%0 Journal Article %J Nature %D 2015 %T Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. %A Do, Ron %A Stitziel, Nathan O %A Won, Hong-Hee %A Jørgensen, Anders Berg %A Duga, Stefano %A Angelica Merlini, Pier %A Kiezun, Adam %A Farrall, Martin %A Goel, Anuj %A Zuk, Or %A Guella, Illaria %A Asselta, Rosanna %A Lange, Leslie A %A Peloso, Gina M %A Auer, Paul L %A Girelli, Domenico %A Martinelli, Nicola %A Farlow, Deborah N %A DePristo, Mark A %A Roberts, Robert %A Stewart, Alexander F R %A Saleheen, Danish %A Danesh, John %A Epstein, Stephen E %A Sivapalaratnam, Suthesh %A Hovingh, G Kees %A Kastelein, John J %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Shah, Svati H %A Kraus, William E %A Davies, Robert %A Nikpay, Majid %A Johansen, Christopher T %A Wang, Jian %A Hegele, Robert A %A Hechter, Eliana %A Marz, Winfried %A Kleber, Marcus E %A Huang, Jie %A Johnson, Andrew D %A Li, Mingyao %A Burke, Greg L %A Gross, Myron %A Liu, Yongmei %A Assimes, Themistocles L %A Heiss, Gerardo %A Lange, Ethan M %A Folsom, Aaron R %A Taylor, Herman A %A Olivieri, Oliviero %A Hamsten, Anders %A Clarke, Robert %A Reilly, Dermot F %A Yin, Wu %A Rivas, Manuel A %A Donnelly, Peter %A Rossouw, Jacques E %A Psaty, Bruce M %A Herrington, David M %A Wilson, James G %A Rich, Stephen S %A Bamshad, Michael J %A Tracy, Russell P %A Cupples, L Adrienne %A Rader, Daniel J %A Reilly, Muredach P %A Spertus, John A %A Cresci, Sharon %A Hartiala, Jaana %A Tang, W H Wilson %A Hazen, Stanley L %A Allayee, Hooman %A Reiner, Alex P %A Carlson, Christopher S %A Kooperberg, Charles %A Jackson, Rebecca D %A Boerwinkle, Eric %A Lander, Eric S %A Schwartz, Stephen M %A Siscovick, David S %A McPherson, Ruth %A Tybjaerg-Hansen, Anne %A Abecasis, Gonçalo R %A Watkins, Hugh %A Nickerson, Deborah A %A Ardissino, Diego %A Sunyaev, Shamil R %A O'Donnell, Christopher J %A Altshuler, David %A Gabriel, Stacey %A Kathiresan, Sekar %K Age Factors %K Age of Onset %K Alleles %K Apolipoprotein A-V %K Apolipoproteins A %K Case-Control Studies %K Cholesterol, LDL %K Coronary Artery Disease %K Exome %K Female %K Genetic Predisposition to Disease %K Genetics, Population %K Heterozygote %K Humans %K Male %K Middle Aged %K Mutation %K Myocardial Infarction %K National Heart, Lung, and Blood Institute (U.S.) %K Receptors, LDL %K Triglycerides %K United States %X

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

%B Nature %V 518 %P 102-6 %8 2015 Feb 05 %G eng %N 7537 %1 https://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract %R 10.1038/nature13917 %0 Journal Article %J Nature %D 2007 %T Genome-wide detection and characterization of positive selection in human populations. %A Sabeti, Pardis C %A Varilly, Patrick %A Fry, Ben %A Lohmueller, Jason %A Hostetter, Elizabeth %A Cotsapas, Chris %A Xie, Xiaohui %A Byrne, Elizabeth H %A McCarroll, Steven A %A Gaudet, Rachelle %A Schaffner, Stephen F %A Lander, Eric S %A Frazer, Kelly A %A Ballinger, Dennis G %A Cox, David R %A Hinds, David A %A Stuve, Laura L %A Gibbs, Richard A %A Belmont, John W %A Boudreau, Andrew %A Hardenbol, Paul %A Leal, Suzanne M %A Pasternak, Shiran %A Wheeler, David A %A Willis, Thomas D %A Yu, Fuli %A Yang, Huanming %A Zeng, Changqing %A Gao, Yang %A Hu, Haoran %A Hu, Weitao %A