Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TGrich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Genetics |
| Vol/bind | 49 |
| Udgave nummer | 12 |
| Sider (fra-til) | 1758-1766 |
| Antal sider | 9 |
| ISSN | 1061-4036 |
| DOI | |
| Status | Udgivet - 1 dec. 2017 |
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Exome-wide association study of plasma lipids in >300,000 individuals. / Liu, Dajiang J.; Peloso, Gina M.; Yu, Haojie; Butterworth, Adam S.; Wang, Xiao; Mahajan, Anubha; Saleheen, Danish; Emdin, Connor; Alam, Dewan; Alves, Alexessander Couto; Amouyel, Philippe; Angelantonio, Emanuele DI; Arveiler, Dominique; Assimes, Themistocles L.; Auer, Paul L.; Baber, Usman; Ballantyne, Christie M.; Bang, Lia E.; Benn, Marianne; Bis, Joshua C.; Boehnke, Michael; Boerwinkle, Eric; Bork-Jensen, Jette; Bottinger, Erwin P.; Brandslund, Ivan; Brown, Morris; Busonero, Fabio; Caulfield, Mark J.; Chambers, John C.; Chasman, Daniel I.; Chen, Y. Eugene; Chen, Yii Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y.; Connell, John M.; Cucca, Francesco; Cupples, L. Adrienne; Damrauer, Scott M.; Davies, Gail; Deary, Ian J.; Dedoussis, George; Denny, Joshua C.; Dominiczak, Anna; Dubé, Marie Pierre; Ebeling, Tapani; Eiriksdottir, Gudny; Esko, Toñu; Farmaki, Aliki Eleni; Feitosa, Mary F.; Ferrario, Marco; Ferrieres, Jean; Ford, Ian; Fornage, Myriam; Franks, Paul W.; Frayling, Timothy M.; Frikke-Schmidt, Ruth; Fritsche, Lars G.; Frossard, Philippe; Fuster, Valentin; Ganesh, Santhi K.; Gao, Wei; Garcia, Melissa E.; Gieger, Christian; Giulianini, Franco; Goodarzi, Mark O.; Grallert, Harald; Grarup, Niels; Groop, Leif; Grove, Megan L.; Gudnason, Vilmundur; Hansen, Torben; Harris, Tamara B.; Hayward, Caroline; Hirschhorn, Joel N.; Holmen, Oddgeir L.; Huffman, Jennifer; Huo, Yong; Hveem, Kristian; Jabeen, Sehrish; Jackson, Anne U.; Jakobsdottir, Johanna; Jarvelin, Marjo Riitta; Jensen, Gorm B.; Jørgensen, Marit E.; Jukema, J. Wouter; Justesen, Johanne M.; Kamstrup, Pia R.; Kanoni, Stavroula; Karpe, Fredrik; Kee, Frank; Khera, Amit V.; Klarin, Derek; Koistinen, Heikki A.; Kooner, Jaspal S.; Kooperberg, Charles; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo; Langenberg, Claudia; Langsted, Anne; Launer, Lenore J.; Lauritzen, Torsten; MLiewald, David C.; Lin, Li An; Linneberg, Allan; Loos, Ruth J.F.; Lu, Yingchang; Lu, Xiangfeng; Mägi, Reedik; Malarstig, Anders; Manichaikul, Ani; Manning, Alisa K.; Mäntyselkä, Pekka; Marouli, Eirini; Masca, Nicholas G.D.; Maschio, Andrea; Meigs, James B.; Melander, Olle; Metspalu, Andres; Morris, Andrew P.; Morrison, Alanna C.; Mulas, Antonella; Müller-Nurasyid, Martina; Munroe, Patricia B.; Neville, Matt J.; Nielsen, Sune F.; Nielsen, Jonas B.; Nordestgaard, Børge G.; Ordovas, Jose M.; Mehran, Roxana; O'Donnell, Christoper J.; Orho-Melander, Marju; Molony, Cliona M.; Muntendam, Pieter; Padmanabhan, Sandosh; Palmer, Colin N.A.; Pasko, Dorota; Patel, Aniruddh P.; Pedersen, Oluf; Perola, Markus; Peters, Annette; Pisinger, Charlotta; Pistis, Giorgio; Polasek, Ozren; Poulter, Neil; Psaty, Bruce M.; Rader, Daniel J.; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F.; Reiner, Alex P.; Renström, Frida; Rich, Stephen S.; Ridker, Paul M.; Rioux, John D.; Robertson, Neil R.; Roden, Dan M.; Rotter, Jerome I.; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J.; Sanna, Serena; Sattar, Naveed; Schmidt, Ellen M.; Scott, Robert A.; Sever, Peter; Sevilla, Raquel S.; Shaffer, Christian M.; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S.; Smith, Albert V.; Smith, Blair H.; Somayajula, Sangeetha; Southam, Lorraine; Spector, Timothy D.; Speliotes, Elizabeth K.; Starr, John M.; Stirrups, Kathleen E.; Stitziel, Nathan; Strauch, Konstantin; Stringham, Heather M.; Surendran, Praveen; Tada, Hayato; Tall, Alan R.; Tang, Hua; Tardif, Jean Claude; Taylor, Kent D.; Trompet, Stella; Tsao, Philip S.; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Zuydam, Natalie R.Van; Varbo, Anette; Varga, Tibor V.; Virtamo, Jarmo; Waldenberger, Melanie; Wang, Nan; Wareham, Nick J.; Warren, Helen R.; Weeke, Peter E.; Weinstock, Joshua; Wessel, Jennifer; Wilson, James G.; Wilson, Peter W.F.; Xu, Ming; Yaghootkar, Hanieh; Young, Robin; Zeggini, Eleftheria; Zhang, He; Zheng, Neil S.; Zhang, Weihua; Zhang, Yan; Zhou, Wei; Zhou, Yanhua; Zoledziewska, Magdalena; Howson, Joanna M.M.; Danesh, John; McCarthy, Mark I.; Cowan, Chad A.; Abecasis, Goncalo; Deloukas, Panos; Musunuru, Kiran; Willer, Cristen J.; Kathiresan, Sekar; V Varga, Tibor.
