Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Margaux F. Keller; Mohamad Saad; Jose Bras; Francesco Bettella; Nayia Nicolaou; Javier Simón-Sánchez; Florian Mittag; Finja Büchel; Manu Sharma; J. Raphael Gibbs; Claudia Schulte; Valentina Moskvina; Alexandra Durr; Peter Holmans; Laura L. Kilarski; Rita Guerreiro; Dena G. Hernandez; Alexis Brice; Pauli Ylikotila; Hreinn Stefánsson; Kari Majamaa; Huw R. Morris; Nigel Williams; Thomas Gasser; Peter Heutink; Nicholas W. Wood; John Hardy; Maria Martinez; Andrew B. Singleton; Michael A. Nalls; Vincent Plagnol; Una Marie Sheerin; Suzanne Lesage; Sigurlaug Sveinbjörnsdóttir; Sampath Arepalli; Roger Barker; Yoav Ben-Shlomo; Henk W. Berendse; Daniela Berg; Kailash Bhatia; Rob M.A. de Bie; Alessandro Biffi; Bas Bloem; Zoltan Bochdanovits; Michael Bonin; Kathrin Brockmann; Janet Brooks; David J. Burn; Gavin Charlesworth; Honglei Chen; Patrick F. Chinnery; Sean Chong; Carl E. Clarke; Mark R. Cookson; J. Mark Cooper; Jean Christophe Corvol; Carl Counsell; Philippe Damier; Jean François Dartigues; Panos Deloukas; Günther Deuschl; David T. Dexter; Karin D. van Dijk; Allissa Dillman; Frank Durif; Alexandra Dürr; Sarah Edkins; Jonathan R. Evans; Thomas Foltynie; Jianjun Gao; Michelle Gardner; Alison Goate; Emma Gray; Ómar Gústafsson; Clare Harris; Jacobus J. van Hilten; Albert Hofman; Albert Hollenbeck; Janice Holton; Michele Hu; Xuemei Huang; Heiko Huber; Gavin Hudson; Sarah E. Hunt; Johanna Huttenlocher; Thomas Illig; Pálmi V. Jónsson; Jean Charles Lambert; Cordelia Langford; Andrew Lees; Peter Lichtner; Patricia Limousin; Grisel Lopez; Delia Lorenz; Alisdair McNeill; Catriona Moorby; Matthew Moore; Karen E. Morrison; Ese Mudanohwo; Sean S. O'Sullivan; Justin Pearson; Joel S. Perlmutter; Hjörvar Pétursson; Pierre Pollak; Bart Post; Simon C. Potter; Bernard Ravina; Tamas Revesz; Olaf Riess; Fernando Rivadeneira; Patrizia Rizzu; Mina Ryten; Stephen J. Sawcer; Anthony Schapira; Hans Scheffer; Karen Shaw; Ira Shoulson; Ellen Sidransky; Colin Smith; Chris C.A. Spencer; Stacy Steinberg; Joanna D. Stockton; Amy Strange; Kevin Talbot; Carlie M. Tanner; Avazeh Tashakkori-Ghanbaria; François Tison; Daniah Trabzuni; Bryan J. Traynor; André G. Uitterlinden; Daan Velseboer; Marie Vidailhet; Robert Walker; Bart van de Warrenburg; Mirdhu Wickremaratchi; Caroline H. Williams-Gray; Sophie Winder-Rhodes; Kári Stefánsson; Peter Donnelly; Ines Barroso; Jenefer M. Blackwell; Elvira Bramon; Matthew A. Brown; Juan P. Casas; Aiden Corvin; Audrey Duncanson; Janusz Jankowski; Hugh S. Markus; Christopher G. Mathew; Colin N.A. Palmer; Robert Plomin; Anna Rautanen; Richard C. Trembath; Ananth C. Viswanathan; Gavin Band; Céline Bellenguez; Colin Freeman; Garrett Hellenthal; Eleni Giannoulatou; Matti Pirinen; Richard Pearson; Zhan Su; Damjan Vukcevic; Rhian Gwilliam; Hannah Blackburn; Suzannah J. Bumpstead; Serge Dronov; Matthew Gillman; Naomi Hammond; Alagurevathi Jayakumar; Owen T. McCann; Jennifer Liddle; Radhi Ravindrarajah; Michelle Ricketts; Matthew Waller; Paul Weston; Sara Widaa; Pamela Whittaker; Mark I. McCarthy