Li, Chaohua %A Lin, Wei %A Liu, Siqi %A Pan, Hao %A Tang, Xiaoli %A Wang, Jian %A Wang, Wei %A Yu, Jun %A Zhang, Bo %A Zhang, Qingrun %A Zhao, Hongbin %A Zhao, Hui %A Zhou, Jun %A Gabriel, Stacey B %A Barry, Rachel %A Blumenstiel, Brendan %A Camargo, Amy %A Defelice, Matthew %A Faggart, Maura %A Goyette, Mary %A Gupta, Supriya %A Moore, Jamie %A Nguyen, Huy %A Onofrio, Robert C %A Parkin, Melissa %A Roy, Jessica %A Stahl, Erich %A Winchester, Ellen %A Ziaugra, Liuda %A Altshuler, David %A Shen, Yan %A Yao, Zhijian %A Huang, Wei %A Chu, Xun %A He, Yungang %A Jin, Li %A Liu, Yangfan %A Shen, Yayun %A Sun, Weiwei %A Wang, Haifeng %A Wang, Yi %A Wang, Ying %A Xiong, Xiaoyan %A Xu, Liang %A Waye, Mary M Y %A Tsui, Stephen K W %A Xue, Hong %A Wong, J Tze-Fei %A Galver, Luana M %A Fan, Jian-Bing %A Gunderson, Kevin %A Murray, Sarah S %A Oliphant, Arnold R %A Chee, Mark S %A Montpetit, Alexandre %A Chagnon, Fanny %A Ferretti, Vincent %A Leboeuf, Martin %A Olivier, Jean-François %A Phillips, Michael S %A Roumy, Stéphanie %A Sallée, Clémentine %A Verner, Andrei %A Hudson, Thomas J %A Kwok, Pui-Yan %A Cai, Dongmei %A Koboldt, Daniel C %A Miller, Raymond D %A Pawlikowska, Ludmila %A Taillon-Miller, Patricia %A Xiao, Ming %A Tsui, Lap-Chee %A Mak, William %A Song, You Qiang %A Tam, Paul K H %A Nakamura, Yusuke %A Kawaguchi, Takahisa %A Kitamoto, Takuya %A Morizono, Takashi %A Nagashima, Atsushi %A Ohnishi, Yozo %A Sekine, Akihiro %A Tanaka, Toshihiro %A Tsunoda, Tatsuhiko %A Deloukas, Panos %A Bird, Christine P %A Delgado, Marcos %A Dermitzakis, Emmanouil T %A Gwilliam, Rhian %A Hunt, Sarah %A Morrison, Jonathan %A Powell, Don %A Stranger, Barbara E %A Whittaker, Pamela %A Bentley, David R %A Daly, Mark J %A de Bakker, Paul I W %A Barrett, Jeff %A Chretien, Yves R %A Maller, Julian %A McCarroll, Steve %A Patterson, Nick %A Pe'er, Itsik %A Price, Alkes %A Purcell, Shaun %A Richter, Daniel J %A Sabeti, Pardis %A Saxena, Richa %A Schaffner, Stephen F %A Sham, Pak C %A Varilly, Patrick %A Altshuler, David %A Stein, Lincoln D %A Krishnan, Lalitha %A Smith, Albert Vernon %A Tello-Ruiz, Marcela K %A Thorisson, Gudmundur A %A Chakravarti, Aravinda %A Chen, Peter E %A Cutler, David J %A Kashuk, Carl S %A Lin, Shin %A Abecasis, Gonçalo R %A Guan, Weihua %A Li, Yun %A Munro, Heather M %A Qin, Zhaohui Steve %A Thomas, Daryl J %A McVean, Gilean %A Auton, Adam %A Bottolo, Leonardo %A Cardin, Niall %A Eyheramendy, Susana %A Freeman, Colin %A Marchini, Jonathan %A Myers, Simon %A Spencer, Chris %A Stephens, Matthew %A Donnelly, Peter %A Cardon, Lon R %A Clarke, Geraldine %A Evans, David M %A Morris, Andrew P %A Weir, Bruce S %A Tsunoda, Tatsuhiko %A Johnson, Todd A %A Mullikin, James C %A Sherry, Stephen T %A Feolo, Michael %A Skol, Andrew %A Zhang, Houcan %A Zeng, Changqing %A Zhao, Hui %A Matsuda, Ichiro %A Fukushima, Yoshimitsu %A Macer, Darryl R %A Suda, Eiko %A Rotimi, Charles N %A Adebamowo, Clement A %A Ajayi, Ike %A Aniagwu, Toyin %A Marshall, Patricia A %A Nkwodimmah, Chibuzor %A Royal, Charmaine D M %A Leppert, Mark F %A Dixon, Missy %A Peiffer, Andy %A Qiu, Renzong %A Kent, Alastair %A Kato, Kazuto %A Niikawa, Norio %A Adewole, Isaac F %A Knoppers, Bartha M %A Foster, Morris W %A Clayton, Ellen Wright %A Watkin, Jessica %A