@article{Lange2014, abstract = {Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.}, author = {Lange, Leslie A. and Hu, Youna and Zhang, He and Xue, Chenyi and Schmidt, Ellen M. and Tang, Zheng-Zheng and Bizon, Chris and Tang, Zheng and Jun, Goo and Peloso, Gina and Kang, Hyun Min and Li, Kuo-Ping and Auer, Paul and Flannick, Jason and Zhang, Ji and Fuchsberger, Christian and Gaulton, Kyle and Li, Yun and Lindgren, Cecilia and Locke, Adam and Manning, Alisa and Sim, Xueling and Gottesman, Omri and Holmen, Oddgeir L. and Lu, Yingchang and Ruderfer, Douglas and Duan, Qing and Stahl, Eli A. and Durda, Peter and Jiao, Shuo and Isaacs, Aaron and Hofman, Albert and Correa, Adolfo and Jakobsdottir, Johanna and Griswold, Michael E. and Smith, Albert V. and Zhang, Qunyuan and Feitosa, Mary F. and Crosby, Jacy and Huffman, Jennifer E. and Do, Ron and Wassel, Christina L. and Franceschini, Nora and Uitterlinden, André G and Tsai, Michael and Rosenthal, Elisabeth A. and Li, Mingyao and Lumley, Thomas and Fox, Ervin R. and Peters, Ulrike and van Duijn, Cornelia M. and Levy, Daniel and Gudnason, Vilmundur and Fornage, Myriam and Hayward, Caroline and Borecki, Ingrid B. and Bis, Joshua C. and Chen, Y. Eugene and Rudan, Igor and Loos, Ruth J. F. and Bottinger, Erwin P. and Sætrom, Pål and Hveem, Kristian and Boehnke, Michael and Groop, Leif and Rivas, Manuel A. and McCarthy, Mark and Meitinger, Thomas and Farlow, Deborah N. and Boerwinkle, Eric and Kathiresan, Sekar and Altshuler, David and Lin, Dan-Yu and Cupples, L. Adrienne and Gabriel, Stacey B. and Kooperberg, Charles and Abecasis, Gonçalo R. and Altshuler, David M. and Abecasis, Gonçalo R. and Allayee, Hooman and Cresci, Sharon and Daly, Mark J. and DePristo, Mark A. and de Bakker, Paul I. W. and Siscovick, David S. and Lange, Ethan M. and Donnelly, Peter and Rich, Stephen S. and Schreiner, Pamela J. and Fennell, Tim and Garimella, Kiran and Hazen, Stanley L. and Jordan, Daniel M. and Folsom, Aaron R. and Ballantyne, Christie M. and Kiezun, Adam and Lettre, Guillaume and Li, Bingshan and Padmanabhan, Sandosh and Newton-Cheh, Christopher H. and Willer, Cristen J. and Pulit, Sara and Reich, David and Rader, Daniel J. and Reilly, Muredach P. and Schwartz, Steve and Scott, Laura and Spertus, John A. and North, Kari E. and Stoletzki, Nina and Stitziel, Nathaniel O. and Sunyaev, Shamil R. and Voight, Benjamin F. and Akylbekova, Ermeg and Atwood, Larry D. and Rich, Stephen S and Barbalic, Maja and Barr, R. Graham and Benjamin, Emelia J. and Bowden, Donald W. and Brody, Jennifer and Budoff, Matthew and Burke, Greg and Rotter, Jerome I. and Buxbaum, Sarah and O’Donnell, Christopher J. and Carr, Jeff and Chen, Donna T. and Chen, Wei-Min and Chen, Ida Y. and Taylor, Herman A. and Concannon, Pat and Post, Wendy S. and D’Agostino, Ralph and DeStefano, Anita L. and Psaty, Bruce M. and Reiner, Alexander P. and Dreisbach, Albert and Dupuis, Josée and Durda, J. Peter and Ellis, Jaclyn and Fox, Caroline S. and Fox, Ervin and Funari, Vincent and Lin, Honghuang and Ganesh, Santhi K. and