaka, Toshiko %A Peden, John F %A Goel, Anuj %A Hicks, Andrew A %A An, Ping %A Müller-Nurasyid, Martina %A Franco-Cereceda, Anders %A Folkersen, Lasse %A Marullo, Letizia %A Jansen, Hanneke %A Oldehinkel, Albertine J %A Bruinenberg, Marcel %A Pankow, James S %A North, Kari E %A Forouhi, Nita G %A Loos, Ruth J F %A Edkins, Sarah %A Varga, Tibor V %A Hallmans, Göran %A Oksa, Heikki %A Antonella, Mulas %A Nagaraja, Ramaiah %A Trompet, Stella %A Ford, Ian %A Bakker, Stephan J L %A Kong, Augustine %A Kumari, Meena %A Gigante, Bruna %A Herder, Christian %A Munroe, Patricia B %A Caulfield, Mark %A Antti, Jula %A Mangino, Massimo %A Small, Kerrin %A Miljkovic, Iva %A Liu, Yongmei %A Atalay, Mustafa %A Kiess, Wieland %A James, Alan L %A Rivadeneira, Fernando %A Uitterlinden, André G %A Palmer, Colin N A %A Doney, Alex S F %A Willemsen, Gonneke %A Smit, Johannes H %A Campbell, Susan %A Polasek, Ozren %A Bonnycastle, Lori L %A Hercberg, Serge %A Dimitriou, Maria %A Bolton, Jennifer L %A Fowkes, Gerard R %A Kovacs, Peter %A Lindström, Jaana %A Zemunik, Tatijana %A Bandinelli, Stefania %A Wild, Sarah H %A Basart, Hanneke V %A Rathmann, Wolfgang %A Grallert, Harald %A Maerz, Winfried %A Kleber, Marcus E %A Boehm, Bernhard O %A Peters, Annette %A Pramstaller, Peter P %A Province, Michael A %A Borecki, Ingrid B %A Hastie, Nicholas D %A Rudan, Igor %A Campbell, Harry %A Watkins, Hugh %A Farrall, Martin %A Stumvoll, Michael %A Ferrucci, Luigi %A Waterworth, Dawn M %A Bergman, Richard N %A Collins, Francis S %A Tuomilehto, Jaakko %A Watanabe, Richard M %A de Geus, Eco J C %A Penninx, Brenda W %A Hofman, Albert %A Oostra, Ben A %A Psaty, Bruce M %A Vollenweider, Peter %A Wilson, James F %A Wright, Alan F %A Hovingh, G Kees %A Metspalu, Andres %A Uusitupa, Matti %A Magnusson, Patrik K E %A Kyvik, Kirsten O %A Kaprio, Jaakko %A Price, Jackie F %A Dedoussis, George V %A Deloukas, Panos %A Meneton, Pierre %A Lind, Lars %A Boehnke, Michael %A Shuldiner, Alan R %A van Duijn, Cornelia M %A Morris, Andrew D %A Toenjes, Anke %A Peyser, Patricia A %A Beilby, John P %A Körner, Antje %A Kuusisto, Johanna %A Laakso, Markku %A Bornstein, Stefan R %A Schwarz, Peter E H %A Lakka, Timo A %A Rauramaa, Rainer %A Adair, Linda S %A Smith, George Davey %A Spector, Tim D %A Illig, Thomas %A de Faire, Ulf %A Hamsten, Anders %A Gudnason, Vilmundur %A Kivimaki, Mika %A Hingorani, Aroon %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Boomsma, Dorret I %A Stefansson, Kari %A van der Harst, Pim %A Dupuis, Josée %A Pedersen, Nancy L %A Sattar, Naveed %A Harris, Tamara B %A Cucca, Francesco %A Ripatti, Samuli %A Salomaa, Veikko %A Mohlke, Karen L %A Balkau, Beverley %A Froguel, Philippe %A Pouta, Anneli %A Jarvelin, Marjo-Riitta %A Wareham, Nicholas J %A Bouatia-Naji, Nabila %A McCarthy, Mark I %A Franks, Paul W %A Meigs, James B %A Teslovich, Tanya M %A Florez, Jose C %A Langenberg, Claudia %A Ingelsson, Erik %A Prokopenko, Inga %A Barroso, Inês %K Adult %K Animals %K Blood Glucose %K Fasting %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Insulin %K Male %K Metabolic Networks and Pathways %K Mice %K Osmolar Concentration %K Quantitative Trait Loci %X

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

%B Nat Genet %V 44 %P 991-1005 %8 2012 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract %R 10.1038/ng.2385 %0 Journal Article %J Nat Genet %D 2013 %T Common variants associated with plasma triglycerides and risk for coronary artery disease. %A Do, Ron %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Gao, Chi %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Eyjolfsson, Gudmundur Ingi %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Altshuler, David %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %A Daly, Mark J %A Neale, Benjamin M %A Kathiresan, Sekar %K Biological Transport %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Triglycerides %X

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

%B Nat Genet %V 45 %P 1345-52 %8 2013 Nov %G eng %N 11 %R 10.1038/ng.2795 %0 Journal Article %J Nat Genet %D 2013 %T Discovery and refinement of loci associated with lipid levels. %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Do, Ron %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Ingi Eyjolfsson, Gudmundur %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Kathiresan, Sekar %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %K African Continental Ancestry Group %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Lipids %K Triglycerides %X

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

%B Nat Genet %V 45 %P 1274-1283 %8 2013 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract %R 10.1038/ng.2797 %0 Journal Article %J Nat Genet %D 2013 %T Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. %A den Hoed, Marcel %A Eijgelsheim, Mark %A Esko, Tõnu %A Brundel, Bianca J J M %A Peal, David S %A Evans, David M %A Nolte, Ilja M %A Segrè, Ayellet V %A Holm, Hilma %A Handsaker, Robert E %A Westra, Harm-Jan %A Johnson, Toby %A Isaacs, Aaron %A Yang, Jian %A Lundby, Alicia %A Zhao, Jing Hua %A Kim, Young Jin %A Go, Min Jin %A Almgren, Peter %A Bochud, Murielle %A Boucher, Gabrielle %A Cornelis, Marilyn C %A Gudbjartsson, Daniel %A Hadley, David %A van der Harst, Pim %A Hayward, Caroline %A den Heijer, Martin %A Igl, Wilmar %A Jackson, Anne U %A Kutalik, Zoltán %A Luan, Jian'an %A Kemp, John P %A Kristiansson, Kati %A Ladenvall, Claes %A Lorentzon, Mattias %A Montasser, May E %A Njajou, Omer T %A O'Reilly, Paul F %A Padmanabhan, Sandosh %A St Pourcain, Beate %A Rankinen, Tuomo %A Salo, Perttu %A Tanaka, Toshiko %A Timpson, Nicholas J %A Vitart, Veronique %A Waite, Lindsay %A Wheeler, William %A Zhang, Weihua %A Draisma, Harmen H M %A Feitosa, Mary F %A Kerr, Kathleen F %A Lind, Penelope A %A Mihailov, Evelin %A Onland-Moret, N Charlotte %A Song, Ci %A Weedon, Michael N %A Xie, Weijia %A Yengo, Loic %A Absher, Devin %A Albert, Christine M %A Alonso, Alvaro %A Arking, Dan E %A de Bakker, Paul I W %A Balkau, Beverley %A Barlassina, Cristina %A Benaglio, Paola %A Bis, Joshua C %A Bouatia-Naji, Nabila %A Brage, Søren %A Chanock, Stephen J %A Chines, Peter S %A Chung, Mina %A Darbar, Dawood %A Dina, Christian %A Dörr, Marcus %A Elliott, Paul %A Felix, Stephan B %A Fischer, Krista %A Fuchsberger, Christian %A de Geus, Eco J C %A Goyette, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Heckbert, Susan R %A Hicks, Andrew A %A Hofman, Albert %A Holewijn, Suzanne %A Hoogstra-Berends, Femke %A Hottenga, Jouke-Jan %A Jensen, Majken K %A Johansson, Asa %A Junttila, Juhani %A Kääb, Stefan %A Kanon, Bart %A Ketkar, Shamika %A Khaw, Kay-Tee %A Knowles, Joshua W %A Kooner, Angrad S %A Kors, Jan A %A Kumari, Meena %A Milani, Lili %A Laiho, Päivi %A Lakatta, Edward G %A Langenberg, Claudia %A Leusink, Maarten %A Liu, Yongmei %A Luben, Robert N %A Lunetta, Kathryn L %A Lynch, Stacey N %A Markus, Marcello R P %A Marques-Vidal, Pedro %A Mateo Leach, Irene %A McArdle, Wendy L %A McCarroll, Steven A %A Medland, Sarah E %A Miller, Kathryn A %A Montgomery, Grant W %A Morrison, Alanna C %A Müller-Nurasyid, Martina %A Navarro, Pau %A Nelis, Mari %A O'Connell, Jeffrey R %A O'Donnell, Christopher J %A Ong, Ken K %A Newman, Anne B %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Psaty, Bruce M %A Rao, Dabeeru C %A Ring, Susan M %A Rossin, Elizabeth J %A Rudan, Diana %A Sanna, Serena %A Scott, Robert A %A Sehmi, Jaban S %A Sharp, Stephen %A Shin, Jordan T %A Singleton, Andrew B %A Smith, Albert V %A Soranzo, Nicole %A Spector, Tim D %A Stewart, Chip %A Stringham, Heather M %A Tarasov, Kirill V %A Uitterlinden, André G %A Vandenput, Liesbeth %A Hwang, Shih-Jen %A Whitfield, John B %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Witteman, Jacqueline C M %A Wong, Andrew %A Wong, Quenna %A Jamshidi, Yalda %A Zitting, Paavo %A Boer, Jolanda M A %A Boomsma, Dorret I %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Ekelund, Ulf %A Forouhi, Nita G %A Froguel, Philippe %A Hingorani, Aroon %A Ingelsson, Erik %A Kivimaki, Mika %A Kronmal, Richard A %A Kuh, Diana %A Lind, Lars %A Martin, Nicholas G %A Oostra, Ben A %A Pedersen, Nancy L %A Quertermous, Thomas %A Rotter, Jerome I %A van der Schouw, Yvonne T %A Verschuren, W M Monique %A Walker, Mark %A Albanes, Demetrius %A Arnar, David O %A Assimes, Themistocles L %A Bandinelli, Stefania %A Boehnke, Michael %A de Boer, Rudolf A %A Bouchard, Claude %A Caulfield, W L Mark %A Chambers, John C %A Curhan, Gary %A Cusi, Daniele %A Eriksson, Johan %A Ferrucci, Luigi %A van Gilst, Wiek H %A Glorioso, Nicola %A de Graaf, Jacqueline %A Groop, Leif %A Gyllensten, Ulf %A Hsueh, Wen-Chi %A Hu, Frank B %A Huikuri, Heikki V %A Hunter, David J %A Iribarren, Carlos %A Isomaa, Bo %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kiemeney, Lambertus A %A van der Klauw, Melanie M %A Kooner, Jaspal S %A Kraft, Peter %A Iacoviello, Licia %A Lehtimäki, Terho %A Lokki, Marja-Liisa L %A Mitchell, Braxton D %A Navis, Gerjan %A Nieminen, Markku S %A Ohlsson, Claes %A Poulter, Neil R %A Qi, Lu %A Raitakari, Olli T %A Rimm, Eric B %A Rioux, John D %A Rizzi, Federica %A Rudan, Igor %A Salomaa, Veikko %A Sever, Peter S %A Shields, Denis C %A Shuldiner, Alan R %A Sinisalo, Juha %A Stanton, Alice V %A Stolk, Ronald P %A Strachan, David P %A Tardif, Jean-Claude %A Thorsteinsdottir, Unnur %A Tuomilehto, Jaako %A van Veldhuisen, Dirk J %A Virtamo, Jarmo %A Viikari, Jorma %A Vollenweider, Peter %A Waeber, Gérard %A Widen, Elisabeth %A Cho, Yoon Shin %A Olsen, Jesper V %A Visscher, Peter M %A Willer, Cristen %A Franke, Lude %A Erdmann, Jeanette %A Thompson, John R %A Pfeufer, Arne %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Ellinor, Patrick T %A Stricker, Bruno H Ch %A Metspalu, Andres %A Perola, Markus %A Beckmann, Jacques S %A Smith, George Davey %A Stefansson, Kari %A Wareham, Nicholas J %A Munroe, Patricia B %A Sibon, Ody C M %A Milan, David J %A Snieder, Harold %A Samani, Nilesh J %A Loos, Ruth J F %K Animals %K Arrhythmias, Cardiac %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Heart Rate %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