Gibbs, Richard A %A Belmont, John W %A Muzny, Donna %A Nazareth, Lynne %A Sodergren, Erica %A Weinstock, George M %A Wheeler, David A %A Yakub, Imtaz %A Gabriel, Stacey B %A Onofrio, Robert C %A Richter, Daniel J %A Ziaugra, Liuda %A Birren, Bruce W %A Daly, Mark J %A Altshuler, David %A Wilson, Richard K %A Fulton, Lucinda L %A Rogers, Jane %A Burton, John %A Carter, Nigel P %A Clee, Christopher M %A Griffiths, Mark %A Jones, Matthew C %A McLay, Kirsten %A Plumb, Robert W %A Ross, Mark T %A Sims, Sarah K %A Willey, David L %A Chen, Zhu %A Han, Hua %A Kang, Le %A Godbout, Martin %A Wallenburg, John C %A L'Archevêque, Paul %A Bellemare, Guy %A Saeki, Koji %A Wang, Hongguang %A An, Daochang %A Fu, Hongbo %A Li, Qing %A Wang, Zhen %A Wang, Renwu %A Holden, Arthur L %A Brooks, Lisa D %A McEwen, Jean E %A Guyer, Mark S %A Wang, Vivian Ota %A Peterson, Jane L %A Shi, Michael %A Spiegel, Jack %A Sung, Lawrence M %A Zacharia, Lynn F %A Collins, Francis S %A Kennedy, Karen %A Jamieson, Ruth %A Stewart, John %K Antiporters %K Edar Receptor %K Gene Frequency %K Genetics, Population %K Genome, Human %K Geography %K Haplotypes %K Humans %K Models, Molecular %K Polymorphism, Single Nucleotide %K Protein Structure, Tertiary %K Selection, Genetic %X

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

%B Nature %V 449 %P 913-8 %8 2007 Oct 18 %G eng %N 7164 %1 https://www.ncbi.nlm.nih.gov/pubmed/17943131?dopt=Abstract %R 10.1038/nature06250 %0 Journal Article %J Nature %D 2007 %T A second generation human haplotype map of over 3.1 million SNPs. %A Frazer, Kelly A %A Ballinger, Dennis G %A Cox, David R %A Hinds, David A %A Stuve, Laura L %A Gibbs, Richard A %A Belmont, John W %A Boudreau, Andrew %A Hardenbol, Paul %A Leal, Suzanne M %A Pasternak, Shiran %A Wheeler, David A %A Willis, Thomas D %A Yu, Fuli %A Yang, Huanming %A Zeng, Changqing %A Gao, Yang %A Hu, Haoran %A Hu, Weitao %A Li, Chaohua %A Lin, Wei %A Liu, Siqi %A Pan, Hao %A Tang, Xiaoli %A Wang, Jian %A Wang, Wei %A Yu, Jun %A Zhang, Bo %A Zhang, Qingrun %A Zhao, Hongbin %A Zhao, Hui %A Zhou, Jun %A Gabriel, Stacey B %A Barry, Rachel %A Blumenstiel, Brendan %A Camargo, Amy %A Defelice, Matthew %A Faggart, Maura %A Goyette, Mary %A Gupta, Supriya %A Moore, Jamie %A Nguyen, Huy %A Onofrio, Robert C %A Parkin, Melissa %A Roy, Jessica %A Stahl, Erich %A Winchester, Ellen %A Ziaugra, Liuda %A Altshuler, David %A Shen, Yan %A Yao, Zhijian %A Huang, Wei %A Chu, Xun %A He, Yungang %A Jin, Li %A Liu, Yangfan %A Shen, Yayun %A Sun, Weiwei %A Wang, Haifeng %A Wang, Yi %A Wang, Ying %A Xiong, Xiaoyan %A Xu, Liang %A Waye, Mary M Y %A Tsui, Stephen K W %A Xue, Hong %A Wong, J Tze-Fei %A Galver, Luana M %A Fan, Jian-Bing %A Gunderson, Kevin %A Murray, Sarah S %A Oliphant, Arnold R %A Chee, Mark S %A Montpetit, Alexandre %A Chagnon, Fanny %A Ferretti, Vincent %A Leboeuf, Martin %A Olivier, Jean-François %A Phillips, Michael S %A Roumy, Stéphanie %A Sallée, Clémentine %A Verner, Andrei %A Hudson, Thomas J %A Kwok, Pui-Yan %A Cai, Dongmei %A Koboldt, Daniel C %A Miller, Raymond D %A Pawlikowska, Ludmila %A Taillon-Miller, Patricia %A Xiao, Ming %A Tsui, Lap-Chee %A Mak, William %A Song, You Qiang %A Tam, Paul K H %A Nakamura, Yusuke %A Kawaguchi, Takahisa %A Kitamoto, Takuya %A