Jackson, Rebecca D. and Gardin, Julius and Goff, David and Gordon, Ora and Tracy, Russell P. and Grody, Wayne and Gross, Myron and Martin, Lisa W. and Guo, Xiuqing and Wilson, James G. and Hall, Ira M. and Heard-Costa, Nancy L. and Heckbert, Susan R. and Heintz, Nicholas and Herrington, David M. and Hickson, DeMarc and Huang, Jie and Hwang, Shih-Jen and Jacobs, David R. and Jenny, Nancy S. and Johnson, Andrew D. and Johnson, Craig W. and Kawut, Steven and Kronmal, Richard and Kurz, Raluca and Larson, Martin G. and Lawson, Mark and Lewis, Cora E. and Li, Dalin and Liu, Chunyu and Liu, Jiankang and Liu, Kiang and Smith, Joshua D. and Liu, Xiaoming and Liu, Yongmei and Turner, Emily H. and Longstreth, William T. and Loria, Cay and Lunetta, Kathryn and Mackey, Aaron J. and Mackey, Rachel and Manichaikul, Ani and Maxwell, Taylor and McKnight, Barbara and Meigs, James B. and Smith, Nicholas L. and Rieder, Mark J. and Morrison, Alanna C. and Crosslin, David R. and Musani, Solomon K. and Mychaleckyj, Josyf C. and Nettleton, Jennifer A. and O’Leary, Daniel and Ong, Frank and Palmas, Walter and Pankow, James S. and Pankratz, Nathan D. and Paul, Shom and Perez, Marco and Person, Sharina D. and Polak, Joseph and Assimes, Themistocles L. and Quinlan, Aaron R. and Raffel, Leslie J. and Carlson, Christopher S. and Ramachandran, Vasan S. and Nickerson, Deborah A. and Rice, Kenneth and Sanders, Jill P. and Jarvik, Gail P. and Seshadri, Sudha and Shea, Steve and Sidney, Stephen and Silverstein, Kevin and Taylor, Kent and Sotoodehnia, Nona and Srinivasan, Asoke and Thomas, Fridtjof and Tsai, Michael Y. and Volcik, Kelly A. and Robinson, Jennifer G. and Wassel, Chrstina L. and Watson, Karol and Wei, Gina and Wiggins, Kerri L. and White, Wendy and Wilk, Jemma B. and Williams, O. Dale and Wilson, Gregory and Zakai, Neil A. and Wolf, Phillip and Meschia, James F. and Hardy, John and Nalls, Michael and Singleton, Andrew and Bamshad, Michael J. and Worrall, Brad and Barnes, Kathleen C. and Abdulhamid, Ibrahim and Accurso, Frank and Anbar, Ran and Beaty, Terri and Bigham, Abigail and Black, Phillip and Bleecker, Eugene and Cairns, Anne Marie and Buckingham, Kati and Caplan, Daniel and Chatfield, Barbara and Chidekel, Aaron and Christiani, David C. and Cho, Michael and Crapo, James D. and Crouch, Julia and Daley, Denise and Dang, Anthony and De Paula, Alicia and Dang, Hong and Drumm, Allen DozorMitch and DeCelie-Germana, Joan and Dyson, Maynard and Emond, Mary J. and Emerson, Julia and Ferkol, Thomas and Fink, Robert and Foster, Cassandra and Froh, Deborah and Gao, Li and Gershan, William and Gibson, Ronald L. and Godwin, Elizabeth and Gondor, Magdalen and Gutierrez, Hector and Hansel, Nadia N. and Hassoun, Paul M. and Hiatt, Peter and Hokanson, John E. and Howenstine, Michelle and Hummer, Laura K. and Kanga, Jamshed and Kim, Yoonhee and Knowles, Michael R. and Konstan, Michael and Lahiri, Thomas and Laird, Nan and Lange, Christoph and Lin, Lin and Lin, Xihong and Louie, Tin L. and Lynch, David and Make, Barry and Martin, Thomas R. and Mathai, Steve