Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia

被引：343

作者：

Johansen, Christopher T. ^{[1
]}

Wang, Jian ^{[1
]}

Lanktree, Matthew B. ^{[1
]}

Cao, Henian ^{[1
]}

McIntyre, Adam D. ^{[1
]}

Ban, Matthew R. ^{[1
]}

Martins, Rebecca A. ^{[1
]}

Kennedy, Brooke A. ^{[1
]}

Hassell, Reina G. ^{[1
]}

Visser, Maartje E. ^{[2
,3
]}

Schwartz, Stephen M. ^{[4
]}

Voight, Benjamin F. ^{[5
,6
,7
]}

Elosua, Roberto ^{[8
]}

Salomaa, Veikko ^{[9
]}

O'Donnell, Christopher J. ^{[10
,11
,12
,13
]}

Dallinga-Thie, Geesje M. ^{[2
,3
]}

Anand, Sonia S. ^{[14
]}

Yusuf, Salim ^{[14
]}

Huff, Murray W. ^{[1
,15
]}

Kathiresan, Sekar ^{[5
,6
,7
]}

Hegele, Robert A. ^{[1
,15
]}

机构：

[1] Univ Western Ontario, Dept Biochem, Robarts Res Inst, London, ON, Canada

[2] Univ Amsterdam, Acad Med Ctr, Dept Expt Vasc Med, NL-1105 AZ Amsterdam, Netherlands

[3] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands

[4] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[5] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[7] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[8] Inst Municipal Invest Med, E-08003 Barcelona, Spain

[9] Natl Inst Hlth & Welf, Chron Dis Epidemiol Unit, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland

[10] Harvard Univ, Sch Med, Cardiovasc Res Ctr, Boston, MA USA

[11] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA

[12] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[13] NHLBI, Framingham Heart Study, Framingham, MA USA

[14] McMaster Univ, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON, Canada

[15] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, London, ON, Canada

来源：

NATURE GENETICS | 2010年 / 42卷 / 08期

基金：

加拿大健康研究院; 美国国家卫生研究院;

关键词：

HYPERLIPOPROTEINEMIA PHENOTYPES; LOCI; DISEASE; RISK; TRIGLYCERIDES; CONTRIBUTE; MUTATIONS; ALLELES;

D O I：

10.1038/ng.628

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations(1-5). Common variants at these loci together explain <10% of variation in each lipid trait(4,5). Rare variants with large individual effects may also contribute to the heritability of lipid traits(6,7); however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.

引用

页码：684 / +

页数：5

共 27 条

[1] Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE) [J].

Anand, SS ;

Yusuf, S ;

Vuksan, V ;

Devanesen, S ;

Teo, KK ;

Montague, PA ;

Kelemen, L ;

Yi, CL ;

Lonn, E ;

Gerstein, H ;

Hegele, RA ;

McQueen, M .

LANCET, 2000, 356 (9226) :279-284

[2] Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts [J].

Aulchenko, Yurii S. ;

Ripatti, Samuli ;

Lindqvist, Ida ;

Boomsma, Dorret ;

Heid, Iris M. ;

Pramstaller, Peter P. ;

Penninx, Brenda W. J. H. ;

Janssens, A. Cecile J. W. ;

Wilson, James F. ;

Spector, Tim ;

Martin, Nicholas G. ;

Pedersen, Nancy L. ;

Kyvik, Kirsten Ohm ;

Kaprio, Jaakko ;

Hofman, Albert ;

Freimer, Nelson B. ;

Jarvelin, Marjo-Riitta ;

Gyllensten, Ulf ;

Campbell, Harry ;

Rudan, Igor ;

Johansson, Asa ;

Marroni, Fabio ;

Hayward, Caroline ;

Vitart, Veronique ;

Jonasson, Inger ;

Pattaro, Cristian ;

Wright, Alan ;

Hastie, Nick ;

Pichler, Irene ;

Hicks, Andrew A. ;

Falchi, Mario ;

Willemsen, Gonneke ;

Hottenga, Jouke-Jan ;

de Geus, Eco J. C. ;

Montgomery, Grant W. ;

Whitfield, John ;

Magnusson, Patrik ;

Saharinen, Juha ;

Perola, Markus ;

Silander, Kaisa ;

Isaacs, Aaron ;

Sijbrands, Eric J. G. ;

Uitterlinden, Andre G. ;

Witteman, Jacqueline C. M. ;

Oostra, Ben A. ;

Elliott, Paul ;

Ruokonen, Aimo ;

Sabatti, Chiara ;

Gieger, Christian ;

Meitinger, Thomas .

NATURE GENETICS, 2009, 41 (01) :47-55

[3] Chylomicronemia With a Mutant GPIHBP1 (Q115P) That Cannot Bind Lipoprotein Lipase [J].

Beigneux, Anne P. ;

Franssen, Remco ;

Bensadoun, Andre ;

Gin, Peter ;

Melford, Kristan ;

Peter, Jorge ;

Walzem, Rosemary L. ;

Weinstein, Michael M. ;

Davies, Brandon S. J. ;

Kuivenhoven, Jan A. ;

Kastelein, John J. P. ;

Fong, Loren G. ;

Dallinga-Thie, Geesje M. ;

Young, Stephen G. .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2009, 29 (06) :956-U447

[4] Multiple rare Alleles contribute to low plasma levels of HDL cholesterol [J].

Cohen, JC ;

Kiss, RS ;

Pertsemlidis, A ;

Marcel, YL ;

McPherson, R ;

Hobbs, HH .

