Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis.
Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis.
复制标题
DOI：
10.1093/hmg/dds491
复制
发表时间：
2013-02-15
影响因子：
3.5
通讯作者：
Visscher PM
中科院分区：
文献类型：
--
作者：
Lee SH;Harold D;Nyholt DR;ANZGene Consortium;International Endogene Consortium;Genetic and Environmental Risk for Alzheimer's disease Consortium;Goddard ME;Zondervan KT;Williams J;Montgomery GW;Wray NR;Visscher PM
子宫内膜异位症（艾德）、阿尔茨海默病（AD）和多发性硬化症（MS）等常见疾病在许多国家的医疗保健负担中占很大比例。针对这些疾病的全基因组关联研究（GWAS）已经确定了一些导致这些疾病风险的个体遗传变异。然而，大多数变体的效应量很小，并且已知变体总体上只能解释估计遗传力的一小部分。我们使用线性混合模型同时拟合所有单核苷酸多态性（SNPs），并使用来自这三种疾病无关个体GWAS的SNPs估计易感性量表上的遗传方差。对于这三种疾病中的每一种，病例和对照样本都不是在同一实验室进行基因分型的。我们证明，仔细的分析可以获得可靠的估计，但也不充分的SNPs的质量控制（QC）可能会导致虚假的结果，过于严格的QC可能会删除真实的遗传信号。我们的估计表明，商业上可获得的基因分型芯片上的常见SNP捕获了导致所有三种疾病的责任的显著变异。所有SNP标记的总变异的估计比例为0.26（SE 0.04）为艾德，0.24（SE 0.03）为AD和0.30（SE 0.03）为MS。此外，我们划分的遗传变异解释为五个类别的次要等位基因频率（MAF），染色体和基因注释。我们提供了强有力的证据表明，很大一部分的变化的责任是由常见的SNP解释，从而提供了深入了解疾病的遗传结构。
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.
登录
查看更多内容
影响因子：
2.1
作者：
Lee, Sang Hong;Nyholt, Dale R.;Visscher, Peter M.
通讯作者：
Visscher, Peter M.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
64.8
作者：
Deary, Ian J.;Yang, Jian;Visscher, Peter M.
通讯作者：
Visscher, Peter M.
DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
通讯作者：
Manolio, Teri A.