C. and Mathias, Rasika A. and McNamara, John and McNamara, Sharon and Meyers, Deborah and Millard, Susan and Mogayzel, Peter and Moss, Richard and Murray, Tanda and Nielson, Dennis and Noyes, Blakeslee and O’Neal, Wanda and Orenstein, David and O’Sullivan, Brian and Pace, Rhonda and Pare, Peter and Parker, H. Worth and Perkett, Elizabeth and Passero, Mary Ann and Prestridge, Adrienne and Ramsey, Bonnie and Rafaels, Nicholas M. and Regan, Elizabeth and Ren, Clement and Retsch-Bogart, George and Rock, Michael and Rosen, Antony and Rosenfeld, Margaret and Ruczinski, Ingo and Sanford, Andrew and Schaeffer, David and Sell, Cindy and Sheehan, Daniel and Sin, Don and Silverman, Edwin K. and Spencer, Terry and Stonebraker, Jackie and Varlotta, Laurie and Tabor, Holly K. and Weiss, Robert and Vergara, Candelaria I. and Wigley, Fred and Eugene Chen, Y. and Wise, Robert A. and Wurfel, Mark M. and Wright, Fred A. and Zanni, Robert and Zou, Fei and Green, Phil and Shendure, Jay and Akey, Joshua M. and Bustamante, Carlos D. and Eichler, Evan E. and Fox, P. Keolu and Fu, Wenqing and Gordon, Adam and Gravel, Simon and Kan, Mengyuan and Johnsen, Jill M. and Kenny, Eimear E. and Lara-Garduno, Fremiet and Kidd, Jeffrey M. and Leal, Suzanne M. and McGee, Sean and Liu, Dajiang J. and Paeper, Bryan and O’Connor, Timothy D. and Robertson, Peggy D. and Staples, Jeffrey C. and Tennessen, Jacob A. and Wang, Gao and Yi, Qian and Anderson, Garnet and Anton-Culver, Hoda and Auer, Paul L. and Beresford, Shirley and Black, Henry and Brunner, Robert and Brzyski, Robert and Burwen, Dale and Caan, Bette and Carty, Cara L. and Chlebowski, Rowan and Cummings, Steven and Curb, J. David and Eaton, Charles B. and Ford, Leslie and Fullerton, Stephanie M. and Gass, Margery and Geller, Nancy and Heiss, Gerardo and Howard, Barbara V. and Hsu, Li and Hutter, Carolyn M. and Ioannidis, John and Johnson, Karen C. and Kuller, Lewis and LaCroix, Andrea and Lakshminarayan, Kamakshi and Lane, Dorothy and Lasser, Norman and LeBlanc, Erin and Adrienne Cupples, L. and Limacher, Marian and Logsdon, Benjamin A. and Ludlam, Shari and Manson, JoAnn E. and Margolis, Karen and McGowan, Joan and Monda, Keri L. and Kotchen, Jane Morley and Nathan, Lauren and Ockene, Judith and O’Sullivan, Mary Jo and Phillips, Lawrence S. and Prentice, Ross L. and Robbins, John and Rossouw, Jacques E. and Sangi-Haghpeykar, Haleh and Sarto, Gloria E. and Shumaker, Sally and Simon, Michael S. and Stefanick, Marcia L. and Stein, Evan and Tang, Hua and Taylor, Kira C. and Thomson, Cynthia A. and Thornton, Timothy A. and Van Horn, Linda and Vitolins, Mara and Wactawski-Wende, Jean and Wallace, Robert and Wassertheil-Smoller, Sylvia and Zeng, Donglin and Applebaum-Bowden, Deborah and Feolo, Michael and Gan, Weiniu and Paltoo, Dina N. and Sholinsky, Phyliss and Sturcke, Anne}, doi = {10.1016/j.ajhg.2014.01.010}, journal = {American Journal of Human Genetics}, month = {feb}, pages = {233-245}, title = {Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24507775}, volume = {94}, year = {2014} }