SCIENCE, 2004, 305 (5685) :869-872

[5] INDEPENDENT MUTATIONS AT CODON-3500 OF THE APOLIPOPROTEIN-B GENE ARE ASSOCIATED WITH HYPERLIPIDEMIA [J].

GAFFNEY, D ;

REID, JM ;

CAMERON, IM ;

VASS, K ;

CASLAKE, MJ ;

SHEPHERD, J ;

PACKARD, CJ .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1995, 15 (08) :1025-1029

[6] A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia [J].

Hegele, Robert A. ;

Ban, Matthew R. ;

Hsueh, Neil ;

Kennedy, Brooke A. ;

Cao, Henian ;

Zou, Guang Yong ;

Anand, Sonia ;

Yusuf, Salim ;

Huff, Murray W. ;

Wang, Jian .

HUMAN MOLECULAR GENETICS, 2009, 18 (21) :4189-4194

[7] Plasma lipoproteins: genetic influences and clinical implications [J].

Hegele, Robert A. .

NATURE REVIEWS GENETICS, 2009, 10 (02) :109-121

[8] Common variants at 30 loci contribute to polygenic dyslipidemia [J].

Kathiresan, Sekar ;

Willer, Cristen J. ;

Peloso, Gina M. ;

Demissie, Serkalem ;

Musunuru, Kiran ;

Schadt, Eric E. ;

Kaplan, Lee ;

Bennett, Derrick ;

Li, Yun ;

Tanaka, Toshiko ;

Voight, Benjamin F. ;

Bonnycastle, Lori L. ;

Jackson, Anne U. ;

Crawford, Gabriel ;

Surti, Aarti ;

Guiducci, Candace ;

Burtt, Noel P. ;

Parish, Sarah ;

Clarke, Robert ;

Zelenika, Diana ;

Kubalanza, Kari A. ;

Morken, Mario A. ;

Scott, Laura J. ;

Stringham, Heather M. ;

Galan, Pilar ;

Swift, Amy J. ;

Kuusisto, Johanna ;

Bergman, Richard N. ;

Sundvall, Jouko ;

Laakso, Markku ;

Ferrucci, Luigi ;

Scheet, Paul ;

Sanna, Serena ;

Uda, Manuela ;

Yang, Qiong ;

Lunetta, Kathryn L. ;

Dupuis, Josee ;

de Bakker, Paul I. W. ;

O'Donnell, Christopher J. ;

Chambers, John C. ;

Kooner, Jaspal S. ;

Hercberg, Serge ;

Meneton, Pierre ;

Lakatta, Edward G. ;

Scuteri, Angelo ;

Schlessinger, David ;

Tuomilehto, Jaakko ;

Collins, Francis S. ;

Groop, Leif ;

Altshuler, David .

NATURE GENETICS, 2009, 41 (01) :56-65

[9] Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans [J].

Kathiresan, Sekar ;

Melander, Olle ;

Guiducci, Candace ;

Surti, Aarti ;

Burtt, Noel P. ;

Rieder, Mark J. ;

Cooper, Gregory M. ;

Roos, Charlotta ;

Voight, Benjamin F. ;

Havulinna, Aki S. ;

Wahlstrand, Bjorn ;

Hedner, Thomas ;

Corella, Dolores ;

Tai, E. Shyong ;

Ordovas, Jose M. ;

Berglund, Goran ;

Vartiainen, Erkki ;

Jousilahti, Pekka ;

Hedblad, Bo ;

Taskinen, Marja-Riitta ;

Newton-Cheh, Christopher ;

Salomaa, Veikko ;

Peltonen, Leena ;

Groop, Leif ;

Altshuler, David M. ;

Orho-Melander, Marju .

NATURE GENETICS, 2008, 40 (02) :189-197

[10] Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants [J].

Kathiresan, Sekar ;

Altschuler, David ;

Anand, Sonia ;

Ardissino, Diego ;

Asselta, Rosanna ;

Ball, Stephen G. ;

Balmforth, Anthony J. ;

Berger, Klaus ;

Berglund, Goran ;

Bernardi, Francesco ;

Bernardinelli, Luisa ;

Berzuini, Carlo ;

Braund, Peter S. ;

Burnett, Mary-Susan ;

Burtt, Noel ;

Cambien, Francois ;

Casari, Giorgio ;

Celli, Patrizia ;

Chen, Zhen ;

Corrocher, Roberto ;

Daly, Mark J. ;

Deloukas, Panos ;

Devaney, Joe ;

Do, Ron ;

Duga, Stefano ;

Elosua, Roberto ;

Engert, James C. ;

Epstein, Stephen E. ;

Erdmann, Jeanette ;

Ferrario, Maurizio ;

Fetiveau, Raffaela ;

Fischer, Marcus ;

Friedlander, Yechiel ;

Gabriel, Stacey B. ;

Galli, Michele ;

Gianniny, Lauren ;

Girelli, Domenico ;

Grosshennig, Anika ;

Guiducci, Candace ;

Hakonarson, Hakon H. ;

Hall, Alistair S. ;

Havulinna, Aki S. ;

Hengstenberg, Christian ;

Hirschhorn, Joel N. ;

Holm, Hilma ;

Huge, Andreas ;

Kent, Kenneth M. ;

Konig, Inke R. ;

Korn, Joshua M. ;

Li, Mingyao .

NATURE GENETICS, 2009, 41 (03) :334-341

← 1 2 3 →