A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci

Abstract

The dominant and sometimes competing theories for the aetiology of complex human disease have been the common disease, common variant (CDCV) hypothesis, and the multiple rare variant (MRV) hypothesis. With the advent of genome wide association studies and of second-generation sequencing, we are fortunate in being able to test these ideas. The results to date suggest that these hypotheses are not mutually exclusive. Further, initial evidence suggests that both MRV and CDCV can be true at the same loci, and that other disease-related genetic mechanisms also exist at some of these loci. We propose calling these, pleomorphic risk loci, and discuss here how such loci not only offer understanding of the genetic basis of disease, but also provide mechanistic biological insight into disease processes.

Figure 1.

Schematic of PRL. (A) This schematic illustrates that at the same locus several disease-related genetic mechanisms may co-exist, each influencing disease through different biological effects on a single gene. In this particular model, expression of a gene is positively correlated with risk. Notably, we predict that common alleles affecting expression are also likely to modulate risk conferred by rare mutations and common coding variants. (B) The LPR model as it applies to genetic variability at SNCA in PD. Notably common non-coding variants that alter SNCA expression are linked to increased risk for disease; whole gene duplication and triplication mutations of SNCA are a known cause of disease (and copy number is correlated with severity) and rare protein-coding mutations have been identified. (C) The LPR model as it applies to LRRK2 in PD. Rare protein-coding disease-causing mutations have been identified, common protein-coding risk variants have been found and, recently, common non-coding variability 5′ to LRRK2 has been implicated as a risk factor for PD.