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

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Lee, SH and Harold, D and Nyholt, DR and Scott, RJ and Lechner-Scott, J and Moscato, P and Booth, DR and Stewart, GJ and Heard, RN and Mason, D and Griffiths, L and Broadley, S and Brown, MA and Slee, M and Foote, SJ and Stankovich, J and Taylor, BV and Wiley, J and Bahlo, M and Perreau, V and Field, J and Butzkueven, H and Kilpatrick, TJ and Rubio, J and Marriott, M and Carroll, WM and Kermode, AG and Anderson, CA and Gordon, SD and Guo, Q and Henders, AK and Lambert, A and Kraft, P and Kennedy, SH and Macgregor, S and Martin, NG and Missmer, SA and Morris, AP and Painter, JN and Roseman, F and Treloar, SA and Wallace, L and Sims, R and Gerrish, A and Chapman, J and Moskvina, V and Abraham, R and Hollingworth, P and Hamshere, M and Pahwa, JS and Dowzell, K and Williams, A and Jones, N and Thomas, C and Stretton, A and Morgan, A and Lovestone, S and Powell, J and Proitsi, P and Lupton, MK and Brayne, C and Rubinsztein, DC and Gill, M and Lawlor, B and Lynch, A and Morgan, K and Brown, K and Passmore, P and Craig, D and McGuinness, B and Todd, S and Holmes, C and Mann, D and Smith, AD and Love, S and Kehoe, PG and Hardy, J and Mead, S and Fox, N and Rossor, M and Collinge, J and Maier, W and Jessen, F and Heun, R and Kolsch, H and Schurmann, B and van den Bussche, H and Heuser, I and Kornhuber, J and Wiltfang, J and Dichgans, M and Frolich, L and Hampel, H and Hull, M and Rujescu, D and Goate, A and Kauwe, JSK and Cruchaga, C and Nowotny, P and Morris, JC and Mayo, K and Livingston, G and Bass, NJ and Gurling, H and McQuillin, A and Gwilliam, R and Deloukas, P and Nothen, MM and Holmans, P and O'Donovan, M and Owen, MJ and Goddard, ME and Zondervan, KT and Williams, J and Montgomery, GW and Wray, NR and Visscher, PM, Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis, Human Molecular Genetics, 22, (4) pp. 832-841. ISSN 0964-6906 (2013) [Refereed Article]


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Licensed under Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) http://creativecommons.org/licenses/by-nc/3.0/

DOI: doi:10.1093/hmg/dds491

Abstract

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
Author:Foote, SJ (Professor Simon Foote)
Author:Stankovich, J (Dr Jim Stankovich)
Author:Taylor, BV (Professor Bruce Taylor)
ID Code:88357
Year Published:2013
Web of Science® Times Cited:79
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-01-30
Last Modified:2017-11-07
Downloads:165 View Download Statistics

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