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

Lee, S.H., Harold, D., Nyholt, D.R., Goddard, M.E., Zondervan, K.T., Williams, J., Montgomery, G.W., Wray, N.R., & Visscher, P.M. (2013) 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.

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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.

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ID Code: 91826
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Alzheimer Disease/*genetics, Case-Control Studies, Chromosomes, Human, Endometriosis/*genetics, Female, Gene Frequency, Genetic Variation, Genotype, Humans, Male, *Models, Genetic, Molecular Sequence Annotation, Multifactorial Inheritance, Multiple Sclerosis/*genetics, *Polymorphism, Single Nucleotide
DOI: 10.1093/hmg/dds491
ISSN: 1460-2083
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 The Author
Copyright Statement: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
Deposited On: 14 Jan 2016 04:17
Last Modified: 20 Jan 2016 00:57

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