I: Nature Genetics, Bind 49, Nr. 12, 01.12.2017, s. 1758-1766.Publikation: Bidrag til tidsskrift › Letter › Forskning › peer review
}
TY - JOUR
T1 - Exome-wide association study of plasma lipids in >300,000 individuals
AU - Liu, Dajiang J.
AU - Peloso, Gina M.
AU - Yu, Haojie
AU - Butterworth, Adam S.
AU - Wang, Xiao
AU - Mahajan, Anubha
AU - Saleheen, Danish
AU - Emdin, Connor
AU - Alam, Dewan
AU - Alves, Alexessander Couto
AU - Amouyel, Philippe
AU - Angelantonio, Emanuele DI
AU - Arveiler, Dominique
AU - Assimes, Themistocles L.
AU - Auer, Paul L.
AU - Baber, Usman
AU - Ballantyne, Christie M.
AU - Bang, Lia E.
AU - Benn, Marianne
AU - Bis, Joshua C.
AU - Boehnke, Michael
AU - Boerwinkle, Eric
AU - Bork-Jensen, Jette
AU - Bottinger, Erwin P.
AU - Brandslund, Ivan
AU - Brown, Morris
AU - Busonero, Fabio
AU - Caulfield, Mark J.
AU - Chambers, John C.
AU - Chasman, Daniel I.
AU - Chen, Y. Eugene
AU - Chen, Yii Der Ida
AU - Chowdhury, Rajiv
AU - Christensen, Cramer
AU - Chu, Audrey Y.
AU - Connell, John M.
AU - Cucca, Francesco
AU - Cupples, L. Adrienne
AU - Damrauer, Scott M.
AU - Davies, Gail
AU - Deary, Ian J.
AU - Dedoussis, George
AU - Denny, Joshua C.
AU - Dominiczak, Anna
AU - Dubé, Marie Pierre
AU - Ebeling, Tapani
AU - Eiriksdottir, Gudny
AU - Esko, Toñu
AU - Farmaki, Aliki Eleni
AU - Feitosa, Mary F.
AU - Ferrario, Marco
AU - Ferrieres, Jean
AU - Ford, Ian
AU - Fornage, Myriam
AU - Franks, Paul W.
AU - Frayling, Timothy M.
AU - Frikke-Schmidt, Ruth
AU - Fritsche, Lars G.
AU - Frossard, Philippe
AU - Fuster, Valentin
AU - Ganesh, Santhi K.
AU - Gao, Wei
AU - Garcia, Melissa E.
AU - Gieger, Christian
AU - Giulianini, Franco
AU - Goodarzi, Mark O.
AU - Grallert, Harald
AU - Grarup, Niels
AU - Groop, Leif
AU - Grove, Megan L.
AU - Gudnason, Vilmundur
AU - Hansen, Torben
AU - Harris, Tamara B.
AU - Hayward, Caroline
AU - Hirschhorn, Joel N.
AU - Holmen, Oddgeir L.
AU - Huffman, Jennifer
AU - Huo, Yong
AU - Hveem, Kristian
AU - Jabeen, Sehrish
AU - Jackson, Anne U.
AU - Jakobsdottir, Johanna
AU - Jarvelin, Marjo Riitta
AU - Jensen, Gorm B.
AU - Jørgensen, Marit E.
AU - Jukema, J. Wouter
AU - Justesen, Johanne M.
AU - Kamstrup, Pia R.
AU - Kanoni, Stavroula
AU - Karpe, Fredrik
AU - Kee, Frank
AU - Khera, Amit V.
AU - Klarin, Derek
AU - Koistinen, Heikki A.
AU - Kooner, Jaspal S.