%B Nat Genet %V 45 %P 621-31 %8 2013 Jun %G eng %N 6 %R 10.1038/ng.2610 %0 Journal Article %J Diabetes %D 2016 %T Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci. %A Walford, Geoffrey A %A Gustafsson, Stefan %A Rybin, Denis %A Stančáková, Alena %A Chen, Han %A Liu, Ching-Ti %A Hong, Jaeyoung %A Jensen, Richard A %A Rice, Ken %A Morris, Andrew P %A Mägi, Reedik %A Tönjes, Anke %A Prokopenko, Inga %A Kleber, Marcus E %A Delgado, Graciela %A Silbernagel, Günther %A Jackson, Anne U %A Appel, Emil V %A Grarup, Niels %A Lewis, Joshua P %A Montasser, May E %A Landenvall, Claes %A Staiger, Harald %A Luan, Jian'an %A Frayling, Timothy M %A Weedon, Michael N %A Xie, Weijia %A Morcillo, Sonsoles %A Martínez-Larrad, María Teresa %A Biggs, Mary L %A Chen, Yii-Der Ida %A Corbaton-Anchuelo, Arturo %A Færch, Kristine %A Gómez-Zumaquero, Juan Miguel %A Goodarzi, Mark O %A Kizer, Jorge R %A Koistinen, Heikki A %A Leong, Aaron %A Lind, Lars %A Lindgren, Cecilia %A Machicao, Fausto %A Manning, Alisa K %A Martín-Núñez, Gracia María %A Rojo-Martínez, Gemma %A Rotter, Jerome I %A Siscovick, David S %A Zmuda, Joseph M %A Zhang, Zhongyang %A Serrano-Ríos, Manuel %A Smith, Ulf %A Soriguer, Federico %A Hansen, Torben %A Jørgensen, Torben J %A Linnenberg, Allan %A Pedersen, Oluf %A Walker, Mark %A Langenberg, Claudia %A Scott, Robert A %A Wareham, Nicholas J %A Fritsche, Andreas %A Häring, Hans-Ulrich %A Stefan, Norbert %A Groop, Leif %A O'Connell, Jeff R %A Boehnke, Michael %A Bergman, Richard N %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A März, Winfried %A Kovacs, Peter %A Stumvoll, Michael %A Psaty, Bruce M %A Kuusisto, Johanna %A Laakso, Markku %A Meigs, James B %A Dupuis, Josée %A Ingelsson, Erik %A Florez, Jose C %X

