Principles of complex trait genetics
- Juan C Celedón, MD, DrPH
Juan C Celedón, MD, DrPH
- Niels K. Jerne Professor of Pediatrics
- Professor of Medicine and Human Genetics
- University of Pittsburgh
- Division Chief
- Pediatric Pulmonary Medicine, Allergy and Immunology
- Children’s Hospital of Pittsburgh of UPMC
- Gary M Hunninghake, MD, MPH
Gary M Hunninghake, MD, MPH
- Assistant Professor of Medicine
- Harvard Medical School
Most human genetic traits can be classified as either monogenic or complex. Monogenic traits are strongly influenced by variation within a single gene and are recognized by their classic patterns of inheritance within families. While monogenic traits formed the basis for "classic" genetics, it has become clear that conditions whose inheritance strictly conforms to Mendelian principles are relatively rare. (See "Overview of Mendelian inheritance" and "Genetics: glossary of terms".)
Complex traits are believed to result from variation within multiple genes and their interaction with behavioral and environmental factors. Complex traits do not follow readily predictable patterns of inheritance.
This distinction between monogenic and complex traits, while useful, can be overly simplistic. Traits that appear to be monogenic can be influenced by variation in multiple genes ("modifier genes") ; complex traits can be predominantly influenced by variation in a single gene .
This topic will review the challenges related to the identification of complex trait susceptibility genes, the factors that contribute to phenotypic complexity, and current understanding of the genetic architecture of complex genetic traits. Genetic traits with monogenic inheritance, either with a Mendelian or a non-Mendelian pattern, are discussed separately. (See "Overview of Mendelian inheritance" and "Non-Mendelian inheritance patterns of monogenic diseases".)
SPECTRUM OF GENETIC VARIATION
Most monogenic diseases are caused by mutations that reduce the function or stability of a single protein by altering its three-dimensional structure. These mutations include point mutations (eg, changes in single nucleotides that alter the amino acid sequence), insertions, or deletions in the DNA sequence that encodes the protein; or changes in the non-coding DNA that interfere with gene splicing. (See "Overview of Mendelian inheritance" and "Non-Mendelian inheritance patterns of monogenic diseases" and "Basic principles of genetic disease", section on 'DNA sequence variation'.)
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