The UK10K project identifies rare variants in health and disease

被引：723

作者：

Walter, Klaudia ^{[1
]}

Min, Josine L. ^{[3
]}

Huang, Jie ^{[1
]}

Crooks, Lucy ^{[1
,4
]}

Memari, Yasin ^{[1
]}

McCarthy, Shane ^{[1
]}

Perry, John R. B. ^{[5
,6
]}

Xu, ChangJiang ^{[7
,8
]}

Futema, Marta ^{[9
]}

Lawson, Daniel ^{[10
,11
]}

Iotchkova, Valentina ^{[1
,12
]}

Schiffels, Stephan

Hendricks, Audrey E. ^{[1
]}

Danecek, Petr ^{[1
]}

Li, Rui ^{[7
,13
]}

Floyd, James ^{[1
,15
]}

Wain, Louise V. ^{[16
]}

Barroso, Ines ^{[1
,18
,19
]}

Humphries, Steve E. ^{[9
]}

Hurles, Matthew E. ^{[1
]}

Zeggini, Eleftheria ^{[1
]}

Barrett, Jeffrey C. ^{[1
]}

Plagnol, Vincent ^{[20
]}

Richards, J. Brent ^{[5
,7
,8
,13
,14
]}

Greenwood, Celia M. T. ^{[7
,8
]}

Timpson, Nicholas J. ^{[3
]}

Durbin, Richard ^{[1
]}

Soranzo, Nicole ^{[1
,2
]}

Bala, Senduran ^{[1
]}

Clapham, Peter

Coates, Guy ^{[1
]}

Cox, Tony ^{[1
]}

Daly, Allan ^{[1
]}

Danecek, Petr ^{[1
]}

Du, Yuanping ^{[21
]}

Durbin, Richard ^{[1
]}

Edkins, Sarah ^{[1
]}

Ellis, Peter ^{[1
]}

Flicek, Paul ^{[1
,12
]}

Guo, Xiaosen ^{[21
,22
]}

Guo, Xueqin ^{[21
]}

Huang, Liren ^{[21
]}

Jackson, David K. ^{[1
]}

Joyce, Chris ^{[1
]}

Keane, Thomas ^{[1
]}

Kolb-Kokocinski, Anja ^{[1
]}

Langford, Cordelia ^{[1
]}

Li, Yingrui ^{[21
]}

Liang, Jieqin ^{[21
]}

Lin, Hong ^{[21
]}

机构：

[1] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1HH, England

[2] Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England

[3] Univ Bristol, Sch Social & Community Med, MRC, Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England

[4] Sheffield Childrens NHS Fdn Trust, Sheffield Diagnost Genet Serv, Sheffield S10 2TH, S Yorkshire, England

[5] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[6] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC,Epidemiol Unit, Cambridge CB2 0QQ, England

[7] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ H3T 1E2, Canada

[8] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H3A 1A2, Canada

[9] UCL, BHF Labs, Cardiovasc Genet, Inst Cardiovasc Sci, London WC1E 6JJ, England

[10] Univ Bristol, Sch Math, Bristol BS8 2BN, Avon, England

[11] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England

[12] European Mol Biol Lab, European Bioinformat Inst, Cambridge CB10 1SD, England

[13] McGill Univ, Jewish Gen Hosp, Dept Med, Montreal, PQ H3A 1B1, Canada

[14] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

[15] Univ London, John Vane Sci Ctr, Genome Ctr, London EC1M 6BQ, England

[16] Univ Leicester, Dept Hlth Sci, Leicester LE1 7RH, Leics, England

[17] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England

[18] Univ Cambridge, Metab Res Labs, Cambridge CB2 0QQ, England

[19] Wellcome Trust MRC Inst Metab Sci, Addenbrookes Hosp, NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England

[20] UCL, Genet Inst UGI, London WC1E 6BT, England

[21] BGI Shenzhen, Shenzhen 518083, Peoples R China

[22] Univ Copenhagen, Dept Biol, DK-2200 Copenhagen, Denmark

[23] BGI Europe, London EC2M 4YE, England

[24] King Abdulaziz Univ, Princess Al Jawhara Albrahim Ctr Excellence Res H, Jeddah 21589, Saudi Arabia

