Yang Quanhe, Khoury Muin J, Friedman Jm, Little Julian, Flanders W Dana
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA.
Int J Epidemiol. 2005 Oct;34(5):1129-37. doi: 10.1093/ije/dyi130. Epub 2005 Jul 25.
Most common human diseases are due to complex interactions among multiple genetic variants and environmental risk factors. There is debate over whether variants of a relatively small number of genes, each with weak or modest individual effects, account for a large proportion of common diseases in the population, or whether a large number of rare variants with large effects underlie genetic susceptibility to these diseases. It is not clear how many genes are necessary to account for an appreciable population-attributable fraction of these diseases.
In this analysis, we estimated the number of disease susceptibility genes needed to account for varying population attributable fractions of a common complex disease, taking into account the genotype prevalence, risk ratios for individual genes, and the model of gene-gene interactions (additive or multiplicative).
Very large numbers of rare genotypes (e.g. those with frequencies of 1 per 5000 or less) are needed to explain 50% of a common disease in the population, even if the individual risk ratios are large (RR = 10-20). On the other hand, only approximately 20 genes are usually needed to explain 50% of the burden of a disease in the population if the predisposing genotypes are common (> or = 25%), even if the individual risk ratios are relatively small (RR = 1.2-1.5).
Our results suggest that a limited number of disease susceptibility genes with common variants can explain a major proportion of common complex diseases in the population. Our findings should help focus the search for common genetic variants that provide the most important predispositions to complex human diseases.
大多数常见人类疾病是由多种基因变异与环境风险因素之间的复杂相互作用所致。对于数量相对较少的基因变异（每个变异的个体效应较弱或适中）是否能解释人群中很大一部分常见疾病，或者大量具有较大效应的罕见变异是否构成这些疾病的遗传易感性，存在争议。目前尚不清楚需要多少基因才能解释这些疾病可观的人群归因分数。
在本分析中，我们估计了对于一种常见复杂疾病，考虑到基因型患病率、单个基因的风险比以及基因 - 基因相互作用模型（加性或乘性），要解释不同的人群归因分数所需的疾病易感基因数量。
即使个体风险比很大（相对危险度 = 10 - 20），也需要大量非常罕见的基因型（例如频率为每5000个或更少出现1次的那些基因型）才能解释人群中50%的常见疾病。另一方面，如果易感基因型较为常见（≥25%），即使个体风险比相对较小（相对危险度 = 1.2 - 1.5），通常仅需约20个基因就能解释人群中50%的疾病负担。
我们的结果表明，有限数量的具有常见变异的疾病易感基因可以解释人群中大部分常见复杂疾病。我们的发现应有助于集中寻找为复杂人类疾病提供最重要易感性的常见基因变异。
