Genomic inflation factors under polygenic inheritance

被引：367

作者：

Yang, Jian ^{[1
]}

Weedon, Michael N. ^{[2
]}

Purcell, Shaun ^{[3
,4
]}

Lettre, Guillaume ^{[5
]}

Estrada, Karol ^{[6
]}

Willer, Cristen J. ^{[7
]}

Smith, Albert V. ^{[8
]}

Ingelsson, Erik ^{[9
]}

O'Connell, Jeffrey R. ^{[10
]}

Mangino, Massimo ^{[11
]}

Maegi, Reedik ^{[12
]}

Madden, Pamela A. ^{[13
]}

Heath, Andrew C. ^{[13
]}

Nyholt, Dale R.

Martin, Nicholas G.

Montgomery, Grant W.

Frayling, Timothy M. ^{[2
]}

Hirschhorn, Joel N. ^{[3
,14
,15
,16
,17
]}

McCarthy, Mark I. ^{[12
,18
]}

Goddard, Michael E. ^{[19
]}

Visscher, Peter M.

机构：

[1] Queensland Inst Med Res, Queensland Stat Genet Lab, Brisbane, Qld 4006, Australia

[2] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England

[3] Broad Inst, Cambridge, MA USA

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

[5] Univ Montreal, Montreal Heart Inst, Res Ctr, Montreal, PQ, Canada

[6] Dept Internal Med, Rotterdam, Netherlands

[7] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

[8] Heart Prevent Clin & Res Inst, Iceland Heart Assoc, Kopavogur, Iceland

[9] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[10] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[11] Kings Coll London, St Thomas Hosp, Twin Res & Genet Epidemiol Dept, London WC2R 2LS, England

[12] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[13] Washington Univ, Dept Psychiat, St Louis, MO USA

[14] Childrens Hosp, Program Genom, Boston, MA 02115 USA

[15] Childrens Hosp, Div Genet, Boston, MA 02115 USA

[16] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

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

[18] Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[19] Univ Melbourne, Dept Food & Agr Syst, Parkville, Vic 3052, Australia

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2011年 / 19卷 / 07期

基金：

英国医学研究理事会; 澳大利亚研究理事会;

关键词：

genome-wide association study; genomic inflation factor; polygenic inheritance; POPULATION STRATIFICATION; ASSOCIATION; LOCI; HERITABILITY;

D O I：

10.1038/ejhg.2011.39

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of similar to 4000 and similar to 133 000 individuals. European Journal of Human Genetics (2011) 19, 807-812; doi:10.1038/ejhg.2011.39; published online 16 March 2011

引用

页码：807 / 812

页数：6

共 24 条

[1] Hundreds of variants clustered in genomic loci and biological pathways affect human height [J].

Allen, Hana Lango ;

Estrada, Karol ;

Lettre, Guillaume ;

Berndt, Sonja I. ;

Weedon, Michael N. ;

Rivadeneira, Fernando ;

Willer, Cristen J. ;

Jackson, Anne U. ;

Vedantam, Sailaja ;

Raychaudhuri, Soumya ;

Ferreira, Teresa ;

Wood, Andrew R. ;

Weyant, Robert J. ;

Segre, Ayellet V. ;

Speliotes, Elizabeth K. ;

Wheeler, Eleanor ;

Soranzo, Nicole ;

Park, Ju-Hyun ;

Yang, Jian ;

Gudbjartsson, Daniel ;

Heard-Costa, Nancy L. ;

Randall, Joshua C. ;

Qi, Lu ;

Smith, Albert Vernon ;

Maegi, Reedik ;

Pastinen, Tomi ;

Liang, Liming ;

Heid, Iris M. ;

Luan, Jian'an ;

Thorleifsson, Gudmar ;

Winkler, Thomas W. ;

Goddard, Michael E. ;

Lo, Ken Sin ;

Palmer, Cameron ;

Workalemahu, Tsegaselassie ;

Aulchenko, Yurii S. ;

Johansson, Asa ;

Zillikens, M. Carola ;

Feitosa, Mary F. ;

Esko, Tonu ;

Johnson, Toby ;

Ketkar, Shamika ;

Kraft, Peter ;

Mangino, Massimo ;

Prokopenko, Inga ;

Absher, Devin ;

Albrecht, Eva ;

Ernst, Florian ;

Glazer, Nicole L. ;

Hayward, Caroline .

NATURE, 2010, 467 (7317) :832-838

[2] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[3] Demonstrating stratification in a European American population [J].

Campbell, CD ;

Ogburn, EL ;

Lunetta, KL ;

Lyon, HN ;

Freedman, ML ;

Groop, LC ;

Altshuler, D ;

Ardlie, KG ;

Hirschhorn, JN .

