Molecular Basis of Complex Traits

Abstract

Most genetically determined differences between individuals, including (but not limited to) susceptibility to specific diseases, depend on functional variation at multiple genes (loci). The frequency of these variants (alleles) in the general population varies from common to rare. The contribution of most common alleles, each in isolation, to disease risk is weak. Most uncommon and rare alleles have not been studied to date and some may have strong effects on disease risk even if they contribute to disease cause each in a small subset of cases. This mixture of strong and weak effects by common and rare alleles is referred to as allelic architecture. Defining the allelic architecture of each disease will be the first step towards using an individual's genetic profile to individualise the molecular diagnosis within a group of cases that all bear the same clinical diagnostic label.

Key Concepts:

  • Most diseases and other human traits have statistically significant familial clustering, indicating the involvement of genetic susceptibility.

  • Genetic susceptibility to most diseases is determined by a large number of gene variants (loci).

  • Disease‐associated variants may change the sequence of the protein product, or the control of its transcription, RNA stability or translational efficiency.

  • Most known loci have a weak genetic association with the disease or trait.

  • A genetic association may be weak because of weak biology, or because the associated allele is merely an imperfect marker for an untested rare allele with strong effect.

  • The discovery, among low‐frequency alleles, of those that have the strongest effects, is the next frontier in the genetics of complex traits and the greatest promise to personalised medicine.

Keywords: complex trait; missing heritability; allele frequency; relative risk; nonsynonymous; genetic marker; linkage disequilibrium; allelic architecture; genome‐wide

Figure 1.

A schematic annotation of certain interesting properties of complex‐trait loci, depending on their position on the two‐dimensional space defined by the two continuums of relative risk (RR) and minor allele frequency (MAF). Please note that the axis markings are arbitrary and not in scale, as the figure is meant to illustrate the concept rather than present specific data.

Figure 2.

Position of 145 known dichotomous complex‐trait loci in the OR‐MAF space, to illustrate that the majority cluster in the low‐OR/high‐MAF quadrant and that few high‐OR/high‐MAF loci exist. Data were from loci for which both values are listed in GWAS Central (http://www.gwascentral.org/index), except for HLA in type 1 diabetes, which were obtained from Erlich et al. . To make ORs directly comparable, they were calculated using the lower‐risk allele as base regardless of frequency, so that all values are >1. Quantitative trait loci from the same database were not included, as the effect magnitude is harder to standardise.

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Further Reading

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Qu HQ, Tien M and Polychronakos C (2010) Statistical significance in genetic association studies. Clinical and Investigative Medicine 33(5): E266–E270.

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Polychronakos, Constantin(Sep 2011) Molecular Basis of Complex Traits. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021448]