Complex Multifactorial Genetic Diseases


Variation in traits can be owing to genetic factors or the environment – nature versus nurture – or more likely, a combination of both. It may be of interest, especially when a trait is detrimental, to localise the regions of the genome that contain the genes involved and beyond that, to map specific risk variants. Understanding the possible roles that genes may play in trait variation and, furthermore, estimating or modelling the genetic component are important first steps to inform subsequent genetic studies. There are many different study designs and genetic analysis techniques, each with their respective strengths and weaknesses for the identification of risk variants. Knowledge of disease susceptibility genes may help in the quest for new treatments and cures.

Key Concepts

  • Types of trait variation.
  • The possible roles of genes in trait variation.
  • The components of phenotypic variation.
  • Study designs for the estimation of genetic effects and heritability.
  • Genetic heterogeneity.
  • Types of genetic study designs.
  • Various analysis techniques used in genetic studies.

Keywords: genetic disease; phenotype; heterogeneity; heritability; linkage; association; complex traits

Figure 1. Visualisations of four types of genetic analyses. Twin studies (a) analyse concordance rates (i.e. both affected/blue) between monozygotic and dizygotic twins. Adoption studies (b) capitalise on the fact that adopted children share genes (no environment) with their biological parents and share the environment (no genes) with their adoptive parents. Linkage analysis (c) uses genetic data in pedigree members to identify alleles that segregate with affection status. Association analysis (d) uses genetic data from large cohorts of affected cases and unaffected controls and tests each allele for association with a trait.
Figure 2. Examples of three types of inheritance in pedigrees. A dominant trait is shown in (a), yet notice that there is incomplete penetrance of the allele, allowing for unaffected carriers. A recessive trait is shown in (b). This allele seems to be somewhat common, as multiple unrelated marry‐in pedigree members are also carriers. A complex trait is shown in (c). Notice that there is no clear inheritance pattern, suggesting that the trait relies on multiple factors, possibly both genetic and environmental.
Figure 3. Illustrates various methods to explain estimated heritability. Linkage and family‐based approaches have largely been used for monogenic diseases with highly penetrant, or causal variants. On the opposite end, genome‐wide association studies (GWAS) identify common variants with low effect sizes that contribute to polygenic risk. The speckled zone highlights variants with low to slightly moderate effects that are yet to be identified but are beginning to be addressed by new methods or a combination of methods.


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Howrigan, Daniel J, William, Nancy, and Darlington, Todd M(Jan 2018) Complex Multifactorial Genetic Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001881.pub3]