NATURE GENETICS, 2005, 37 (08) :868-872

[4] Population stratification and spurious allelic association [J].

Cardon, LR ;

Palmer, LJ .

LANCET, 2003, 361 (9357) :598-604

[5] Detecting disease associations due to linkage disequilibrium using haplotype tags: A class of tests and the determinants of statistical power [J].

Chapman, JM ;

Cooper, JD ;

Todd, JA ;

Clayton, DG .

HUMAN HEREDITY, 2003, 56 (1-3) :18-31

[6] Genomic control for association studies [J].

Devlin, B ;

Roeder, K .

BIOMETRICS, 1999, 55 (04) :997-1004

[7] Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci [J].

Franke, Andre ;

McGovern, Dermot P. B. ;

Barrett, Jeffrey C. ;

Wang, Kai ;

Radford-Smith, Graham L. ;

Ahmad, Tariq ;

Lees, Charlie W. ;

Balschun, Tobias ;

Lee, James ;

Roberts, Rebecca ;

Anderson, Carl A. ;

Bis, Joshua C. ;

Bumpstead, Suzanne ;

Ellinghaus, David ;

Festen, Eleonora M. ;

Georges, Michel ;

Green, Todd ;

Haritunians, Talin ;

Jostins, Luke ;

Latiano, Anna ;

Mathew, Christopher G. ;

Montgomery, Grant W. ;

Prescott, Natalie J. ;

Raychaudhuri, Soumya ;

Rotter, Jerome I. ;

Schumm, Philip ;

Sharma, Yashoda ;

Simms, Lisa A. ;

Taylor, Kent D. ;

Whiteman, David ;

Wijmenga, Cisca ;

Baldassano, Robert N. ;

Barclay, Murray ;

Bayless, Theodore M. ;

Brand, Stephan ;

Buening, Carsten ;

Cohen, Albert ;

Colombel, Jean-Frederick ;

Cottone, Mario ;

Stronati, Laura ;

Denson, Ted ;

De Vos, Martine ;

D'Inca, Renata ;

Dubinsky, Marla ;

Edwards, Cathryn ;

Florin, Tim ;

Franchimont, Denis ;

Gearry, Richard ;

Glas, Juergen ;

Van Gossum, Andre .

NATURE GENETICS, 2010, 42 (12) :1118-+

[8] Detect and adjust for population stratification in population-based association study using genomic control markers:: an application of Affymetrix Genechip® Human Mapping 10K array [J].

Hao, K ;

Li, C ;

Rosenow, C ;

Wong, WH .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2004, 12 (12) :1001-1006

[9] Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution [J].

Heid, Iris M. ;

Jackson, Anne U. ;

Randall, Joshua C. ;

Winkler, Thomas W. ;

Qi, Lu ;

Steinthorsdottir, Valgerdur ;

Thorleifsson, Gudmar ;

Zillikens, M. Carola ;

Speliotes, Elizabeth K. ;

Maegi, Reedik ;

Workalemahu, Tsegaselassie ;

White, Charles C. ;

Bouatia-Naji, Nabila ;

Harris, Tamara B. ;

Berndt, Sonja I. ;

Ingelsson, Erik ;

Willer, Cristen J. ;

Weedon, Michael N. ;

Luan, Jianan ;

Vedantam, Sailaja ;

Esko, Tonu ;

Kilpelaeinen, Tuomas O. ;

Kutalik, Zoltan ;

Li, Shengxu ;

Monda, Keri L. ;

Dixon, Anna L. ;

Holmes, Christopher C. ;

Kaplan, Lee M. ;

Liang, Liming ;

Min, Josine L. ;

Moffatt, Miriam F. ;

Molony, Cliona ;

Nicholson, George ;

Schadt, Eric E. ;

Zondervan, Krina T. ;

Feitosa, Mary F. ;

Ferreira, Teresa ;

Allen, Hana Lango ;

Weyant, Robert J. ;

Wheeler, Eleanor ;

Wood, Andrew R. ;

Estrada, Karol ;

Goddard, Michael E. ;

Lettre, Guillaume ;

Mangino, Massimo ;

Nyholt, Dale R. ;

Purcell, Shaun ;

Smith, Albert Vernon ;

Visscher, Peter M. ;

Yang, Jian .

NATURE GENETICS, 2010, 42 (11) :949-U160

[10] Potential etiologic and functional implications of genome-wide association loci for human diseases and traits [J].

Hindorff, Lucia A. ;

Sethupathy, Praveen ;

Junkins, Heather A. ;

Ramos, Erin M. ;

Mehta, Jayashri P. ;

Collins, Francis S. ;

Manolio, Teri A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (23) :9362-9367

← 1 2 3 →