comparison of family history and snps for predicting risk of complex disease比较家庭历史和单核苷酸多态性预测复杂的疾病的风险.pdfVIP

Comparison of Family History and SNPs for Predicting Risk of Complex Disease 1 1 1,2 1 Chuong B. Do *, David A. Hinds , Uta Francke , Nicholas Eriksson 1 23andMe, Mountain View, California, United States of America, 2 Department of Genetics, Stanford University, Stanford, California, United States of America Abstract The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is presently known regarding the performance of these methods in situations where disease susceptibility depends on the cumulative contribution of multiple genetic factors of moderate or low penetrance. Using quantitative genetic theory, we develop a model for studying the predictive ability of family history and single nucleotide polymorphism (SNP)–based methods for assessing risk of polygenic disorders. We show that family history is most useful for highly common, heritable conditions (e.g., coronary artery disease), where it explains roughly 20%–30% of disease heritability, on par with the most successful SNP models based on associations discovered to date. In contrast, we find that for diseases of moderate or low frequency (e.g., Crohn disease) family history accounts for less than 4% of disease heritability, substantially lagging behind SNPs in almost all cases. These results indicate that, for a broad range of diseases, already identified SNP associations may be better predictors of risk than their family history–based counterparts, despite the large fraction of missing heritability that remains to be explained. Our model illustrates the difficulty of using either family history or SNPs for standalon