常见疾病罕见变异-Synthetic association（一个新概念）

drjiangbo

Abstract
Genome-wide association studies (GWAS) have now identified at least 2,000 common variants that appear associated with
common diseases or related traits (http://www.genome.gov/gwastudies), hundreds of which have been convincingly
replicated. It is generally thought that the associated markers reflect the effect of a nearby common (minor allele frequency
.0.05) causal site, which is associated with the marker, leading to extensive resequencing efforts to find causal sites. We
propose as an alternative explanation that variants much less common than the associated one may create ‘‘synthetic
associations’’ by occurring, stochastically, more often in association with one of the alleles at the common site versus the
other allele. Although synthetic associations are an obvious theoretical possibility, they have never been systematically
explored as a possible explanation for GWAS findings. Here, we use simple computer simulations to show the conditions
under which such synthetic associations will arise and how they may be recognized. We show that they are not only
possible, but inevitable, and that under simple but reasonable genetic models, they are likely to account for or contribute to
many of the recently identified signals reported in genome-wide association studies. We also illustrate the behavior of
synthetic associations in real datasets by showing that rare causal mutations responsible for both hearing loss and sickle cell
anemia create genome-wide significant synthetic associations, in the latter case extending over a 2.5-Mb interval
encompassing scores of ‘‘blocks’’ of associated variants. In conclusion, uncommon or rare genetic variants can easily create
synthetic associations that are credited to common variants, and this possibility requires careful consideration in the
interpretation and follow up of GWAS signals.

阿平

这是不是说很多信号都不可信，需要先检验过是否Synthetic association

drjiangbo

回复 阿平 的帖子

    近年来，遗传学家越来越重视对复杂性疾病和性状的研究。复杂疾病(Complex diseases)是指由多个基因，环境因素及基因-环境相互作用共同造成的疾病，如近视、糖尿病、高血压和哮喘等(图1)。常见疾病/常见变异(Common disease/Common variant，CD/CV)假说提出常见复杂疾病(发病率不小于1%)的遗传风险是由多个微效基因的多个常见多态性（频率大于1%）的累加效应构成。

drjiangbo

回复 drjiangbo 的帖子

       近几年，根据CD/CV理论，通过GWS对大量复杂性疾病进行研究，然而很少寻找到真正的致病common variants。遗传学家们通过对已有研究的分析，提出了CD/RV即common disease，rare viriants的理论，而寻找rare viriants，通过GWS是很难获得解决的。只有通过全基因序列扫描或exomes扫描基于家系的患者或极端表现型的病例才有可能证明这个理论。
       而至于通过GWS寻找到与causal variants关联的common variants，但经过resequencing附件区域仍无法找到causal variants的解释可以通过下图解释：

drjiangbo

感觉复杂疾病的遗传因素研究真是好玩