doi:10.1093/hmg/dds335

Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

Margaux F. Keller, Mohamad Saad, Jose Bras, Francesco Bettella, Nayia Nicolaou, Javier Simón-Sánchez, Florian Mittag, Finja Büchel, Manu Sharma, J. Raphael Gibbs, Claudia Schulte, Valentina Moskvina, Alexandra Durr, Peter Holmans, Laura L. Kilarski, Rita Guerreiro, Dena G. Hernandez, Alexis Brice, Pauli Ylikotila, Hreinn StefánssonKari Majamaa, Huw R. Morris, Nigel Williams, Thomas Gasser, Peter Heutink, Nicholas W. Wood, John Hardy, Maria Martinez, Andrew B. Singleton, Michael A. Nalls, Vincent Plagnol, Una Marie Sheerin, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Roger Barker, Yoav Ben-Shlomo, Henk W. Berendse, Daniela Berg, Kailash Bhatia, Rob M.A. de Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Kathrin Brockmann, Janet Brooks, David J. Burn, Gavin Charlesworth, Honglei Chen, Patrick F. Chinnery, Sean Chong, Carl E. Clarke, Mark R. Cookson, J. Mark Cooper, Jean Christophe Corvol, Carl Counsell, Philippe Damier, Jean François Dartigues, Panos Deloukas, Günther Deuschl, David T. Dexter, Karin D. van Dijk, Allissa Dillman, Frank Durif, Alexandra Dürr, Sarah Edkins, Jonathan R. Evans, Thomas Foltynie, Jianjun Gao, Michelle Gardner, Alison Goate, Emma Gray, Ómar Gústafsson, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Heiko Huber, Gavin Hudson, Sarah E. Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V. Jónsson, Jean Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Alisdair McNeill, Catriona Moorby, Matthew Moore, Karen E. Morrison, Ese Mudanohwo, Sean S. O'Sullivan, Justin Pearson, Joel S. Perlmutter, Hjörvar Pétursson, Pierre Pollak, Bart Post, Simon C. Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen J. Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Colin Smith, Chris C.A. Spencer, Stacy Steinberg, Joanna D. Stockton, Amy Strange, Kevin Talbot, Carlie M. Tanner, Avazeh Tashakkori-Ghanbaria, François Tison, Daniah Trabzuni, Bryan J. Traynor, André G. Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Caroline H. Williams-Gray, Sophie Winder-Rhodes, Kári Stefánsson, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Richard C. Trembath, Ananth C. Viswanathan, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Zhan Su, Damjan Vukcevic, Rhian Gwilliam, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Naomi Hammond, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Mark I. McCarthy

Research output: Contribution to journal › Article › peer-review

156 Scopus citations

Abstract

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

Original language	English
Pages (from-to)	4996-5009
Number of pages	14
Journal	Human molecular genetics
Volume	21
Issue number	22
DOIs	https://doi.org/10.1093/hmg/dds335
State	Published - Nov 2012

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10.1093/hmg/dds335

Cite this

Keller, M. F., Saad, M., Bras, J., Bettella, F., Nicolaou, N., Simón-Sánchez, J., Mittag, F., Büchel, F., Sharma, M., Gibbs, J. R., Schulte, C., Moskvina, V., Durr, A., Holmans, P., Kilarski, L. L., Guerreiro, R., Hernandez, D. G., Brice, A., Ylikotila, P., ... McCarthy, M. I. (2012). Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Human molecular genetics, 21(22), 4996-5009. https://doi.org/10.1093/hmg/dds335