Morizono, Takashi %A Nagashima, Atsushi %A Ohnishi, Yozo %A Sekine, Akihiro %A Tanaka, Toshihiro %A Tsunoda, Tatsuhiko %A Deloukas, Panos %A Bird, Christine P %A Delgado, Marcos %A Dermitzakis, Emmanouil T %A Gwilliam, Rhian %A Hunt, Sarah %A Morrison, Jonathan %A Powell, Don %A Stranger, Barbara E %A Whittaker, Pamela %A Bentley, David R %A Daly, Mark J %A de Bakker, Paul I W %A Barrett, Jeff %A Chretien, Yves R %A Maller, Julian %A McCarroll, Steve %A Patterson, Nick %A Pe'er, Itsik %A Price, Alkes %A Purcell, Shaun %A Richter, Daniel J %A Sabeti, Pardis %A Saxena, Richa %A Schaffner, Stephen F %A Sham, Pak C %A Varilly, Patrick %A Altshuler, David %A Stein, Lincoln D %A Krishnan, Lalitha %A Smith, Albert Vernon %A Tello-Ruiz, Marcela K %A Thorisson, Gudmundur A %A Chakravarti, Aravinda %A Chen, Peter E %A Cutler, David J %A Kashuk, Carl S %A Lin, Shin %A Abecasis, Gonçalo R %A Guan, Weihua %A Li, Yun %A Munro, Heather M %A Qin, Zhaohui Steve %A Thomas, Daryl J %A McVean, Gilean %A Auton, Adam %A Bottolo, Leonardo %A Cardin, Niall %A Eyheramendy, Susana %A Freeman, Colin %A Marchini, Jonathan %A Myers, Simon %A Spencer, Chris %A Stephens, Matthew %A Donnelly, Peter %A Cardon, Lon R %A Clarke, Geraldine %A Evans, David M %A Morris, Andrew P %A Weir, Bruce S %A Tsunoda, Tatsuhiko %A Mullikin, James C %A Sherry, Stephen T %A Feolo, Michael %A Skol, Andrew %A Zhang, Houcan %A Zeng, Changqing %A Zhao, Hui %A Matsuda, Ichiro %A Fukushima, Yoshimitsu %A Macer, Darryl R %A Suda, Eiko %A Rotimi, Charles N %A Adebamowo, Clement A %A Ajayi, Ike %A Aniagwu, Toyin %A Marshall, Patricia A %A Nkwodimmah, Chibuzor %A Royal, Charmaine D M %A Leppert, Mark F %A Dixon, Missy %A Peiffer, Andy %A Qiu, Renzong %A Kent, Alastair %A Kato, Kazuto %A Niikawa, Norio %A Adewole, Isaac F %A Knoppers, Bartha M %A Foster, Morris W %A Clayton, Ellen Wright %A Watkin, Jessica %A Gibbs, Richard A %A Belmont, John W %A Muzny, Donna %A Nazareth, Lynne %A Sodergren, Erica %A Weinstock, George M %A Wheeler, David A %A Yakub, Imtaz %A Gabriel, Stacey B %A Onofrio, Robert C %A Richter, Daniel J %A Ziaugra, Liuda %A Birren, Bruce W %A Daly, Mark J %A Altshuler, David %A Wilson, Richard K %A Fulton, Lucinda L %A Rogers, Jane %A Burton, John %A Carter, Nigel P %A Clee, Christopher M %A Griffiths, Mark %A Jones, Matthew C %A McLay, Kirsten %A Plumb, Robert W %A Ross, Mark T %A Sims, Sarah K %A Willey, David L %A Chen, Zhu %A Han, Hua %A Kang, Le %A Godbout, Martin %A Wallenburg, John C %A L'Archevêque, Paul %A Bellemare, Guy %A Saeki, Koji %A Wang, Hongguang %A An, Daochang %A Fu, Hongbo %A Li, Qing %A Wang, Zhen %A Wang, Renwu %A Holden, Arthur L %A Brooks, Lisa D %A McEwen, Jean E %A Guyer, Mark S %A Wang, Vivian Ota %A Peterson, Jane L %A Shi, Michael %A Spiegel, Jack %A Sung, Lawrence M %A Zacharia, Lynn F %A Collins, Francis S %A Kennedy, Karen %A Jamieson, Ruth %A Stewart, John %K Female %K Haplotypes %K Homozygote %K Humans %K Linkage Disequilibrium %K Male %K Polymorphism, Single Nucleotide %K Racial Groups %K Recombination, Genetic %K Selection, Genetic %X

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

%B Nature %V 449 %P 851-61 %8 2007 Oct 18 %G eng %N 7164 %1 https://www.ncbi.nlm.nih.gov/pubmed/17943122?dopt=Abstract %R 10.1038/nature06258