[25] Macau Univ Sci & Technol, Taipa 999078, Macau, Peoples R China

[26] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China

[27] Univ Hong Kong, State Key Lab Pharmaceut Biotechnol, Hong Kong, Hong Kong, Peoples R China

[28] Great Ormond St Hosp NHS Fdn Trust, North East Thames Reg Genet Serv, London WC1N 3JH, England

[29] Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Med Genet, I-34100 Trieste, Italy

[30] Univ Trieste, Dept Med Surg & Hlth Sci, I-34100 Trieste, Italy

[31] Univ Bristol, Sch Social & Community Med, Bristol Genet Epidemiol Labs, Bristol BS8 2BN, Avon, England

[32] Biogen Idec Inc, Computat Biol & Genom, Cambridge, MA 02142 USA

[33] Kings Coll London, Div Genet & Mol Med, Dept Med & Mol Genet, Sch Med,Guys Hosp, London SE1 9RT, England

[34] Univ Queensland, Diamantina Inst, Translat Res Inst, Brisbane, Qld 4102, Australia

[35] Adapt Biotechnol Corp, Seattle, WA 98102 USA

[36] St Georges Univ London, Human Genet Res Ctr, London SW17 0RE, England

[37] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[38] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[39] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[40] Illumina Cambridge Ltd, Saffron Walden CB10 1XL, Essex, England

[41] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[42] Guys & St Thomas Fdn Trust, Natl Inst Hlth Res NIHR Biomed Res Ctr, London SE1 9RT, England

[43] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA

[44] UCL, Farr Inst Hlth Informat Res, Inst Hlth Informat, London NW1 2DA, England

[45] Univ Bristol, ALSPAC, Bristol BS8 2BN, Avon, England

[46] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England

[47] Univ Bristol, Sch Oral & Dent Sci, Bristol BS1 2LY, Avon, England

[48] Univ Bristol, Sch Expt Psychol, Bristol BS8 1TU, Avon, England

[49] Glenfield Gen Hosp, Natl Inst Hlth Res NIHR Leicester Resp Biomed Res, Leicester LE3 9QP, Leics, England

[50] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

来源：

NATURE | 2015年 / 526卷 / 7571期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; LOW-FREQUENCY; INCIDENTAL FINDINGS; COMMON; HERITABILITY; EXOME; APOC3; RISK; LOCI; SNP;

D O I：

10.1038/nature14962

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

引用

页码：82 / +

页数：21

共 49 条

[41] The NHGRI GWAS Catalog, a curated resource of SNP-trait associations [J].

Welter, Danielle ;

MacArthur, Jacqueline ;

Morales, Joannella ;

Burdett, Tony ;

Hall, Peggy ;

Junkins, Heather ;

Klemm, Alan ;

Flicek, Paul ;

Manolio, Teri ;

Hindorff, Lucia ;

Parkinson, Helen .

NUCLEIC ACIDS RESEARCH, 2014, 42 (D1) :D1001-D1006

[42] Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity [J].

Wheeler, Eleanor ;

Huang, Ni ;

Bochukova, Elena G. ;

Keogh, Julia M. ;

Lindsay, Sarah ;

Garg, Sumedha ;

Henning, Elana ;

Blackburn, Hannah ;

Loos, Ruth J. F. ;

Wareham, Nick J. ;

O'Rahilly, Stephen ;

Hurles, Matthew E. ;

Barroso, Ines ;

Farooqi, I. Sadaf .

NATURE GENETICS, 2013, 45 (05) :513-U76

[43]

Whittall R A, 2002, J Med Genet, V39, pe57, DOI 10.1136/jmg.39.9.e57

[44] Genes Contributing to Pain Sensitivity in the Normal Population: An Exome Sequencing Study [J].

