Identifying Genes Underlying Human Inherited Disease


The field of genetic epidemiology seeks to identify the genetic risk factors underlying human disease. First, one must assess whether the trait has an underlying genetic influence, by estimating familial relative risk and/or conducting segregation analysis. In order to discover genes influencing human disease, both family‐ and population‐based studies are designed, and linkage and association methods are used to analyse the relationship between the trait(s) of interest and genetic markers. In general, linkage analysis is more powerful for detecting rare genes with large effects, whereas association analysis is more powerful for detecting common alleles with smaller effects. For the genetics of complex traits, additional factors must be considered, including rare variants, interactions with other genes and the environment, parent‐of‐origin effects and structural variants. Finally, casualty needs to be established beyond statistical implication of association with disease.

Key Concepts

  • Genetic epidemiologists design both family‐ and population‐based studies to find genes influencing disease risk.
  • Before conducting a gene‐mapping study, one must first ascertain whether the trait is influenced by genetic effects.
  • Linkage and association analysis are two complementary methods used to analyse the relationship between trait(s) and genetic markers.
  • The approach used (linkage vs association) depends on the study design, and these approaches depend on the genetic parameters (rare vs common alleles and large vs small effects).
  • Other factors – rare variants, gene–gene and gene–environment interaction, existence of structural variants and parent‐of‐origin effects – further complicate the search for disease genes.

Keywords: gene mapping; linkage analysis; genetic association analysis; complex traits; genetic epidemiology; multifactorial diseases; rare variants

Figure 1. The most appropriate analysis strategy depends in part on the disease allele frequency (common vs rare) and the strength of genetic effect due to that locus. Note that neither linkage nor association analysis has good power to detect rare loci with weak effects. Adapted with permission from Ardlie et al. © Nature Publishing Group.


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Natanzon, Yanina, Stein, Catherine M, and Cooke Bailey, Jessica N(Nov 2016) Identifying Genes Underlying Human Inherited Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022395.pub2]