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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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posted on 2023-05-17, 21:33 authored by Lee, SH, Harold, D, Nyholt, DR, Scott, RJ, Lechner-Scott, J, Moscato, P, Booth, DR, Stewart, GJ, Heard, RN, Mason, D, Griffiths, L, Broadley, S, Brown, MA, Slee, M, Simon James FooteSimon James Foote, Jim StankovichJim Stankovich, Bruce TaylorBruce Taylor, Wiley, J, Bahlo, M, Perreau, V, Field, J, Butzkueven, H, Kilpatrick, TJ, Rubio, J, Marriott, M, Carroll, WM, Kermode, AG, Anderson, CA, Gordon, SD, Guo, Q, Henders, AK, Lambert, A, Kraft, P, Kennedy, SH, Macgregor, S, Martin, NG, Missmer, SA, Morris, AP, Painter, JN, Roseman, F, Treloar, SA, Wallace, L, Sims, R, Gerrish, A, Chapman, J, Moskvina, V, Abraham, R, Hollingworth, P, Hamshere, M, Pahwa, JS, Dowzell, K, Williams, A, Jones, N, Thomas, C, Stretton, A, Morgan, A, Lovestone, S, Powell, J, Proitsi, P, Lupton, MK, Brayne, C, Rubinsztein, DC, Gill, M, Lawlor, B, Lynch, A, Morgan, K, Brown, K, Passmore, P, Craig, D, McGuinness, B, Todd, S, Holmes, C, Mann, D, Smith, AD, Love, S, Kehoe, PG, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Heun, R, Kolsch, H, Schurmann, B, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frolich, L, Hampel, H, Hull, M, Rujescu, D, Goate, A, Kauwe, JSK, Cruchaga, C, Nowotny, P, Morris, JC, Mayo, K, Livingston, G, Bass, NJ, Gurling, H, McQuillin, A, Gwilliam, R, Deloukas, P, Nothen, MM, Holmans, P, O'Donovan, M, Owen, MJ, Goddard, ME, Zondervan, KT, J Williams, Montgomery, GW, Wray, NR, Visscher, PM
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.


Publication title

Human Molecular Genetics










Menzies Institute for Medical Research


Oxford Univ Press

Place of publication

Great Clarendon St, Oxford, England, Ox2 6Dp

Rights statement

Licensed under Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0)

Repository Status

  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

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