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

%B Diabetes %V 65 %P 3200-11 %8 2016 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/27416945?dopt=Abstract %R 10.2337/db16-0199 %0 Journal Article %J Nat Commun %D 2016 %T A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. %A Ried, Janina S %A Jeff M, Janina %A Chu, Audrey Y %A Bragg-Gresham, Jennifer L %A van Dongen, Jenny %A Huffman, Jennifer E %A Ahluwalia, Tarunveer S %A Cadby, Gemma %A Eklund, Niina %A Eriksson, Joel %A Esko, Tõnu %A Feitosa, Mary F %A Goel, Anuj %A Gorski, Mathias %A Hayward, Caroline %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jokinen, Eero %A Kanoni, Stavroula %A Kristiansson, Kati %A Kutalik, Zoltán %A Lahti, Jari %A Luan, Jian'an %A Mägi, Reedik %A Mahajan, Anubha %A Mangino, Massimo %A Medina-Gómez, Carolina %A Monda, Keri L %A Nolte, Ilja M %A Perusse, Louis %A Prokopenko, Inga %A Qi, Lu %A Rose, Lynda M %A Salvi, Erika %A Smith, Megan T %A Snieder, Harold %A Stančáková, Alena %A Ju Sung, Yun %A Tachmazidou, Ioanna %A Teumer, Alexander %A Thorleifsson, Gudmar %A van der Harst, Pim %A Walker, Ryan W %A Wang, Sophie R %A Wild, Sarah H %A Willems, Sara M %A Wong, Andrew %A Zhang, Weihua %A Albrecht, Eva %A Couto Alves, Alexessander %A Bakker, Stephan J L %A Barlassina, Cristina %A Bartz, Traci M %A Beilby, John %A Bellis, Claire %A Bergman, Richard N %A Bergmann, Sven %A Blangero, John %A Blüher, Matthias %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Bruinenberg, Marcel %A Campbell, Harry %A Chen, Yii-Der Ida %A Chiang, Charleston W K %A Chines, Peter S %A Collins, Francis S %A Cucca, Fracensco %A Cupples, L Adrienne %A D'Avila, Francesca %A de Geus, Eco J C %A Dedoussis, George %A Dimitriou, Maria %A Döring, Angela %A Eriksson, Johan G %A Farmaki, Aliki-Eleni %A Farrall, Martin %A Ferreira, Teresa %A Fischer, Krista %A Forouhi, Nita G %A Friedrich, Nele %A Gjesing, Anette Prior %A Glorioso, Nicola %A Graff, Mariaelisa %A Grallert, Harald %A Grarup, Niels %A Gräßler, Jürgen %A Grewal, Jagvir %A Hamsten, Anders %A Harder, Marie Neergaard %A Hartman, Catharina A %A Hassinen, Maija %A Hastie, Nicholas %A Hattersley, Andrew Tym %A Havulinna, Aki S %A Heliövaara, Markku %A Hillege, Hans %A Hofman, Albert %A Holmen, Oddgeir %A Homuth, Georg %A Hottenga, Jouke-Jan %A Hui, Jennie %A Husemoen, Lise Lotte %A Hysi, Pirro G %A Isaacs, Aaron %A Ittermann, Till %A Jalilzadeh, Shapour %A James, Alan L %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Marie Justesen, Johanne %A Justice, Anne E %A Kähönen, Mika %A Karaleftheri, Maria %A Tee Khaw, Kay %A Keinanen-Kiukaanniemi, Sirkka M %A Kinnunen, Leena %A Knekt, Paul B %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooner, Ishminder K %A Koskinen, Seppo %A Kovacs, Peter %A Kyriakou, Theodosios %A Laitinen, Tomi %A Langenberg, Claudia %A Lewin, Alexandra M %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindström, Jaana %A Linneberg, Allan %A Lorbeer, Roberto %A Lorentzon, Mattias %A Luben, Robert %A Lyssenko, Valeriya %A Männistö, Satu %A Manunta, Paolo %A Leach, Irene Mateo %A McArdle, Wendy L %A McKnight, Barbara %A Mohlke, Karen L %A Mihailov, Evelin %A Milani, Lili %A Mills, Rebecca %A Montasser, May E %A Morris, Andrew P %A Müller, Gabriele %A Musk, Arthur W %A Narisu, Narisu %A Ong, Ken K %A Oostra, Ben A %A Osmond, Clive %A Palotie, Aarno %A Pankow, James S %A Paternoster, Lavinia %A Penninx, Brenda W %A Pichler, Irene %A Pilia, Maria G %A Polasek, Ozren %A Pramstaller, Peter P %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rayner, Nigel W %A Ribel-Madsen, Rasmus %A Rice, Treva K %A Richards, Marcus %A Ridker, Paul M %A Rivadeneira, Fernando %A Ryan, Kathy A %A Sanna, Serena %A Sarzynski, Mark A %A Scholtens, Salome %A Scott, Robert A %A Sebert, Sylvain %A Southam, Lorraine %A Sparsø, Thomas Hempel %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen %A Stolk, Ronald P %A Strauch, Konstantin %A Stringham, Heather M %A Swertz, Morris A %A Swift, Amy J %A Tönjes, Anke %A Tsafantakis, Emmanouil %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Vartiainen, Erkki %A Venturini, Cristina %A Verweij, Niek %A Viikari, Jorma S %A Vitart, Veronique %A Vohl, Marie-Claude %A Vonk, Judith M %A Waeber, Gérard %A Widen, Elisabeth %A Willemsen, Gonneke %A Wilsgaard, Tom %A Winkler, Thomas W %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Hua Zhao, Jing %A Zillikens, M Carola %A Boomsma, Dorret I %A Bouchard, Claude %A Chambers, John C %A Chasman, Daniel I %A Cusi, Daniele %A Gansevoort, Ron T %A Gieger, Christian %A Hansen, Torben %A Hicks, Andrew A %A Hu, Frank %A Hveem, Kristian %A Jarvelin, Marjo-Riitta %A Kajantie, Eero %A Kooner, Jaspal S %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Metspalu, Andres %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Psaty, Bruce M %A Puolijoki, Hannu %A Rauramaa, Rainer %A Rudan, Igor %A Salomaa, Veikko %A Schwarz, Peter E H %A Shudiner, Alan R %A Smit, Jan H %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Tremblay, Angelo %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A Völker, Uwe %A Vollenweider, Peter %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Zeggini, Eleftheria %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A van Duijn, Cornelia M %A Fox, Caroline %A Groop, Leif C %A Heid, Iris M %A Hunter, David J %A Kaplan, Robert C %A McCarthy, Mark I %A North, Kari E %A O'Connell, Jeffrey R %A Schlessinger, David %A Thorsteinsdottir, Unnur %A Strachan, David P %A Frayling, Timothy %A Hirschhorn, Joel N %A Müller-Nurasyid, Martina %A Loos, Ruth J F %K Anthropometry %K Body Size %K Genome-Wide Association Study %K Genotype %K Humans %K Models, Genetic %K Principal Component Analysis %X

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

%B Nat Commun %V 7 %P 13357 %8 2016 11 23 %G eng %R 10.1038/ncomms13357 %0 Journal Article %J Am J Hum Genet %D 2017 %T DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation. %A Richard, Melissa A %A Huan, Tianxiao %A Ligthart, Symen %A Gondalia, Rahul %A Jhun, Min A %A Brody, Jennifer A %A Irvin, Marguerite R %A Marioni, Riccardo %A Shen, Jincheng %A Tsai, Pei-Chien %A Montasser, May E %A Jia, Yucheng %A Syme, Catriona %A Salfati, Elias L %A Boerwinkle, Eric %A Guan, Weihua %A Mosley, Thomas H %A Bressler, Jan %A Morrison, Alanna C %A Liu, Chunyu %A Mendelson, Michael M %A Uitterlinden, André G %A van Meurs, Joyce B %A Franco, Oscar H %A Zhang, Guosheng %A Li, Yun %A Stewart, James D %A Bis, Joshua C %A Psaty, Bruce M %A Chen, Yii-Der Ida %A Kardia, Sharon L R %A Zhao, Wei %A Turner, Stephen T %A Absher, Devin %A Aslibekyan, Stella %A Starr, John M %A McRae, Allan F %A Hou, Lifang %A Just, Allan C %A Schwartz, Joel D %A Vokonas, Pantel S %A Menni, Cristina %A Spector, Tim D %A Shuldiner, Alan %A Damcott, Coleen M %A Rotter, Jerome I %A Palmas, Walter %A Liu, Yongmei %A Paus, Tomáš %A Horvath, Steve %A O'Connell, Jeffrey R %A Guo, Xiuqing %A Pausova, Zdenka %A Assimes, Themistocles L %A Sotoodehnia, Nona %A Smith, Jennifer A %A Arnett, Donna K %A Deary, Ian J %A Baccarelli, Andrea A %A Bell, Jordana T %A Whitsel, Eric %A Dehghan, Abbas %A Levy, Daniel %A Fornage, Myriam %K Aged %K Blood Pressure %K CpG Islands %K Cross-Sectional Studies %K DNA Methylation %K Epigenesis, Genetic %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Mendelian Randomization Analysis %K Middle Aged %K Nerve Tissue Proteins %K Quantitative Trait Loci %K Tetraspanins %X

