Evaluating the Heritability Explained by Known Susceptibility Variants: A Survey of Ten Complex Diseases
Evaluating the Heritability Explained by Known Susceptibility Variants: A Survey of Ten Complex Diseases
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DOI：
10.1002/gepi.20579
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发表时间：
2011-07-01
影响因子：
2.1
通讯作者：
Sham, Pak C.
中科院分区：
文献类型：
--
作者：
So, Hon-Cheong;Gui, Allen H. S.;Sham, Pak C.
最近，越来越多的易感性变异已被确定为复杂的疾病。与此同时，“缺失遗传性”的担忧也出现了。然而，没有统一的方法来评估由个体遗传变异解释的二元结果的遗传性。缺乏对复杂疾病“遗传缺失”程度的系统和定量评估。在这项研究中，我们测量了由个体变异解释的责任方差，这可以直接解释为基因座特异性遗传力。该方法扩展到处理单倍型，多等位基因标记，多位点基因型，和标记的连锁不平衡。提出了估计标准误差和置信区间的方法。为了评估我们目前对复杂疾病遗传基础的理解水平，我们对10种疾病进行了调查，评估了已知变异解释的总方差。评估的疾病包括阿尔茨海默病、双相情感障碍、乳腺癌、冠状动脉疾病、克罗恩病、前列腺癌、精神分裂症、系统性红斑狼疮（SLE）、1型糖尿病和2型糖尿病。在10种疾病中解释的总方差中位数为9.81%，而每个相关SNP解释的方差中位数约为0.25%。我们的研究结果表明，很大一部分的遗传性仍然无法解释的疾病正在研究。实现本文所述方法的程序可在http://sites.google.com/site/honcheongso/software/varexp上获得。Genet.流行病学35：310-317，2011. (C)2011 Wiley-Liss，Inc.
Recently, an increasing number of susceptibility variants have been identified for complex diseases. At the same time, the concern of "missing heritability'' has also emerged. There is however no unified way to assess the heritability explained by individual genetic variants for binary outcomes. A systemic and quantitative assessment of the degree of "missing heritability'' for complex diseases is lacking. In this study, we measure the variance in liability explained by individual variants, which can be directly interpreted as the locus-specific heritability. The method is extended to deal with haplotypes, multi-allelic markers, multi-locus genotypes, and markers in linkage disequilibrium. Methods to estimate the standard error and confidence interval are proposed. To assess our current level of understanding of the genetic basis of complex diseases, we conducted a survey of 10 diseases, evaluating the total variance explained by the known variants. The diseases under evaluation included Alzheimer's disease, bipolar disorder, breast cancer, coronary artery disease, Crohn's disease, prostate cancer, schizophrenia, systemic lupus erythematosus (SLE), type 1 diabetes and type 2 diabetes. The median total variance explained across the 10 diseases was 9.81%, while the median variance explained per associated SNP was around 0.25%. Our results suggest that a substantial proportion of heritability remains unexplained for the diseases under study. Programs to implement the methodologies described in this paper are available at http://sites.google.com/site/honcheongso/software/varexp. Genet. Epidemiol. 35: 310-317, 2011. (C) 2011 Wiley-Liss, Inc.