Department of Psychiatry, University of Hong Kong, Hong Kong SAR, China.
Genet Epidemiol. 2011 Jul;35(5):310-7. doi: 10.1002/gepi.20579. Epub 2011 Mar 3.
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.
最近，越来越多的易感性变异被确定为复杂疾病。与此同时，“遗传缺失”的担忧也出现了。然而，对于二分类结果，还没有一种统一的方法来评估单个遗传变异所解释的遗传率。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，我们测量了个体变异所解释的易患性方差，这可以直接解释为特定基因座的遗传率。该方法扩展到处理单倍型、多等位基因标记、多基因座基因型和连锁不平衡标记。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程度，我们对 10 种疾病进行了调查，评估了已知变异所解释的总方差。评估的疾病包括阿尔茨海默病、双相情感障碍、乳腺癌、冠心病、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。这 10 种疾病的总方差解释中位数为 9.81%，而每个相关 SNP 的方差解释中位数约为 0.25%。我们的结果表明，在所研究的疾病中，很大一部分遗传率仍未得到解释。可在 http://sites.google.com/site/honcheongso/software/varexp 上获取实施本文中描述的方法的程序。
