Genetic architecture of quantitative traits and complex diseases

Abstract

More than 150 years after Mendel discovered the laws of heredity, the genetic architecture of phenotypic variation remains elusive. Here, we discuss recent progress in deciphering how genotypes map onto phenotypes, sources of genetic complexity, and how model organisms are illuminating general principles about the relationship between genetic and phenotypic variation. Moreover, we highlight insights gleaned from large-scale sequencing studies in humans, and how this knowledge informs outstanding questions about the genetic architecture of quantitative traits and complex diseases. Finally, we articulate how the confluence of technologies enabling whole-genome sequencing, comprehensive phenotyping, and high-throughput functional assays of polymorphisms will facilitate a more principled and mechanistic understanding of the genetic architecture of phenotypic variation.

Figure 1.. Schematic illustration of the mapping of genotypes onto phenotypes.

The top two rectangles represent the set of all possible genotypic and environmental states, respectively. Genetic architecture refers to the rules that govern how a set of multilocus genotypes maps onto phenotypes, and how the environment influences this mapping. Genotype space can be extremely large with 3ⁿ possible multilocus genotypes, where n denotes the number of trait influencing variants. Lines represent the mapping of particular multilocus genotypes (red circles) in particular environments to trait values. For simplicity, phenotypic space is only shown for two traits (the height of the bivariate distribution indicates population frequency). Note, identical genotypes in different environments can culminate in different phenotypic values (representing gene-environment interactions) and distinct genotypes either in the same or different environments can result in the same phenotypic values (representing robustness).

Figure 2.. Most protein-coding variants found in individuals are common at the population level.

The plot shows the cumulative proportion of protein-coding variants found in individuals as a function of minor allele frequency. The data used in this analysis is based on exome sequencing data from 4,298 European Americans and 2,217 African Americans [29]. Light pink lines show each of the 6,515 individuals and the dark red line is the median across all individuals.