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

%B Am J Hum Genet %V 101 %P 888-902 %8 2017 Dec 07 %G eng %N 6 %R 10.1016/j.ajhg.2017.09.028 %0 Journal Article %J Nat Commun %D 2019 %T Associations of autozygosity with a broad range of human phenotypes. %A Clark, David W %A Okada, Yukinori %A Moore, Kristjan H S %A Mason, Dan %A Pirastu, Nicola %A Gandin, Ilaria %A Mattsson, Hannele %A Barnes, Catriona L K %A Lin, Kuang %A Zhao, Jing Hua %A Deelen, Patrick %A Rohde, Rebecca %A Schurmann, Claudia %A Guo, Xiuqing %A Giulianini, Franco %A Zhang, Weihua %A Medina-Gómez, Carolina %A Karlsson, Robert %A Bao, Yanchun %A Bartz, Traci M %A Baumbach, Clemens %A Biino, Ginevra %A Bixley, Matthew J %A Brumat, Marco %A Chai, Jin-Fang %A Corre, Tanguy %A Cousminer, Diana L %A Dekker, Annelot M %A Eccles, David A %A van Eijk, Kristel R %A Fuchsberger, Christian %A Gao, He %A Germain, Marine %A Gordon, Scott D %A de Haan, Hugoline G %A Harris, Sarah E %A Hofer, Edith %A Huerta-Chagoya, Alicia %A Igartua, Catherine %A Jansen, Iris E %A Jia, Yucheng %A Kacprowski, Tim %A Karlsson, Torgny %A Kleber, Marcus E %A Li, Shengchao Alfred %A Li-Gao, Ruifang %A Mahajan, Anubha %A Matsuda, Koichi %A Meidtner, Karina %A Meng, Weihua %A Montasser, May E %A van der Most, Peter J %A Munz, Matthias %A Nutile, Teresa %A Palviainen, Teemu %A Prasad, Gauri %A Prasad, Rashmi B %A Priyanka, Tallapragada Divya Sri %A Rizzi, Federica %A Salvi, Erika %A Sapkota, Bishwa R %A Shriner, Daniel %A Skotte, Line %A Smart, Melissa C %A Smith, Albert Vernon %A van der Spek, Ashley %A Spracklen, Cassandra N %A Strawbridge, Rona J %A Tajuddin, Salman M %A Trompet, Stella %A Turman, Constance %A Verweij, Niek %A Viberti, Clara %A Wang, Lihua %A Warren, Helen R %A Wootton, Robyn E %A Yanek, Lisa R %A Yao, Jie %A Yousri, Noha A %A Zhao, Wei %A Adeyemo, Adebowale A %A Afaq, Saima %A Aguilar-Salinas, Carlos Alberto %A Akiyama, Masato %A Albert, Matthew L %A Allison, Matthew A %A Alver, Maris %A Aung, Tin %A Azizi, Fereidoun %A Bentley, Amy R %A Boeing, Heiner %A Boerwinkle, Eric %A Borja, Judith B %A de Borst, Gert J %A Bottinger, Erwin P %A Broer, Linda %A Campbell, Harry %A Chanock, Stephen %A Chee, Miao-Li %A Chen, Guanjie %A Chen, Yii-der I %A Chen, Zhengming %A Chiu, Yen-Feng %A Cocca, Massimiliano %A Collins, Francis S %A Concas, Maria Pina %A Corley, Janie %A Cugliari, Giovanni %A van Dam, Rob M %A Damulina, Anna %A Daneshpour, Maryam S %A Day, Felix R %A Delgado, Graciela E %A Dhana, Klodian %A Doney, Alexander S F %A Dörr, Marcus %A Doumatey, Ayo P %A Dzimiri, Nduna %A Ebenesersdóttir, S Sunna %A Elliott, Joshua %A Elliott, Paul %A Ewert, Ralf %A Felix, Janine F %A Fischer, Krista %A Freedman, Barry I %A Girotto, Giorgia %A Goel, Anuj %A Gögele, Martin %A Goodarzi, Mark O %A Graff, Mariaelisa %A Granot-Hershkovitz, Einat %A Grodstein, Francine %A Guarrera, Simonetta %A Gudbjartsson, Daniel F %A Guity, Kamran %A Gunnarsson, Bjarni %A Guo, Yu %A Hagenaars, Saskia P %A Haiman, Christopher A %A Halevy, Avner %A Harris, Tamara B %A Hedayati, Mehdi %A van Heel, David A %A Hirata, Makoto %A Höfer, Imo %A Hsiung, Chao Agnes %A Huang, Jinyan %A Hung, Yi-Jen %A Ikram, M Arfan %A Jagadeesan, Anuradha %A Jousilahti, Pekka %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerrison, Nicola D %A Kessler, Thorsten %A Khaw, Kay-Tee %A Khor, Chiea Chuen %A de Kleijn, Dominique P V %A Koh, Woon-Puay %A Kolcic, Ivana %A Kraft, Peter %A Krämer, Bernhard K %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lawlor, Deborah A %A Lee, I-Te %A Lee, Wen-Jane %A Lerch, Markus M %A Li, Liming %A Liu, Jianjun %A Loh, Marie %A London, Stephanie J %A Loomis, Stephanie %A Lu, Yingchang %A Luan, Jian'an %A Mägi, Reedik %A Manichaikul, Ani W %A Manunta, Paolo %A Másson, Gísli %A Matoba, Nana %A Mei, Xue W %A Meisinger, Christa %A Meitinger, Thomas %A Mezzavilla, Massimo %A Milani, Lili %A Millwood, Iona Y %A Momozawa, Yukihide %A Moore, Amy %A Morange, Pierre-Emmanuel %A Moreno-Macias, Hortensia %A Mori, Trevor A %A Morrison, Alanna C %A Muka, Taulant %A Murakami, Yoshinori %A Murray, Alison D %A de Mutsert, Renée %A Mychaleckyj, Josyf C %A Nalls, Mike A %A Nauck, Matthias %A Neville, Matt J %A Nolte, Ilja M %A Ong, Ken K %A Orozco, Lorena %A Padmanabhan, Sandosh %A Pálsson, Gunnar %A Pankow, James S %A Pattaro, Cristian %A Pattie, Alison %A Polasek, Ozren %A Poulter, Neil %A Pramstaller, Peter P %A Quintana-Murci, Lluis %A Räikkönen, Katri %A Ralhan, Sarju %A Rao, Dabeeru C %A van Rheenen, Wouter %A Rich, Stephen S %A Ridker, Paul M %A Rietveld, Cornelius A %A Robino, Antonietta %A van Rooij, Frank J A %A Ruggiero, Daniela %A Saba, Yasaman %A Sabanayagam, Charumathi %A Sabater-Lleal, Maria %A Sala, Cinzia Felicita %A Salomaa, Veikko %A Sandow, Kevin %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sedaghati-Khayat, Bahareh %A Sennblad, Bengt %A van Setten, Jessica %A Sever, Peter J %A Sheu, Wayne H-H %A Shi, Yuan %A Shrestha, Smeeta %A Shukla, Sharvari Rahul %A Sigurdsson, Jon K %A Sikka, Timo Tonis %A Singh, Jai Rup %A Smith, Blair H %A Stančáková, Alena %A Stanton, Alice %A Starr, John M %A Stefansdottir, Lilja %A Straker, Leon %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Swertz, Morris A %A Taylor, Adele M %A Taylor, Kent D %A Terzikhan, Natalie %A Tham, Yih-Chung %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tillander, Annika %A Tracy, Russell P %A Tusié-Luna, Teresa %A Tzoulaki, Ioanna %A Vaccargiu, Simona %A Vangipurapu, Jagadish %A Veldink, Jan H %A Vitart, Veronique %A Völker, Uwe %A Vuoksimaa, Eero %A Wakil, Salma M %A Waldenberger, Melanie %A Wander, Gurpreet S %A Wang, Ya Xing %A Wareham, Nicholas J %A Wild, Sarah %A Yajnik, Chittaranjan S %A Yuan, Jian-Min %A Zeng, Lingyao %A Zhang, Liang %A Zhou, Jie %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Becker, Diane M %A Lehne, Benjamin %A Bennett, David A %A van den Berg, Leonard H %A Berndt, Sonja I %A Bharadwaj, Dwaipayan %A Bielak, Lawrence F %A Bochud, Murielle %A Boehnke, Mike %A Bouchard, Claude %A Bradfield, Jonathan P %A Brody, Jennifer A %A Campbell, Archie %A Carmi, Shai %A Caulfield, Mark J %A Cesarini, David %A Chambers, John C %A Chandak, Giriraj Ratan %A Cheng, Ching-Yu %A Ciullo, Marina %A Cornelis, Marilyn %A Cusi, Daniele %A Smith, George Davey %A Deary, Ian J %A Dorajoo, Rajkumar %A van Duijn, Cornelia M %A Ellinghaus, David %A Erdmann, Jeanette %A Eriksson, Johan G %A Evangelou, Evangelos %A Evans, Michele K %A Faul, Jessica D %A Feenstra, Bjarke %A Feitosa, Mary %A Foisy, Sylvain %A Franke, Andre %A Friedlander, Yechiel %A Gasparini, Paolo %A Gieger, Christian %A Gonzalez, Clicerio %A Goyette, Philippe %A Grant, Struan F A %A Griffiths, Lyn R %A Groop, Leif %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hakonarson, Hakon %A Hamsten, Anders %A van der Harst, Pim %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hochner, Hagit %A Huikuri, Heikki %A Hunt, Steven C %A Jaddoe, Vincent W V %A De Jager, Philip L %A Johannesson, Magnus %A Johansson, Asa %A Jonas, Jost B %A Jukema, J Wouter %A Junttila, Juhani %A Kaprio, Jaakko %A Kardia, Sharon L R %A Karpe, Fredrik %A Kumari, Meena %A Laakso, Markku %A van der Laan, Sander W %A Lahti, Jari %A Laudes, Matthias %A Lea, Rodney A %A Lieb, Wolfgang %A Lumley, Thomas %A Martin, Nicholas G %A März, Winfried %A Matullo, Giuseppe %A McCarthy, Mark I %A Medland, Sarah E %A Merriman, Tony R %A Metspalu, Andres %A Meyer, Brian F %A Mohlke, Karen L %A Montgomery, Grant W %A Mook-Kanamori, Dennis %A Munroe, Patricia B %A North, Kari E %A Nyholt, Dale R %A O'Connell, Jeffery R %A Ober, Carole %A Oldehinkel, Albertine J %A Palmas, Walter %A Palmer, Colin %A Pasterkamp, Gerard G %A Patin, Etienne %A Pennell, Craig E %A Perusse, Louis %A Peyser, Patricia A %A Pirastu, Mario %A Polderman, Tinca J C %A Porteous, David J %A Posthuma, Danielle %A Psaty, Bruce M %A Rioux, John D %A Rivadeneira, Fernando %A Rotimi, Charles %A Rotter, Jerome I %A Rudan, Igor %A den Ruijter, Hester M %A Sanghera, Dharambir K %A Sattar, Naveed %A Schmidt, Reinhold %A Schulze, Matthias B %A Schunkert, Heribert %A Scott, Robert A %A Shuldiner, Alan R %A Sim, Xueling %A Small, Neil %A Smith, Jennifer A %A Sotoodehnia, Nona %A Tai, E-Shyong %A Teumer, Alexander %A Timpson, Nicholas J %A Toniolo, Daniela %A Trégouët, David-Alexandre %A Tuomi, Tiinamaija %A Vollenweider, Peter %A Wang, Carol A %A Weir, David R %A Whitfield, John B %A Wijmenga, Cisca %A Wong, Tien-Yin %A Wright, John %A Yang, Jingyun %A Yu, Lei %A Zemel, Babette S %A Zonderman, Alan B %A Perola, Markus %A Magnusson, Patrik K E %A Uitterlinden, André G %A Kooner, Jaspal S %A Chasman, Daniel I %A Loos, Ruth J F %A Franceschini, Nora %A Franke, Lude %A Haley, Chris S %A Hayward, Caroline %A Walters, Robin G %A Perry, John R B %A Esko, Tõnu %A Helgason, Agnar %A Stefansson, Kari %A Joshi, Peter K %A Kubo, Michiaki %A Wilson, James F %X

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

%B Nat Commun %V 10 %P 4957 %8 2019 Oct 31 %G eng %N 1 %R 10.1038/s41467-019-12283-6 %0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Boerwinkle, Eric %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %X