@article{eda48b7938cf45888aff1759550e153b,

title = "Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease",

abstract = "Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.",

author = "Keller, {Margaux F.} and Mohamad Saad and Jose Bras and Francesco Bettella and Nayia Nicolaou and Javier Sim{\'o}n-S{\'a}nchez and Florian Mittag and Finja B{\"u}chel and Manu Sharma and Gibbs, {J. Raphael} and Claudia Schulte and Valentina Moskvina and Alexandra Durr and Peter Holmans and Kilarski, {Laura L.} and Rita Guerreiro and Hernandez, {Dena G.} and Alexis Brice and Pauli Ylikotila and Hreinn Stef{\'a}nsson and Kari Majamaa and Morris, {Huw R.} and Nigel Williams and Thomas Gasser and Peter Heutink and Wood, {Nicholas W.} and John Hardy and Maria Martinez and Singleton, {Andrew B.} and Nalls, {Michael A.} and Vincent Plagnol and Sheerin, {Una Marie} and Suzanne Lesage and Sigurlaug Sveinbj{\"o}rnsd{\'o}ttir and Sampath Arepalli and Roger Barker and Yoav Ben-Shlomo and Berendse, {Henk W.} and Daniela Berg and Kailash Bhatia and {de Bie}, {Rob M.A.} and Alessandro Biffi and Bas Bloem and Zoltan Bochdanovits and Michael Bonin and Kathrin Brockmann and Janet Brooks and Burn, {David J.} and Gavin Charlesworth and Honglei Chen and Chinnery, {Patrick F.} and Sean Chong and Clarke, {Carl E.} and Cookson, {Mark R.} and Cooper, {J. Mark} and Corvol, {Jean Christophe} and Carl Counsell and Philippe Damier and Dartigues, {Jean Fran{\c c}ois} and Panos Deloukas and G{\"u}nther Deuschl and Dexter, {David T.} and {van Dijk}, {Karin D.} and Allissa Dillman and Frank Durif and Alexandra D{\"u}rr and Sarah Edkins and Evans, {Jonathan R.} and Thomas Foltynie and Jianjun Gao and Michelle Gardner and Alison Goate and Emma Gray and {\'O}mar G{\'u}stafsson and Clare Harris and {van Hilten}, {Jacobus J.} and Albert Hofman and Albert Hollenbeck and Janice Holton and Michele Hu and Xuemei Huang and Heiko Huber and Gavin Hudson and Hunt, {Sarah E.} and Johanna Huttenlocher and Thomas Illig and J{\'o}nsson, {P{\'a}lmi V.} and Lambert, {Jean Charles} and Cordelia Langford and Andrew Lees and Peter Lichtner and Patricia Limousin and Grisel Lopez and Delia Lorenz and Alisdair McNeill and Catriona Moorby and Matthew Moore and Morrison, {Karen E.} and Ese Mudanohwo and O'Sullivan, {Sean S.} and Justin Pearson and Perlmutter, {Joel S.} and Hj{\"o}rvar P{\'e}tursson and Pierre Pollak and Bart Post and Potter, {Simon C.} and Bernard Ravina and Tamas Revesz and Olaf Riess and Fernando Rivadeneira and Patrizia Rizzu and Mina Ryten and Sawcer, {Stephen J.} and Anthony Schapira and Hans Scheffer and Karen Shaw and Ira Shoulson and Ellen Sidransky and Colin Smith and Spencer, {Chris C.A.} and Stacy Steinberg and Stockton, {Joanna D.} and Amy Strange and Kevin Talbot and Tanner, {Carlie M.} and Avazeh Tashakkori-Ghanbaria and Fran{\c c}ois Tison and Daniah Trabzuni and Traynor, {Bryan J.} and Uitterlinden, {Andr{\'e} G.} and Daan Velseboer and Marie Vidailhet and Robert Walker and {van de Warrenburg}, Bart and Mirdhu Wickremaratchi and Williams-Gray, {Caroline H.} and Sophie Winder-Rhodes and K{\'a}ri Stef{\'a}nsson and Peter Donnelly and Ines Barroso and Blackwell, {Jenefer M.} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan P.} and Aiden Corvin and Audrey Duncanson and Janusz Jankowski and Markus, {Hugh S.} and Mathew, {Christopher G.} and Palmer, {Colin N.A.} and Robert Plomin and Anna Rautanen and Trembath, {Richard C.} and Viswanathan, {Ananth C.} and Gavin Band and C{\'e}line Bellenguez and Colin Freeman and Garrett Hellenthal and Eleni Giannoulatou and Matti Pirinen and Richard Pearson and Zhan Su and Damjan Vukcevic and Rhian Gwilliam and Hannah Blackburn and Bumpstead, {Suzannah J.} and Serge Dronov and Matthew Gillman and Naomi Hammond and Alagurevathi Jayakumar and McCann, {Owen T.} and Jennifer Liddle and Radhi Ravindrarajah and Michelle Ricketts and Matthew Waller and Paul Weston and Sara Widaa and Pamela Whittaker and McCarthy, {Mark I.}",