Williams, Frances M. K. ;

Scollen, Serena ;

Cao, Dandan ;

Memari, Yasin ;

Hyde, Craig L. ;

Zhang, Baohong ;

Sidders, Benjamin ;

Ziemek, Daniel ;

Shi, Yujian ;

Harris, Juliette ;

Harrow, Ian ;

Dougherty, Brian ;

Malarstig, Anders ;

McEwen, Robert ;

Stephens, Joel C. ;

Patel, Ketan ;

Menni, Cristina ;

Shin, So-Youn ;

Hodgkiss, Dylan ;

Surdulescu, Gabriela ;

He, Wen ;

Jin, Xin ;

McMahon, Stephen B. ;

Soranzo, Nicole ;

John, Sally ;

Wang, Jun ;

Spector, Tim D. .

PLOS GENETICS, 2012, 8 (12)

[45] Rare-Variant Association Testing for Sequencing Data with the Sequence Kernel Association Test [J].

Wu, Michael C. ;

Lee, Seunggeun ;

Cai, Tianxi ;

Li, Yun ;

Boehnke, Michael ;

Lin, Xihong .

AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 89 (01) :82-93

[46] Estimating Genome-Wide Significance for Whole-Genome Sequencing Studies [J].

Xu, ChangJiang ;

Tachmazidou, Ioanna ;

Walter, Klaudia ;

Ciampi, Antonio ;

Zeggini, Eleftheria ;

Greenwood, Celia M. T. .

GENETIC EPIDEMIOLOGY, 2014, 38 (04) :281-290

[47] Common SNPs explain a large proportion of the heritability for human height [J].

Yang, Jian ;

Benyamin, Beben ;

McEvoy, Brian P. ;

Gordon, Scott ;

Henders, Anjali K. ;

Nyholt, Dale R. ;

Madden, Pamela A. ;

Heath, Andrew C. ;

Martin, Nicholas G. ;

Montgomery, Grant W. ;

Goddard, Michael E. ;

Visscher, Peter M. .

NATURE GENETICS, 2010, 42 (07) :565-U131

[48] Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture [J].

Zheng, Hou-Feng ;

Forgetta, Vincenzo ;

Hsu, Yi-Hsiang ;

Estrada, Karol ;

Rosello-Diez, Alberto ;

Leo, Paul J. ;

Dahia, Chitra L. ;

Park-Min, Kyung Hyun ;

Tobias, Jonathan H. ;

Kooperberg, Charles ;

Kleinman, Aaron ;

Styrkarsdottir, Unnur ;

Liu, Ching-Ti ;

Uggla, Charlotta ;

Evans, Daniel S. ;

Nielson, Carrie M. ;

Walter, Klaudia ;

Pettersson-Kymmer, Ulrika ;

McCarthy, Shane ;

Eriksson, Joel ;

Kwan, Tony ;

Jhamai, Mila ;

Trajanoska, Katerina ;

Memari, Yasin ;

Min, Josine ;

Huang, Jie ;

Danecek, Petr ;

Wilmot, Beth ;

Li, Rui ;

Chou, Wen-Chi ;

Mokry, Lauren E. ;

Moayyeri, Alireza ;

Claussnitzer, Melina ;

Cheng, Chia-Ho ;

Cheung, Warren ;

Medina-Gomez, Carolina ;

Ge, Bing ;

Chen, Shu-Huang ;

Choi, Kwangbom ;

Oei, Ling ;

Fraser, James ;

Kraaij, Robert ;

Hibbs, Matthew A. ;

Gregson, Celia L. ;

Paquette, Denis ;

Hofman, Albert ;

Wibom, Carl ;

Tranah, Gregory J. ;

Marshall, Mhairi ;

Gardiner, Brooke B. .

NATURE, 2015, 526 (7571) :112-+

[49] Searching for missing heritability: Designing rare variant association studies [J].

Zuk, Or ;

Schaffner, Stephen F. ;

Samocha, Kaitlin ;

Do, Ron ;

Hechter, Eliana ;

Kathiresan, Sekar ;

Daly, Mark J. ;

Neale, Benjamin M. ;

Sunyaev, Shamil R. ;

Lander, Eric S. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (04) :E455-E464

← 1 2 3 4 5 →