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

Margaux F. Keller; Mohamad Saad; groep; 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; Yoav Ben-Shlomo; Karin D. van Dijk; Albert Hofman; Bart Post; Olaf Riess; Olaf Riess; André G. Uitterlinden

doi:10.1093/hmg/dds335

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

Margaux F. Keller, Mohamad Saad, groep, 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 YlikotilaHreinn 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^*, Yoav Ben-Shlomo, Karin D. van Dijk, Albert Hofman, Bart Post, Olaf Riess, Olaf Riess, André G. Uitterlinden

^*Corresponding author for this work

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

158 Citations (Scopus)

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
Publication status	Published - 15 Nov 2012

Bibliographical 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 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.

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Keller, M. F., Saad, M., groep, 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., ... Uitterlinden, A. G. (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{7d303933b96c4ebca228f1c31db0a2b2,

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 groep 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 {van Dijk}, {Karin D.} and Albert Hofman and Bart Post and Olaf Riess and Olaf Riess and Uitterlinden, {Andr{\'e} G.}",

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,

day = "15",

doi = "10.1093/hmg/dds335",

language = "English",

volume = "21",

pages = "4996--5009",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "22",

}

Keller, MF, Saad, M, groep, 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, Ben-Shlomo, Y, van Dijk, KD, Hofman, A, Post, B, Riess, O , Riess, O & Uitterlinden, AG 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 - groep

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 - van Dijk, Karin D.

AU - Hofman, Albert

AU - Post, Bart

AU - Riess, Olaf

AU - Uitterlinden, André G.

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 - 2012/11/15

Y1 - 2012/11/15

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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