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

%B Nature %V 586 %P 763-768 %8 2020 10 %G eng %N 7831 %R 10.1038/s41586-020-2819-2 %0 Journal Article %J Nat Commun %D 2020 %T Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. %A Ntalla, Ioanna %A Weng, Lu-Chen %A Cartwright, James H %A Hall, Amelia Weber %A Sveinbjornsson, Gardar %A Tucker, Nathan R %A Choi, Seung Hoan %A Chaffin, Mark D %A Roselli, Carolina %A Barnes, Michael R %A Mifsud, Borbala %A Warren, Helen R %A Hayward, Caroline %A Marten, Jonathan %A Cranley, James J %A Concas, Maria Pina %A Gasparini, Paolo %A Boutin, Thibaud %A Kolcic, Ivana %A Polasek, Ozren %A Rudan, Igor %A Araujo, Nathalia M %A Lima-Costa, Maria Fernanda %A Ribeiro, Antonio Luiz P %A Souza, Renan P %A Tarazona-Santos, Eduardo %A Giedraitis, Vilmantas %A Ingelsson, Erik %A Mahajan, Anubha %A Morris, Andrew P %A del Greco M, Fabiola %A Foco, Luisa %A Gögele, Martin %A Hicks, Andrew A %A Cook, James P %A Lind, Lars %A Lindgren, Cecilia M %A Sundström, Johan %A Nelson, Christopher P %A Riaz, Muhammad B %A Samani, Nilesh J %A Sinagra, Gianfranco %A Ulivi, Sheila %A Kähönen, Mika %A Mishra, Pashupati P %A Mononen, Nina %A Nikus, Kjell %A Caulfield, Mark J %A Dominiczak, Anna %A Padmanabhan, Sandosh %A Montasser, May E %A O'Connell, Jeff R %A Ryan, Kathleen %A Shuldiner, Alan R %A Aeschbacher, Stefanie %A Conen, David %A Risch, Lorenz %A Thériault, Sébastien %A Hutri-Kähönen, Nina %A Lehtimäki, Terho %A Lyytikäinen, Leo-Pekka %A Raitakari, Olli T %A Barnes, Catriona L K %A Campbell, Harry %A Joshi, Peter K %A Wilson, James F %A Isaacs, Aaron %A Kors, Jan A %A van Duijn, Cornelia M %A Huang, Paul L %A Gudnason, Vilmundur %A Harris, Tamara B %A Launer, Lenore J %A Smith, Albert V %A Bottinger, Erwin P %A Loos, Ruth J F %A Nadkarni, Girish N %A Preuss, Michael H %A Correa, Adolfo %A Mei, Hao %A Wilson, James %A Meitinger, Thomas %A Müller-Nurasyid, Martina %A Peters, Annette %A Waldenberger, Melanie %A Mangino, Massimo %A Spector, Timothy D %A Rienstra, Michiel %A van de Vegte, Yordi J %A van der Harst, Pim %A Verweij, Niek %A Kääb, Stefan %A Schramm, Katharina %A Sinner, Moritz F %A Strauch, Konstantin %A Cutler, Michael J %A Fatkin, Diane %A London, Barry %A Olesen, Morten %A Roden, Dan M %A Benjamin Shoemaker, M %A Gustav Smith, J %A Biggs, Mary L %A Bis, Joshua C %A Brody, Jennifer A %A Psaty, Bruce M %A Rice, Kenneth %A Sotoodehnia, Nona %A De Grandi, Alessandro %A Fuchsberger, Christian %A Pattaro, Cristian %A Pramstaller, Peter P %A Ford, Ian %A Wouter Jukema, J %A Macfarlane, Peter W %A Trompet, Stella %A Dörr, Marcus %A Felix, Stephan B %A Völker, Uwe %A Weiss, Stefan %A Havulinna, Aki S %A Jula, Antti %A Sääksjärvi, Katri %A Salomaa, Veikko %A Guo, Xiuqing %A Heckbert, Susan R %A Lin, Henry J %A Rotter, Jerome I %A Taylor, Kent D %A Yao, Jie %A de Mutsert, Renée %A Maan, Arie C %A Mook-Kanamori, Dennis O %A Noordam, Raymond %A Cucca, Francesco %A Ding, Jun %A Lakatta, Edward G %A Qian, Yong %A Tarasov, Kirill V %A Levy, Daniel %A Lin, Honghuang %A Newton-Cheh, Christopher H %A Lunetta, Kathryn L %A Murray, Alison D %A Porteous, David J %A Smith, Blair H %A Stricker, Bruno H %A Uitterlinden, Andre %A van den Berg, Marten E %A Haessler, Jeffrey %A Jackson, Rebecca D %A Kooperberg, Charles %A Peters, Ulrike %A Reiner, Alexander P %A Whitsel, Eric A %A Alonso, Alvaro %A Arking, Dan E %A Boerwinkle, Eric %A Ehret, Georg B %A Soliman, Elsayed Z %A Avery, Christy L %A Gogarten, Stephanie M %A Kerr, Kathleen F %A Laurie, Cathy C %A Seyerle, Amanda A %A Stilp, Adrienne %A Assa, Solmaz %A Abdullah Said, M %A Yldau van der Ende, M %A Lambiase, Pier D %A Orini, Michele %A Ramirez, Julia %A Van Duijvenboden, Stefan %A Arnar, David O %A Gudbjartsson, Daniel F %A Holm, Hilma %A Sulem, Patrick %A Thorleifsson, Gudmar %A Thorolfsdottir, Rosa B %A Thorsteinsdottir, Unnur %A Benjamin, Emelia J %A Tinker, Andrew %A Stefansson, Kari %A Ellinor, Patrick T %A Jamshidi, Yalda %A Lubitz, Steven A %A Munroe, Patricia B %X

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

%B Nat Commun %V 11 %P 2542 %8 2020 May 21 %G eng %N 1 %R 10.1038/s41467-020-15706-x %0 Journal Article %J Nat Commun %D 2021 %T Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. %A Natarajan, Pradeep %A Pampana, Akhil %A Graham, Sarah E %A Ruotsalainen, Sanni E %A Perry, James A %A de Vries, Paul S %A Broome, Jai G %A Pirruccello, James P %A Honigberg, Michael C %A Aragam, Krishna %A Wolford, Brooke %A Brody, Jennifer A %A Antonacci-Fulton, Lucinda %A Arden, Moscati %A Aslibekyan, Stella %A Assimes, Themistocles L %A Ballantyne, Christie M %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Do, Ron %A Doddapaneni, Harsha %A Emery, Leslie S %A Hung, Yi-Jen %A Irvin, Marguerite R %A Khan, Alyna T %A Lange, Leslie %A Lee, Jiwon %A Lemaitre, Rozenn N %A Martin, Lisa W %A Metcalf, Ginger %A Montasser, May E %A Moon, Jee-Young %A Muzny, Donna %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peralta, Juan M %A Peyser, Patricia A %A Stilp, Adrienne M %A Tsai, Michael %A Wang, Fei Fei %A Weeks, Daniel E %A Yanek, Lisa R %A Wilson, James G %A Abecasis, Goncalo %A Arnett, Donna K %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Chang, Yi-Cheng %A Chen, Yii-der I %A Choi, Won Jung %A Correa, Adolfo %A Curran, Joanne E %A Daly, Mark J %A Dutcher, Susan K %A Ellinor, Patrick T %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A He, Jiang %A Hveem, Kristian %A Jarvik, Gail P %A Kaplan, Robert C %A Kardia, Sharon L R %A Kenny, Eimear %A Kim, Ryan W %A Kooperberg, Charles %A Laurie, Cathy C %A Lee, Seonwook %A Lloyd-Jones, Don M %A Loos, Ruth J F %A Lubitz, Steven A %A Mathias, Rasika A %A Martinez, Karine A Viaud %A McGarvey, Stephen T %A Mitchell, Braxton D %A Nickerson, Deborah A %A North, Kari E %A Palotie, Aarno %A Park, Cheol Joo %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Seo, Daekwan %A Seo, Jeong-Sun %A Smith, Albert V %A Tracy, Russell P %A Vasan, Ramachandran S %A Kathiresan, Sekar %A Cupples, L Adrienne %A Rotter, Jerome I %A Morrison, Alanna C %A Rich, Stephen S %A Ripatti, Samuli %A Willer, Cristen %A Peloso, Gina M %X

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 × 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 × 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 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.

