Heterozygosity for a Mendelian disorder as a risk factor for complex disease

Clin Genet. 2006 Oct;70(4):275-82. doi: 10.1111/j.1399-0004.2006.00688.x.


While genetic diseases are generally classified as being either 'simple' monogenic or 'complex' polygenic, the distinction between Mendelian and complex disorders is becoming increasingly blurred. Mendelian disorders may demonstrate qualities more typical of multifactorial diseases through shared clinical presentations, the effect of genetic modifiers, moonlighting proteins, synergistic heterozygosity, disease manifestations in heterozygotes and situations where heterozygosity for a 'simple' disorder proves to be a risk factor for seemingly unrelated complex diseases. A recent example of the last instance is the observation that mutations in glucocerebrosidase, the enzyme deficient in Gaucher disease, may be a risk factor for the development of Parkinson disease and other synucleinopathies. Insights gleaned from the study of Mendelian disorders may ultimately lead to a better understanding of factors influencing complex diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Gaucher Disease / genetics
  • Genetic Diseases, Inborn / genetics*
  • Genetic Predisposition to Disease*
  • Glucosylceramidase / genetics
  • Heterozygote*
  • Humans
  • Multifactorial Inheritance
  • Parkinson Disease / genetics
  • Phenotype
  • Risk Factors


  • Glucosylceramidase