note = "Funding Information: This work was supported by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, NIEHS and NHGRI of the National Institutes of Health, Department of Health and Human Services (project numbers Z01-AG000949-02 and Z01-ES101986), human subjects protocol 2003-077. This work was also supported by the US Department of Defense (award number W81XWH-09-2-0128); National Institutes of Health (grants NS057105 and RR024992); American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum f{\"u}r Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also funded by the Michael J. Fox Foundation (MS), and sponsored by the Landspitali University Hospital Research Fund (grant to S.Sv.); Icelandic Research Council (grant to S.Sv.); and European Community Framework Programme 7, People Programme and IAPP on novel genetic and phenotypic markers of Parkinson{\textquoteright}s disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to H.P. and J.Hu.). Genotyping of UK replication cases on ImmunoChip was part of the WTCCC2 project, which was funded by the Wellcome Trust (083948/Z/07/Z). This study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to N.W.W., J.Ha. and A.Sc.). This study was also supported by Parkinson{\textquoteright}s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). DNA extraction work that was done in the UK was undertaken at University College London Hospitals, University College London, which received a proportion of funding from the Department of Health{\textquoteright}s National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson{\textquoteright}s Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. Mohamad Saad was funded by the France Parkinson Association.",

year = "2012",

month = nov,

doi = "10.1093/hmg/dds335",

language = "English",

volume = "21",

pages = "4996--5009",

journal = "Human molecular genetics",

issn = "0964-6906",

number = "22",

}

Keller, MF, Saad, M, Bras, J, Bettella, F, Nicolaou, N, Simón-Sánchez, J, Mittag, F, Büchel, F, Sharma, M, Gibbs, JR, Schulte, C, Moskvina, V, Durr, A, Holmans, P, Kilarski, LL, Guerreiro, R, Hernandez, DG, Brice, A, Ylikotila, P, Stefánsson, H, Majamaa, K, Morris, HR, Williams, N, Gasser, T, Heutink, P, Wood, NW, Hardy, J, Martinez, M, Singleton, AB, Nalls, MA, Plagnol, V, Sheerin, UM, Lesage, S, Sveinbjörnsdóttir, S, Arepalli, S, Barker, R, Ben-Shlomo, Y, Berendse, HW, Berg, D, Bhatia, K, de Bie, RMA, Biffi, A, Bloem, B, Bochdanovits, Z, Bonin, M, Brockmann, K, Brooks, J, Burn, DJ, Charlesworth, G, Chen, H, Chinnery, PF, Chong, S, Clarke, CE, Cookson, MR, Cooper, JM, Corvol, JC, Counsell, C, Damier, P, Dartigues, JF, Deloukas, P, Deuschl, G, Dexter, DT, van Dijk, KD, Dillman, A, Durif, F, Dürr, A, Edkins, S, Evans, JR, Foltynie, T, Gao, J, Gardner, M, Goate, A, Gray, E, Gústafsson, Ó, Harris, C, van Hilten, JJ, Hofman, A, Hollenbeck, A, Holton, J, Hu, M, Huang, X, Huber, H, Hudson, G, Hunt, SE, Huttenlocher, J, Illig, T, Jónsson, PV, Lambert, JC, Langford, C, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Lorenz, D, McNeill, A, Moorby, C, Moore, M, Morrison, KE, Mudanohwo, E, O'Sullivan, SS, Pearson, J, Perlmutter, JS, Pétursson, H, Pollak, P, Post, B, Potter, SC, Ravina, B, Revesz, T, Riess, O, Rivadeneira, F, Rizzu, P, Ryten, M, Sawcer, SJ, Schapira, A, Scheffer, H, Shaw, K, Shoulson, I, Sidransky, E, Smith, C, Spencer, CCA, Steinberg, S, Stockton, JD, Strange, A, Talbot, K, Tanner, CM, Tashakkori-Ghanbaria, A, Tison, F, Trabzuni, D, Traynor, BJ, Uitterlinden, AG, Velseboer, D, Vidailhet, M, Walker, R, van de Warrenburg, B, Wickremaratchi, M, Williams-Gray, CH, Winder-Rhodes, S, Stefánsson, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Trembath, RC, Viswanathan, AC, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Su, Z, Vukcevic, D, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P & McCarthy, MI 2012, 'Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease', Human molecular genetics, vol. 21, no. 22, pp. 4996-5009. https://doi.org/10.1093/hmg/dds335

TY - JOUR

T1 - Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

AU - Keller, Margaux F.

