UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Principles of complex trait genetics

Authors
Juan C Celedón, MD, DrPH
Gary M Hunninghake, MD, MPH
Section Editor
Benjamin A Raby, MD, MPH
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

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 "Glossary of genetic 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") [1]; complex traits can be predominantly influenced by variation in a single gene [2].

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'.)

        

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Mon Aug 31 00:00:00 GMT+00:00 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Gu Y, Harley IT, Henderson LB, et al. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 2009; 458:1039.
  2. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007; 357:639.
  3. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447:661.
  4. Harismendy O, Notani D, Song X, et al. 9p21 DNA variants associated with coronary artery disease impair interferon-γ signalling response. Nature 2011; 470:264.
  5. Verlaan DJ, Berlivet S, Hunninghake GM, et al. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease. Am J Hum Genet 2009; 85:377.
  6. Hunninghake GM, Cho MH, Tesfaigzi Y, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med 2009; 361:2599.
  7. Goldstein DB. Common genetic variation and human traits. N Engl J Med 2009; 360:1696.
  8. Hirschhorn JN. Genomewide association studies--illuminating biologic pathways. N Engl J Med 2009; 360:1699.
  9. DOLL R. Mortality from lung cancer in asbestos workers. Br J Ind Med 1955; 12:81.
  10. Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet 2001; 17:502.
  11. Cargill M, Daley GQ. Mining for SNPs: putting the common variants--common disease hypothesis to the test. Pharmacogenomics 2000; 1:27.
  12. Welter D, MacArthur J, Morales J, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 2014; 42:D1001.
  13. Dickson SP, Wang K, Krantz I, et al. Rare variants create synthetic genome-wide associations. PLoS Biol 2010; 8:e1000294.
  14. Carmichael CM, McGue M. A cross-sectional examination of height, weight, and body mass index in adult twins. J Gerontol A Biol Sci Med Sci 1995; 50:B237.
  15. Silventoinen K, Sammalisto S, Perola M, et al. Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res 2003; 6:399.
  16. Weedon MN, Lango H, Lindgren CM, et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 2008; 40:575.
  17. Meigs JB, Shrader P, Sullivan LM, et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 2008; 359:2208.
  18. Paynter NP, Chasman DI, Buring JE, et al. Cardiovascular disease risk prediction with and without knowledge of genetic variation at chromosome 9p21.3. Ann Intern Med 2009; 150:65.
  19. Kraft P, Hunter DJ. Genetic risk prediction--are we there yet? N Engl J Med 2009; 360:1701.
  20. Bell GI, Polonsky KS. Diabetes mellitus and genetically programmed defects in beta-cell function. Nature 2001; 414:788.
  21. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993; 90:1977.
  22. International HapMap Consortium. A haplotype map of the human genome. Nature 2005; 437:1299.
  23. Wang DG, Fan JB, Siao CJ, et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 1998; 280:1077.
  24. Kathiresan S, Melander O, Anevski D, et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 2008; 358:1240.
  25. Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314:1461.
  26. Gudmundsson J, Sulem P, Steinthorsdottir V, et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 2007; 39:977.
  27. Yasuda K, Miyake K, Horikawa Y, et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 2008; 40:1092.
  28. Tennessen JA, Bigham AW, O'Connor TD, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 2012; 337:64.
  29. Panoutsopoulou K, Tachmazidou I, Zeggini E. In search of low-frequency and rare variants affecting complex traits. Hum Mol Genet 2013; 22:R16.