%B Nat Commun %V 12 %P 2182 %8 2021 04 12 %G eng %N 1 %R 10.1038/s41467-021-22339-1 %0 Journal Article %J Nature %D 2021 %T Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. %A Taliun, Daniel %A Harris, Daniel N %A Kessler, Michael D %A Carlson, Jedidiah %A Szpiech, Zachary A %A Torres, Raul %A Taliun, Sarah A Gagliano %A Corvelo, André %A Gogarten, Stephanie M %A Kang, Hyun Min %A Pitsillides, Achilleas N %A LeFaive, Jonathon %A Lee, Seung-Been %A Tian, Xiaowen %A Browning, Brian L %A Das, Sayantan %A Emde, Anne-Katrin %A Clarke, Wayne E %A Loesch, Douglas P %A Shetty, Amol C %A Blackwell, Thomas W %A Smith, Albert V %A Wong, Quenna %A Liu, Xiaoming %A Conomos, Matthew P %A Bobo, Dean M %A Aguet, Francois %A Albert, Christine %A Alonso, Alvaro %A Ardlie, Kristin G %A Arking, Dan E %A Aslibekyan, Stella %A Auer, Paul L %A Barnard, John %A Barr, R Graham %A Barwick, Lucas %A Becker, Lewis C %A Beer, Rebecca L %A Benjamin, Emelia J %A Bielak, Lawrence F %A Blangero, John %A Boehnke, Michael %A Bowden, Donald W %A Brody, Jennifer A %A Burchard, Esteban G %A Cade, Brian E %A Casella, James F %A Chalazan, Brandon %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Cho, Michael H %A Choi, Seung Hoan %A Chung, Mina K %A Clish, Clary B %A Correa, Adolfo %A Curran, Joanne E %A Custer, Brian %A Darbar, Dawood %A Daya, Michelle %A de Andrade, Mariza %A DeMeo, Dawn L %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Eng, Celeste %A Fatkin, Diane %A Fingerlin, Tasha %A Forer, Lukas %A Fornage, Myriam %A Franceschini, Nora %A Fuchsberger, Christian %A Fullerton, Stephanie M %A Germer, Soren %A Gladwin, Mark T %A Gottlieb, Daniel J %A Guo, Xiuqing %A Hall, Michael E %A He, Jiang %A Heard-Costa, Nancy L %A Heckbert, Susan R %A Irvin, Marguerite R %A Johnsen, Jill M %A Johnson, Andrew D %A Kaplan, Robert %A Kardia, Sharon L R %A Kelly, Tanika %A Kelly, Shannon %A Kenny, Eimear E %A Kiel, Douglas P %A Klemmer, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Köttgen, Anna %A Lange, Leslie A %A Lasky-Su, Jessica %A Levy, Daniel %A Lin, Xihong %A Lin, Keng-Han %A Liu, Chunyu %A Loos, Ruth J F %A Garman, Lori %A Gerszten, Robert %A Lubitz, Steven A %A Lunetta, Kathryn L %A Mak, Angel C Y %A Manichaikul, Ani %A Manning, Alisa K %A Mathias, Rasika A %A McManus, David D %A McGarvey, Stephen T %A Meigs, James B %A Meyers, Deborah A %A Mikulla, Julie L %A Minear, Mollie A %A Mitchell, Braxton D %A Mohanty, Sanghamitra %A Montasser, May E %A Montgomery, Courtney %A Morrison, Alanna C %A Murabito, Joanne M %A Natale, Andrea %A Natarajan, Pradeep %A Nelson, Sarah C %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pankratz, Nathan %A Peloso, Gina M %A Peyser, Patricia A %A Pleiness, Jacob %A Post, Wendy S %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Roden, Dan %A Rotter, Jerome I %A Ruczinski, Ingo %A Sarnowski, Chloe %A Schoenherr, Sebastian %A Schwartz, David A %A Seo, Jeong-Sun %A Seshadri, Sudha %A Sheehan, Vivien A %A Sheu, Wayne H %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stilp, Adrienne M %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn %A Thornton, Timothy A %A Tracy, Russell P %A Van Den Berg, David J %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Vrieze, Scott %A Weeks, Daniel E %A Weir, Bruce S %A Weiss, Scott T %A Weng, Lu-Chen %A Willer, Cristen J %A Zhang, Yingze %A Zhao, Xutong %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Boerwinkle, Eric %A Gabriel, Stacey %A Gibbs, Richard %A Rice, Kenneth M %A Rich, Stephen S %A Silverman, Edwin K %A Qasba, Pankaj %A Gan, Weiniu %A Papanicolaou, George J %A Nickerson, Deborah A %A Browning, Sharon R %A Zody, Michael C %A Zöllner, Sebastian %A Wilson, James G %A Cupples, L Adrienne %A Laurie, Cathy C %A Jaquish, Cashell E %A Hernandez, Ryan D %A O'Connor, Timothy D %A Abecasis, Goncalo R %X

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

%B Nature %V 590 %P 290-299 %8 2021 02 %G eng %N 7845 %R 10.1038/s41586-021-03205-y %0 Journal Article %J Am J Epidemiol %D 2021 %T A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. %A Stilp, Adrienne M %A Emery, Leslie S %A Broome, Jai G %A Buth, Erin J %A Khan, Alyna T %A Laurie, Cecelia A %A Wang, Fei Fei %A Wong, Quenna %A Chen, Dongquan %A D'Augustine, Catherine M %A Heard-Costa, Nancy L %A Hohensee, Chancellor R %A Johnson, William Craig %A Juarez, Lucia D %A Liu, Jingmin %A Mutalik, Karen M %A Raffield, Laura M %A Wiggins, Kerri L %A de Vries, Paul S %A Kelly, Tanika N %A Kooperberg, Charles %A Natarajan, Pradeep %A Peloso, Gina M %A Peyser, Patricia A %A Reiner, Alex P %A Arnett, Donna K %A Aslibekyan, Stella %A Barnes, Kathleen C %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Chen, Ming-Huei %A Correa, Adolfo %A Cupples, L Adrienne %A de Andrade, Mariza %A Ellinor, Patrick T %A Fornage, Myriam %A Franceschini, Nora %A Gan, Weiniu %A Ganesh, Santhi K %A Graffelman, Jan %A Grove, Megan L %A Guo, Xiuqing %A Hawley, Nicola L %A Hsu, Wan-Ling %A Jackson, Rebecca D %A Jaquish, Cashell E %A Johnson, Andrew D %A Kardia, Sharon L R %A Kelly, Shannon %A Lee, Jiwon %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A North, Kari E %A Nouraie, Seyed Mehdi %A Oelsner, Elizabeth C %A Pankratz, Nathan %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Weeks, Daniel E %A Weiss, Scott T %A Wilson, Carla G %A Yanek, Lisa R %A Psaty, Bruce M %A Heckbert, Susan R %A Laurie, Cathy C %X

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute's Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

%B Am J Epidemiol %8 2021 Apr 16 %G eng %R 10.1093/aje/kwab115 %0 Journal Article %J Nat Methods %D 2022 %T A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. %A Li, Zilin %A Li, Xihao %A Zhou, Hufeng %A Gaynor, Sheila M %A Selvaraj, Margaret Sunitha %A Arapoglou, Theodore %A Quick, Corbin %A Liu, Yaowu %A Chen, Han %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Auer, Paul L %A Bielak, Lawrence F %A Bis, Joshua C %A Blackwell, Thomas W %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Conomos, Matthew P %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Franceschini, Nora %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Lin, Bridget M %A Manichaikul, Ani %A Manning, Alisa K %A Martin, Lisa W %A Mathias, Rasika A %A Meigs, James B %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Smith, Jennifer A %A Taylor, Kent D %A Taub, Margaret A %A Vasan, Ramachandran S %A Weeks, Daniel E %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Willer, Cristen J %A Natarajan, Pradeep %A Peloso, Gina M %A Lin, Xihong %K Genetic Variation %K Genome %K Genome-Wide Association Study %K Humans %K Phenotype %K Whole Genome Sequencing %X

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

%B Nat Methods %V 19 %P 1599-1611 %8 2022 Dec %G eng %N 12 %R 10.1038/s41592-022-01640-x %0 Journal Article %J Hypertension %D 2022 %T Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. %A Kelly, Tanika N %A Sun, Xiao %A He, Karen Y %A Brown, Michael R %A Taliun, Sarah A Gagliano %A Hellwege, Jacklyn N %A Irvin, Marguerite R %A Mi, Xuenan %A Brody, Jennifer A %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A de Vries, Paul S %A Gao, Yan %A Moscati, Arden %A Nadkarni, Girish N %A Yanek, Lisa R %A Elfassy, Tali %A Smith, Jennifer A %A Chung, Ren-Hua %A Beitelshees, Amber L %A Patki, Amit %A Aslibekyan, Stella %A Blobner, Brandon M %A Peralta, Juan M %A Assimes, Themistocles L %A Palmas, Walter R %A Liu, Chunyu %A Bress, Adam P %A Huang, Zhijie %A Becker, Lewis C %A Hwa, Chii-Min %A O'Connell, Jeffrey R %A Carlson, Jenna C %A Warren, Helen R %A Das, Sayantan %A Giri, Ayush %A Martin, Lisa W %A Craig Johnson, W %A Fox, Ervin R %A Bottinger, Erwin P %A Razavi, Alexander C %A Vaidya, Dhananjay %A Chuang, Lee-Ming %A Chang, Yen-Pei C %A Naseri, Take %A Jain, Deepti %A Kang, Hyun Min %A Hung, Adriana M %A Srinivasasainagendra, Vinodh %A Snively, Beverly M %A Gu, Dongfeng %A Montasser, May E %A Reupena, Muagututi'a Sefuiva %A Heavner, Benjamin D %A LeFaive, Jonathon %A Hixson, James E %A Rice, Kenneth M %A Wang, Fei Fei %A Nielsen, Jonas B %A Huang, Jianfeng %A Khan, Alyna T %A Zhou, Wei %A Nierenberg, Jovia L %A Laurie, Cathy C %A Armstrong, Nicole D %A Shi, Mengyao %A Pan, Yang %A Stilp, Adrienne M %A Emery, Leslie %A Wong, Quenna %A Hawley, Nicola L %A Minster, Ryan L %A Curran, Joanne E %A Munroe, Patricia B %A Weeks, Daniel E %A North, Kari E %A Tracy, Russell P %A Kenny, Eimear E %A Shimbo, Daichi %A Chakravarti, Aravinda %A Rich, Stephen S %A Reiner, Alex P %A Blangero, John %A Redline, Susan %A Mitchell, Braxton D %A Rao, Dabeeru C %A Ida Chen, Yii-Der %A Kardia, Sharon L R %A Kaplan, Robert C %A Mathias, Rasika A %A He, Jiang %A Psaty, Bruce M %A Fornage, Myriam %A Loos, Ruth J F %A Correa, Adolfo %A Boerwinkle, Eric %A Rotter, Jerome I %A Kooperberg, Charles %A Edwards, Todd L %A Abecasis, Goncalo R %A Zhu, Xiaofeng %A Levy, Daniel %A Arnett, Donna K %A Morrison, Alanna C %X