AU - Saad, Mohamad

AU - Bras, Jose

AU - Bettella, Francesco

AU - Nicolaou, Nayia

AU - Simón-Sánchez, Javier

AU - Mittag, Florian

AU - Büchel, Finja

AU - Sharma, Manu

AU - Gibbs, J. Raphael

AU - Schulte, Claudia

AU - Moskvina, Valentina

AU - Durr, Alexandra

AU - Holmans, Peter

AU - Kilarski, Laura L.

AU - Guerreiro, Rita

AU - Hernandez, Dena G.

AU - Brice, Alexis

AU - Ylikotila, Pauli

AU - Stefánsson, Hreinn

AU - Majamaa, Kari

AU - Morris, Huw R.

AU - Williams, Nigel

AU - Gasser, Thomas

AU - Heutink, Peter

AU - Wood, Nicholas W.

AU - Hardy, John

AU - Martinez, Maria

AU - Singleton, Andrew B.

AU - Nalls, Michael A.

AU - Plagnol, Vincent

AU - Sheerin, Una Marie

AU - Lesage, Suzanne

AU - Sveinbjörnsdóttir, Sigurlaug

AU - Arepalli, Sampath

AU - Barker, Roger

AU - Ben-Shlomo, Yoav

AU - Berendse, Henk W.

AU - Berg, Daniela

AU - Bhatia, Kailash

AU - de Bie, Rob M.A.

AU - Biffi, Alessandro

AU - Bloem, Bas

AU - Bochdanovits, Zoltan

AU - Bonin, Michael

AU - Brockmann, Kathrin

AU - Brooks, Janet

AU - Burn, David J.

AU - Charlesworth, Gavin

AU - Chen, Honglei

AU - Chinnery, Patrick F.

AU - Chong, Sean

AU - Clarke, Carl E.

AU - Cookson, Mark R.

AU - Cooper, J. Mark

AU - Corvol, Jean Christophe

AU - Counsell, Carl

AU - Damier, Philippe

AU - Dartigues, Jean François

AU - Deloukas, Panos

AU - Deuschl, Günther

AU - Dexter, David T.

AU - van Dijk, Karin D.

AU - Dillman, Allissa

AU - Durif, Frank

AU - Dürr, Alexandra

AU - Edkins, Sarah

AU - Evans, Jonathan R.

AU - Foltynie, Thomas

AU - Gao, Jianjun

AU - Gardner, Michelle

AU - Goate, Alison

AU - Gray, Emma

AU - Gústafsson, Ómar

AU - Harris, Clare

AU - van Hilten, Jacobus J.

AU - Hofman, Albert

AU - Hollenbeck, Albert

AU - Holton, Janice

AU - Hu, Michele

AU - Huang, Xuemei

AU - Huber, Heiko

AU - Hudson, Gavin

AU - Hunt, Sarah E.

AU - Huttenlocher, Johanna

AU - Illig, Thomas

AU - Jónsson, Pálmi V.

AU - Lambert, Jean Charles

AU - Langford, Cordelia

AU - Lees, Andrew

AU - Lichtner, Peter

AU - Limousin, Patricia

AU - Lopez, Grisel

AU - Lorenz, Delia

AU - McNeill, Alisdair

AU - Moorby, Catriona

AU - Moore, Matthew

AU - Morrison, Karen E.

AU - Mudanohwo, Ese

AU - O'Sullivan, Sean S.

AU - Pearson, Justin

AU - Perlmutter, Joel S.

AU - Pétursson, Hjörvar

AU - Pollak, Pierre

AU - Post, Bart

AU - Potter, Simon C.

AU - Ravina, Bernard

AU - Revesz, Tamas

AU - Riess, Olaf

AU - Rivadeneira, Fernando

AU - Rizzu, Patrizia

AU - Ryten, Mina

AU - Sawcer, Stephen J.