AU - Kooperberg, Charles
AU - Kuulasmaa, Kari
AU - Kuusisto, Johanna
AU - Laakso, Markku
AU - Lakka, Timo
AU - Langenberg, Claudia
AU - Langsted, Anne
AU - Launer, Lenore J.
AU - Lauritzen, Torsten
AU - MLiewald, David C.
AU - Lin, Li An
AU - Linneberg, Allan
AU - Loos, Ruth J.F.
AU - Lu, Yingchang
AU - Lu, Xiangfeng
AU - Mägi, Reedik
AU - Malarstig, Anders
AU - Manichaikul, Ani
AU - Manning, Alisa K.
AU - Mäntyselkä, Pekka
AU - Marouli, Eirini
AU - Masca, Nicholas G.D.
AU - Maschio, Andrea
AU - Meigs, James B.
AU - Melander, Olle
AU - Metspalu, Andres
AU - Morris, Andrew P.
AU - Morrison, Alanna C.
AU - Mulas, Antonella
AU - Müller-Nurasyid, Martina
AU - Munroe, Patricia B.
AU - Neville, Matt J.
AU - Nielsen, Sune F.
AU - Nielsen, Jonas B.
AU - Nordestgaard, Børge G.
AU - Ordovas, Jose M.
AU - Mehran, Roxana
AU - O'Donnell, Christoper J.
AU - Orho-Melander, Marju
AU - Molony, Cliona M.
AU - Muntendam, Pieter
AU - Padmanabhan, Sandosh
AU - Palmer, Colin N.A.
AU - Pasko, Dorota
AU - Patel, Aniruddh P.
AU - Pedersen, Oluf
AU - Perola, Markus
AU - Peters, Annette
AU - Pisinger, Charlotta
AU - Pistis, Giorgio
AU - Polasek, Ozren
AU - Poulter, Neil
AU - Psaty, Bruce M.
AU - Rader, Daniel J.
AU - Rasheed, Asif
AU - Rauramaa, Rainer
AU - Reilly, Dermot F.
AU - Reiner, Alex P.
AU - Renström, Frida
AU - Rich, Stephen S.
AU - Ridker, Paul M.
AU - Rioux, John D.
AU - Robertson, Neil R.
AU - Roden, Dan M.
AU - Rotter, Jerome I.
AU - Rudan, Igor
AU - Salomaa, Veikko
AU - Samani, Nilesh J.
AU - Sanna, Serena
AU - Sattar, Naveed
AU - Schmidt, Ellen M.
AU - Scott, Robert A.
AU - Sever, Peter
AU - Sevilla, Raquel S.
AU - Shaffer, Christian M.
AU - Sim, Xueling
AU - Sivapalaratnam, Suthesh
AU - Small, Kerrin S.
AU - Smith, Albert V.
AU - Smith, Blair H.
AU - Somayajula, Sangeetha
AU - Southam, Lorraine
AU - Spector, Timothy D.
AU - Speliotes, Elizabeth K.
AU - Starr, John M.
AU - Stirrups, Kathleen E.
AU - Stitziel, Nathan
AU - Strauch, Konstantin
AU - Stringham, Heather M.
AU - Surendran, Praveen
AU - Tada, Hayato
AU - Tall, Alan R.
AU - Tang, Hua
AU - Tardif, Jean Claude
AU - Taylor, Kent D.
AU - Trompet, Stella
AU - Tsao, Philip S.
AU - Tuomilehto, Jaakko
AU - Tybjaerg-Hansen, Anne
AU - Zuydam, Natalie R.Van
AU - Varbo, Anette
AU - Varga, Tibor V.
AU - Virtamo, Jarmo
AU - Waldenberger, Melanie
AU - Wang, Nan
AU - Wareham, Nick J.
AU - Warren, Helen R.
AU - Weeke, Peter E.
AU - Weinstock, Joshua
AU - Wessel, Jennifer
AU - Wilson, James G.
AU - Wilson, Peter W.F.
AU - Xu, Ming
AU - Yaghootkar, Hanieh
AU - Young, Robin
AU - Zeggini, Eleftheria
AU - Zhang, He
AU - Zheng, Neil S.
AU - Zhang, Weihua
AU - Zhang, Yan
AU - Zhou, Wei
AU - Zhou, Yanhua
AU - Zoledziewska, Magdalena
AU - Howson, Joanna M.M.
AU - Danesh, John
AU - McCarthy, Mark I.
AU - Cowan, Chad A.
AU - Abecasis, Goncalo
AU - Deloukas, Panos
AU - Musunuru, Kiran
AU - Willer, Cristen J.
AU - Kathiresan, Sekar
AU - V Varga, Tibor
PY - 2017/12/1
Y1 - 2017/12/1
N2 - We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TGrich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
AB - We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TGrich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
U2 - 10.1038/ng.3977
DO - 10.1038/ng.3977
M3 - Letter
C2 - 29083408
AN - SCOPUS:85035766416
VL - 49
SP - 1758
EP - 1766
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 12
ER -