Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis

S. Hong Lee, Denise Harold, Jeannette Lechner-Scott, Dan Rujescu, Alison Goate, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Pablo Moscato, Rhian Gwilliam, Panagiotis Deloukas, Markus M. Nöthen, Peter Holmans, Michael O'Donovan, Michael J. OwenDavid R. Booth, Graeme J. Stewart, Robert N. Heard, Deborah Mason, Lyn Griffiths, Simon Broadley, Matthew A. Brown, Mark Slee, Dale R. Nyholt, Simon J. Foote, Jim Stankovich, Bruce V. Taylor, James Wiley, Melanie Bahlo, Victoria Perreau, Judith Field, Helmut Butzkueven, Trevor J. Kilpatrick, Justin Rubio, Michael E. Goddard, Mark Marriott, William M. Carroll, Allan G. Kermode, Carl A. Anderson, Scott D. Gordon, Qun Guo, Anjali K. Henders, Ann Lambert, Peter Kraft, Stephen H. Kennedy, Krina T. Zondervan, Stuart Macgregor, Nicholas G. Martin, Stacey A. Missmer, Andrew P. Morris, Jodie N. Painter, Fenella Roseman, Susan A. Treloar, Leanne Wallace, Rebecca Sims, Amy Gerrish, Julie Williams, Jade Chapman, Valentina Moskvina, Richard Abraham, Paul Hollingworth, Marian Hamshere, Jaspreet Singh Pahwa, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Grant W. Montgomery, Alexandra Stretton, Angharad Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian Lawlor, Naomi R. Wray, Aoibhinn Lynch, Kevin Morgan, Kristelle Brown, Peter Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A. David Smith, Peter M. Visscher, Seth Love, Patrick G. Kehoe, John Hardy, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Reiner Heun, Rodney J. Scott, Heike Kölsch, Britta Schürmann, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Dichgans Martin, Lutz Frölich, Harald Hampel, Michael Hüll

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    161 Citations (Scopus)


    Common diseases such as endometriosis (ED), Alzheimer's disease (AD) and multiple sclerosis (MS) account for a significant proportion of the health care burden in many countries. Genome-wide association studies (GWASs) for these diseases have identified a number of individual genetic variants contributing to the risk of those diseases. However, the effect size for most variants is small and collectively the known variants explain only a small proportion of the estimated heritability. We used a linear mixed model to fit all single nucleotide polymorphisms (SNPs) simultaneously, and estimated genetic variances on the liability scale using SNPs from GWASs in unrelated individuals for these three diseases. For each of the three diseases, case and control samples were not all genotyped in the same laboratory. We demonstrate that a careful analysis can obtain robust estimates, but also that insufficient quality control (QC) of SNPs can lead to spurious results and that too stringent QC is likely to remove real genetic signals. Our estimates show that common SNPs on commercially available genotyping chips capture significant variation contributing to liability for all three diseases. The estimated proportion of total variation tagged by all SNPs was 0.26 (SE 0.04) for ED, 0.24 (SE 0.03) for AD and 0.30 (SE 0.03) for MS. Further, we partitioned the genetic variance explained into five categories by a minor allele frequency (MAF), by chromosomes and gene annotation. We provide strong evidence that a substantial proportion of variation in liability is explained by common SNPs, and thereby give insights into the genetic architecture of the diseases.
    Original languageEnglish
    Pages (from-to)832-841
    Number of pages10
    JournalHuman Molecular Genetics
    Issue number4
    Publication statusPublished - 2013


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