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

ANZGene Consortium, International Endogene Consortium, Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium, S. Hong Lee, Denise Harold, Dale R. Nyholt, Michael E. Goddard, Krina T. Zondervan, Julie Williams, Grant W. Montgomery, Naomi R. Wray, Hong Lee

Research output: Contribution to journalArticle

100 Citations (Scopus)

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.

LanguageEnglish
Pages832-841
Number of pages10
JournalHuman Molecular Genetics
Volume22
Issue number4
DOIs
Publication statusPublished - 1 Feb 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

ANZGene Consortium, International Endogene Consortium, & Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium (2013). Estimation and partitioning of polygenic variation captured by common snps for alzheimer's disease, multiple sclerosis and endometriosis. Human Molecular Genetics, 22(4), 832-841. https://doi.org/10.1093/hmg/dds491
ANZGene Consortium ; International Endogene Consortium ; Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium. / Estimation and partitioning of polygenic variation captured by common snps for alzheimer's disease, multiple sclerosis and endometriosis. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 4. pp. 832-841.
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ANZGene Consortium, International Endogene Consortium & Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium 2013, 'Estimation and partitioning of polygenic variation captured by common snps for alzheimer's disease, multiple sclerosis and endometriosis', Human Molecular Genetics, vol. 22, no. 4, pp. 832-841. https://doi.org/10.1093/hmg/dds491

Estimation and partitioning of polygenic variation captured by common snps for alzheimer's disease, multiple sclerosis and endometriosis. / ANZGene Consortium; International Endogene Consortium; Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium.

In: Human Molecular Genetics, Vol. 22, No. 4, 01.02.2013, p. 832-841.

Research output: Contribution to journalArticle

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AU - International Endogene Consortium

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AU - Lee, S. Hong

AU - Harold, Denise

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AU - Goddard, Michael E.

AU - Zondervan, Krina T.

AU - Williams, Julie

AU - Montgomery, Grant W.

AU - Wray, Naomi R.

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ANZGene Consortium, International Endogene Consortium, Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium. Estimation and partitioning of polygenic variation captured by common snps for alzheimer's disease, multiple sclerosis and endometriosis. Human Molecular Genetics. 2013 Feb 1;22(4):832-841. https://doi.org/10.1093/hmg/dds491