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5×10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99×10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18×10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28×10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1×10 and <1×10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

%B Hypertension %P 101161HYPERTENSIONAHA12219324 %8 2022 Jun 02 %G eng %R 10.1161/HYPERTENSIONAHA.122.19324 %0 Journal Article %J Am J Hum Genet %D 2022 %T Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. %A Hindy, George %A Dornbos, Peter %A Chaffin, Mark D %A Liu, Dajiang J %A Wang, Minxian %A Selvaraj, Margaret Sunitha %A Zhang, David %A Park, Joseph %A Aguilar-Salinas, Carlos A %A Antonacci-Fulton, Lucinda %A Ardissino, Diego %A Arnett, Donna K %A Aslibekyan, Stella %A Atzmon, Gil %A Ballantyne, Christie M %A Barajas-Olmos, Francisco %A Barzilai, Nir %A Becker, Lewis C %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bottinger, Erwin %A Bowden, Donald W %A Bown, Matthew J %A Brody, Jennifer A %A Broome, Jai G %A Burtt, Noel P %A Cade, Brian E %A Centeno-Cruz, Federico %A Chan, Edmund %A Chang, Yi-Cheng %A Chen, Yii-der I %A Cheng, Ching-Yu %A Choi, Won Jung %A Chowdhury, Rajiv %A Contreras-Cubas, Cecilia %A Córdova, Emilio J %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Danesh, John %A de Vries, Paul S %A DeFronzo, Ralph A %A Doddapaneni, Harsha %A Duggirala, Ravindranath %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Florez, Jose C %A Fornage, Myriam %A Freedman, Barry I %A Fuster, Valentin %A Garay-Sevilla, Ma Eugenia %A García-Ortiz, Humberto %A Germer, Soren %A Gibbs, Richard A %A Gieger, Christian %A Glaser, Benjamin %A Gonzalez, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Graff, Mariaelisa %A Graham, Sarah E %A Grarup, Niels %A Groop, Leif C %A Guo, Xiuqing %A Gupta, Namrata %A Han, Sohee %A Hanis, Craig L %A Hansen, Torben %A He, Jiang %A Heard-Costa, Nancy L %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Irvin, Marguerite R %A Islas-Andrade, Sergio %A Jarvik, Gail P %A Kang, Hyun Min %A Kardia, Sharon L R %A Kelly, Tanika %A Kenny, Eimear E %A Khan, Alyna T %A Kim, Bong-Jo %A Kim, Ryan W %A Kim, Young Jin %A Koistinen, Heikki A %A Kooperberg, Charles %A Kuusisto, Johanna %A Kwak, Soo Heon %A Laakso, Markku %A Lange, Leslie A %A Lee, Jiwon %A Lee, Juyoung %A Lee, Seonwook %A Lehman, Donna M %A Lemaitre, Rozenn N %A Linneberg, Allan %A Liu, Jianjun %A Loos, Ruth J F %A Lubitz, Steven A %A Lyssenko, Valeriya %A Ma, Ronald C W %A Martin, Lisa Warsinger %A Martínez-Hernández, Angélica %A Mathias, Rasika A %A McGarvey, Stephen T %A McPherson, Ruth %A Meigs, James B %A Meitinger, Thomas %A Melander, Olle %A Mendoza-Caamal, Elvia %A Metcalf, Ginger A %A Mi, Xuenan %A Mohlke, Karen L %A Montasser, May E %A Moon, Jee-Young %A Moreno-Macias, Hortensia %A Morrison, Alanna C %A Muzny, Donna M %A Nelson, Sarah C %A Nilsson, Peter M %A O'Connell, Jeffrey R %A Orho-Melander, Marju %A Orozco, Lorena %A Palmer, Colin N A %A Palmer, Nicholette D %A Park, Cheol Joo %A Park, Kyong Soo %A Pedersen, Oluf %A Peralta, Juan M %A Peyser, Patricia A %A Post, Wendy S %A Preuss, Michael %A Psaty, Bruce M %A Qi, Qibin %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Rich, Stephen S %A Samani, Nilesh %A Schunkert, Heribert %A Schurmann, Claudia %A Seo, Daekwan %A Seo, Jeong-Sun %A Sim, Xueling %A Sladek, Rob %A Small, Kerrin S %A So, Wing Yee %A Stilp, Adrienne M %A Tai, E Shyong %A Tam, Claudia H T %A Taylor, Kent D %A Teo, Yik Ying %A Thameem, Farook %A Tomlinson, Brian %A Tsai, Michael Y %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A van Dam, Rob M %A Vasan, Ramachandran S %A Viaud Martinez, Karine A %A Wang, Fei Fei %A Wang, Xuzhi %A Watkins, Hugh %A Weeks, Daniel E %A Wilson, James G %A Witte, Daniel R %A Wong, Tien-Yin %A Yanek, Lisa R %A Kathiresan, Sekar %A Rader, Daniel J %A Rotter, Jerome I %A Boehnke, Michael %A McCarthy, Mark I %A Willer, Cristen J %A Natarajan, Pradeep %A Flannick, Jason A %A Khera, Amit V %A Peloso, Gina M %K Alleles %K Blood Glucose %K Case-Control Studies %K Computational Biology %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Predisposition to Disease %K Genetic Variation %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Lipids %K Liver %K Molecular Sequence Annotation %K Multifactorial Inheritance %K Open Reading Frames %K Phenotype %K Polymorphism, Single Nucleotide %X

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

%B Am J Hum Genet %V 109 %P 81-96 %8 2022 01 06 %G eng %N 1 %R 10.1016/j.ajhg.2021.11.021 %0 Journal Article %J Commun Biol %D 2022 %T Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. %A DiCorpo, Daniel %A Gaynor, Sheila M %A Russell, Emily M %A Westerman, Kenneth E %A Raffield, Laura M %A Majarian, Timothy D %A Wu, Peitao %A Sarnowski, Chloe %A Highland, Heather M %A Jackson, Anne %A Hasbani, Natalie R %A de Vries, Paul S %A Brody, Jennifer A %A Hidalgo, Bertha %A Guo, Xiuqing %A Perry, James A %A O'Connell, Jeffrey R %A Lent, Samantha %A Montasser, May E %A Cade, Brian E %A Jain, Deepti %A Wang, Heming %A D'Oliveira Albanus, Ricardo %A Varshney, Arushi %A Yanek, Lisa R %A Lange, Leslie %A Palmer, Nicholette D %A Almeida, Marcio %A Peralta, Juan M %A Aslibekyan, Stella %A Baldridge, Abigail S %A Bertoni, Alain G %A Bielak, Lawrence F %A Chen, Chung-Shiuan %A Chen, Yii-Der Ida %A Choi, Won Jung %A Goodarzi, Mark O %A Floyd, James S %A Irvin, Marguerite R %A Kalyani, Rita R %A Kelly, Tanika N %A Lee, Seonwook %A Liu, Ching-Ti %A Loesch, Douglas %A Manson, JoAnn E %A Minster, Ryan L %A Naseri, Take %A Pankow, James S %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Selvin, Elizabeth %A Smith, Jennifer A %A Weeks, Daniel E %A Xu, Huichun %A Yao, Jie %A Zhao, Wei %A Parker, Stephen %A Alonso, Alvaro %A Arnett, Donna K %A Blangero, John %A Boerwinkle, Eric %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Duggirala, Ravindranath %A He, Jiang %A Heckbert, Susan R %A Kardia, Sharon L R %A Kim, Ryan W %A Kooperberg, Charles %A Liu, Simin %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A Morrison, Alanna C %A Peyser, Patricia A %A Psaty, Bruce M %A Redline, Susan %A Shuldiner, Alan R %A Taylor, Kent D %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Florez, Jose C %A Wilson, James G %A Sladek, Robert %A Rich, Stephen S %A Rotter, Jerome I %A Lin, Xihong %A Dupuis, Josée %A Meigs, James B %A Wessel, Jennifer %A Manning, Alisa K %K Diabetes Mellitus, Type 2 %K Fasting %K Glucose %K Humans %K Insulin %K National Heart, Lung, and Blood Institute (U.S.) %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Precision Medicine %K Receptors, Immunologic %K United States %X

