Sporadic cases are the norm for complex disease

Abstract

The results of genome-wide association studies have revealed that most human complex diseases (for example, cancer, diabetes and psychiatric disorders) are affected by a large number of variants, each of which explains a small increase in disease risk, suggesting a pattern of polygenic inheritance. At the same time, it has been argued that most complex diseases are genetically heterogeneous because many sporadic cases are observed, as well as cases with a family history. In this study, under the assumption of polygenic inheritance, we derive the expected proportion of sporadic cases using analytical methods and simulation. We show how the proportion of sporadic cases depends on disease prevalence (K) and heritability on the underlying liability scale (h L 2 ). We predict the underlying heritability and the proportion of sporadic cases for a range of human complex diseases, and show that this proportion is typically large. For a disease with h L 2 ¼63% and K¼0.4%, such as schizophrenia, 483% of proband cases are predicted to be sporadic (no affected first-, second-and third-degree relatives) in typical families (on an average, two children per couple). For the majority of these diseases, a large proportion of sporadic cases is expected under the polygenic model, implying that the observed large proportion of sporadic cases is not informative to the causal mechanism of a complex genetic disease. European Journal of Human Genetics (2010Genetics ( ) 18, 1039Genetics ( -1043 doi:10.1038/ejhg.2009 published online 14 October 2009 Keywords: sporadic case; polygenic inheritance; complex disease INTRODUCTION Large-scale, high-density genome-wide association studies (GWAS) have greatly facilitated the discovery of genetic variants that affect the predisposition to human complex diseases. 1 The results of recent GWAS suggest that the majority of susceptible loci have small contributions to phenotypic variation, which indicates that there should be a large number of susceptibility loci involved in the genetic basis of complex disease. [2][3][4][5][6][7][8] These findings are consistent with the polygenic model, proposed almost a century ago, 9 underlying the genetic etiology of complex diseases. At the same time, on the basis of the knowledge of family history, differentiation is often made between sporadic and familial cases. This differentiation implies some sort of genetic heterogeneity, either that environmental factors are more important in sporadic cases or that sporadic cases arise from new mutations of large effect size. Integrating this differentiation into an understanding of the genetic architecture of complex disease depends on the frequency of sporadic cases, consistent with the polygenic model.In this study, we investigate the relative proportion of sporadic and familial cases expected under the polygenic threshold model. We assume that disease susceptibility is genetically homogeneous in the population and the observed illness results from the accumulative effect of multiple common genetic and environment...

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