AU - Schapira, Anthony

AU - Scheffer, Hans

AU - Shaw, Karen

AU - Shoulson, Ira

AU - Sidransky, Ellen

AU - Smith, Colin

AU - Spencer, Chris C.A.

AU - Steinberg, Stacy

AU - Stockton, Joanna D.

AU - Strange, Amy

AU - Talbot, Kevin

AU - Tanner, Carlie M.

AU - Tashakkori-Ghanbaria, Avazeh

AU - Tison, François

AU - Trabzuni, Daniah

AU - Traynor, Bryan J.

AU - Uitterlinden, André G.

AU - Velseboer, Daan

AU - Vidailhet, Marie

AU - Walker, Robert

AU - van de Warrenburg, Bart

AU - Wickremaratchi, Mirdhu

AU - Williams-Gray, Caroline H.

AU - Winder-Rhodes, Sophie

AU - Stefánsson, Kári

AU - Donnelly, Peter

AU - Barroso, Ines

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Palmer, Colin N.A.

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Band, Gavin

AU - Bellenguez, Céline

AU - Freeman, Colin

AU - Hellenthal, Garrett

AU - Giannoulatou, Eleni

AU - Pirinen, Matti

AU - Pearson, Richard

AU - Su, Zhan

AU - Vukcevic, Damjan

AU - Gwilliam, Rhian

AU - Blackburn, Hannah

AU - Bumpstead, Suzannah J.

AU - Dronov, Serge

AU - Gillman, Matthew

AU - Hammond, Naomi

AU - Jayakumar, Alagurevathi

AU - McCann, Owen T.

AU - Liddle, Jennifer

AU - Ravindrarajah, Radhi

AU - Ricketts, Michelle

AU - Waller, Matthew

AU - Weston, Paul

AU - Widaa, Sara

AU - Whittaker, Pamela

AU - McCarthy, Mark I.

N1 - Funding Information: This work was supported by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, NIEHS and NHGRI of the National Institutes of Health, Department of Health and Human Services (project numbers Z01-AG000949-02 and Z01-ES101986), human subjects protocol 2003-077. This work was also supported by the US Department of Defense (award number W81XWH-09-2-0128); National Institutes of Health (grants NS057105 and RR024992); American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA; Hersenstichting Nederland; Neuroscience Campus Amsterdam; and the section of medical genomics, the Prinses Beatrix Fonds. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German National Genome Network (NGFNplus number 01GS08134, German Ministry for Education and Research); by the German Federal Ministry of Education and Research (NGFN 01GR0468, PopGen); and 01EW0908 in the frame of ERA-NET NEURON and Helmholtz Alliance Mental Health in an Ageing Society (HA-215), which was funded by the Initiative and Networking Fund of the Helmholtz Association. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also funded by the Michael J. Fox Foundation (MS), and sponsored by the Landspitali University Hospital Research Fund (grant to S.Sv.); Icelandic Research Council (grant to S.Sv.); and European Community Framework Programme 7, People Programme and IAPP on novel genetic and phenotypic markers of Parkinson’s disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD (to H.P. and J.Hu.). Genotyping of UK replication cases on ImmunoChip was part of the WTCCC2 project, which was funded by the Wellcome Trust (083948/Z/07/Z). This study was supported by the Medical Research Council and Wellcome Trust disease centre (grant WT089698/Z/09/Z to N.W.W., J.Ha. and A.Sc.). This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943). DNA extraction work that was done in the UK was undertaken at University College London Hospitals, University College London, which received a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding. This study was supported in part by the Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award (WT089698) to the Parkinson’s Disease Consortium (UKPDC), whose members are from the UCL Institute of Neurology, University of Sheffield and the Medical Research Council Protein Phosphorylation Unit at the University of Dundee. Mohamad Saad was funded by the France Parkinson Association.

PY - 2012/11

Y1 - 2012/11

N2 - Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

AB - Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

UR - http://www.scopus.com/inward/record.url?scp=84868134823&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds335

DO - 10.1093/hmg/dds335

M3 - Article

C2 - 22892372

AN - SCOPUS:84868134823

SN - 0964-6906

VL - 21

SP - 4996

EP - 5009

JO - Human molecular genetics

JF - Human molecular genetics

IS - 22

ER -

Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease

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