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

%B Commun Biol %V 5 %P 756 %8 2022 07 28 %G eng %N 1 %R 10.1038/s42003-022-03702-4 %0 Journal Article %J medRxiv %D 2023 %T Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. %A Georgakis, Marios K %A Malik, Rainer %A Hasbani, Natalie R %A Shakt, Gabrielle %A Morrison, Alanna C %A Tsao, Noah L %A Judy, Renae %A Mitchell, Braxton D %A Xu, Huichun %A Montasser, May E %A Do, Ron %A Kenny, Eimear E %A Loos, Ruth J F %A Terry, James G %A Carr, John Jeffrey %A Bis, Joshua C %A Psaty, Bruce M %A Longstreth, W T %A Young, Kendra A %A Lutz, Sharon M %A Cho, Michael H %A Broome, Jai %A Khan, Alyna T %A Wang, Fei Fei %A Heard-Costa, Nancy %A Seshadri, Sudha %A Vasan, Ramachandran S %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Yanek, Lisa R %A Kral, Brian G %A Becker, Lewis C %A Peyser, Patricia A %A Bielak, Lawrence F %A Ammous, Farah %A Carson, April P %A Hall, Michael E %A Raffield, Laura M %A Rich, Stephen S %A Post, Wendy S %A Tracy, Russel P %A Taylor, Kent D %A Guo, Xiuqing %A Mahaney, Michael C %A Curran, Joanne E %A Blangero, John %A Clarke, Shoa L %A Haessler, Jeffrey W %A Hu, Yao %A Assimes, Themistocles L %A Kooperberg, Charles %A Damrauer, Scott M %A Rotter, Jerome I %A de Vries, Paul S %A Dichgans, Martin %X

BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.

METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.

RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95%CI: 0.39-0.96; OR : 0.64 95%CI: 0.34-1.19; OR : 0.64 95%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.

CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

%B medRxiv %8 2023 Aug 16 %G eng %R 10.1101/2023.08.14.23294063 %0 Journal Article %J Nat Genet %D 2023 %T Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies. %A Li, Xihao %A Quick, Corbin %A Zhou, Hufeng %A Gaynor, Sheila M %A Liu, Yaowu %A Chen, Han %A Selvaraj, Margaret Sunitha %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Haessler, Jeffrey %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Manichaikul, Ani %A Martin, Lisa W %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Sitlani, Colleen M %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Willer, Cristen J %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Natarajan, Pradeep %A Peloso, Gina M %A Li, Zilin %A Lin, Xihong %K Exome Sequencing %K Genome-Wide Association Study %K Lipids %K Phenotype %K Whole Genome Sequencing %X

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

%B Nat Genet %V 55 %P 154-164 %8 2023 Jan %G eng %N 1 %R 10.1038/s41588-022-01225-6 %0 Journal Article %J medRxiv %D 2023 %T Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. %A Wang, Yuxuan %A Selvaraj, Margaret Sunitha %A Li, Xihao %A Li, Zilin %A Holdcraft, Jacob A %A Arnett, Donna K %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Cade, Brian E %A Carlson, Jenna C %A Carson, April P %A Chen, Yii-Der Ida %A Curran, Joanne E %A de Vries, Paul S %A Dutcher, Susan K %A Ellinor, Patrick T %A Floyd, James S %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A Guo, Xiuqing %A He, Jiang %A Heard-Costa, Nancy %A Hildalgo, Bertha %A Hou, Lifang %A Irvin, Marguerite R %A Joehanes, Roby %A Kaplan, Robert C %A Kardia, Sharon Lr %A Kelly, Tanika N %A Kim, Ryan %A Kooperberg, Charles %A Kral, Brian G %A Levy, Daniel %A Li, Changwei %A Liu, Chunyu %A Lloyd-Jone, Don %A Loos, Ruth Jf %A Mahaney, Michael C %A Martin, Lisa W %A Mathias, Rasika A %A Minster, Ryan L %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Murabito, Joanne M %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Rao, Dabeeru C %A Redline, Susan %A Reiner, Alexander P %A Rich, Stephen S %A Ruepena, Muagututi'a Sefuiva %A Sheu, Wayne H-H %A Smith, Jennifer A %A Smith, Albert %A Tiwari, Hemant K %A Tsai, Michael Y %A Viaud-Martinez, Karine A %A Wang, Zhe %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Lin, Xihong %A Natarajan, Pradeep %A Peloso, Gina M %X

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

%B medRxiv %8 2023 Jun 29 %G eng %R 10.1101/2023.06.28.23291966 %0 Journal Article %J bioRxiv %D 2023 %T A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies. %A Li, Xihao %A Chen, Han %A Selvaraj, Margaret Sunitha %A Van Buren, Eric %A Zhou, Hufeng %A Wang, Yuxuan %A Sun, Ryan %A McCaw, Zachary R %A Yu, Zhi %A Arnett, Donna K %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Carson, April P %A Carlson, Jenna C %A Chami, Nathalie %A Chen, Yii-Der Ida %A Curran, Joanne E %A de Vries, Paul S %A Fornage, Myriam %A Franceschini, Nora %A Freedman, Barry I %A Gu, Charles %A Heard-Costa, Nancy L %A He, Jiang %A Hou, Lifang %A Hung, Yi-Jen %A Irvin, Marguerite R %A Kaplan, Robert C %A Kardia, Sharon L R %A Kelly, Tanika %A Konigsberg, Iain %A Kooperberg, Charles %A Kral, Brian G %A Li, Changwei %A Loos, Ruth J F %A Mahaney, Michael C %A Martin, Lisa W %A Mathias, Rasika A %A Minster, Ryan L %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Rich, Stephen S %A Sitlani, Colleen M %A Smith, Jennifer A %A Taylor, Kent D %A Tiwari, Hemant %A Vasan, Ramachandran S %A Wang, Zhe %A Yanek, Lisa R %A Yu, Bing %A Rice, Kenneth M %A Rotter, Jerome I %A Peloso, Gina M %A Natarajan, Pradeep %A Li, Zilin %A Liu, Zhonghua %A Lin, Xihong %X

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

%B bioRxiv %8 2023 Nov 02 %G eng %R 10.1101/2023.10.30.564764 %0 Journal Article %J Circ Genom Precis Med %D 2023 %T Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis. %A Hasbani, Natalie R %A Westerman, Kenneth E %A Heon Kwak, Soo %A Chen, Han %A Li, Xihao %A DiCorpo, Daniel %A Wessel, Jennifer %A Bis, Joshua C %A Sarnowski, Chloe %A Wu, Peitao %A Bielak, Lawrence F %A Guo, Xiuqing %A Heard-Costa, Nancy %A Kinney, Gregory %A Mahaney, Michael C %A Montasser, May E %A Palmer, Nicholette D %A Raffield, Laura M %A Terry, James G %A Yanek, Lisa R %A Bon, Jessica %A Bowden, Donald W %A Brody, Jennifer A %A Duggirala, Ravindranath %A Jacobs, David R %A Kalyani, Rita R %A Lange, Leslie A %A Mitchell, Braxton D %A Smith, Jennifer A %A Taylor, Kent D %A Carson, April %A Curran, Joanne E %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Gibbs, Richard A %A Gupta, Namrata %A Kardia, Sharon L R %A Kral, Brian G %A Momin, Zeineen %A Newman, Anne B %A Post, Wendy S %A Viaud-Martinez, Karine A %A Young, Kendra A %A Becker, Lewis C %A Bertoni, Alain %A Blangero, John %A Carr, John J %A Pratte, Katherine %A Psaty, Bruce M %A Rich, Stephen S %A Wu, Joseph C %A Malhotra, Rajeev %A Peyser, Patricia A %A Morrison, Alanna C %A Vasan, Ramachandran S %A Lin, Xihong %A Rotter, Jerome I %A Meigs, James B %A Manning, Alisa K %A de Vries, Paul S %X

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

RESULTS: Using a Bonferroni-corrected significance threshold of <1.6×10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

%B Circ Genom Precis Med %P e004176 %8 2023 Nov 28 %G eng %R 10.1161/CIRCGEN.123.004176 %0 Journal Article %J Front Genet %D 2023 %T Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program. %A Armstrong, Nicole D %A Srinivasasainagendra, Vinodh %A Ammous, Farah %A Assimes, Themistocles L %A Beitelshees, Amber L %A Brody, Jennifer %A Cade, Brian E %A Ida Chen, Yii-Der %A Chen, Han %A de Vries, Paul S %A Floyd, James S %A Franceschini, Nora %A Guo, Xiuqing %A Hellwege, Jacklyn N %A House, John S %A Hwu, Chii-Min %A Kardia, Sharon L R %A Lange, Ethan M %A Lange, Leslie A %A McDonough, Caitrin W %A Montasser, May E %A O'Connell, Jeffrey R %A Shuey, Megan M %A Sun, Xiao %A Tanner, Rikki M %A Wang, Zhe %A Zhao, Wei %A Carson, April P %A Edwards, Todd L %A Kelly, Tanika N %A Kenny, Eimear E %A Kooperberg, Charles %A Loos, Ruth J F %A Morrison, Alanna C %A Motsinger-Reif, Alison %A Psaty, Bruce M %A Rao, Dabeeru C %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Jennifer A %A Smith, Albert V %A Irvin, Marguerite R %A Arnett, Donna K %X

Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

%B Front Genet %V 14 %P 1278215 %8 2023 %G eng %R 10.3389/fgene.2023.1278215