Complex Genetic Systems and Diseases

Abstract

Most traits of interest in medical (including psychiatric) contexts are complex traits, generally of multifactorial aetiology including genetic factors. These genetic factors may include coding and noncoding sequences (with the variation in the latter being the dominant mode of human genetic variation). Epigenetic factors may also be involved in the aetiology of diseases. The study of genetic aspects of complex traits presents a level of conceptual and technical difficulties not seen elsewhere in genetics. New molecular techniques, especially those that have emerged in the post‐genomic era, provide promise for a solution to these problems. Genome‐wide association studies have provided evidence for the common disease–common variant hypothesis. However, other studies have noted the importance of rare variants including some with severe effects. The importance of epigenetic factors has recently come to be recognised. Over all, the advances of genomics and the post‐genomic era have underscored the complexity of disease aetiology in most cases.

Key Concepts:

  • Disease traits are a result of complex developmental interactions between genomic and environmental factors.

  • Complex genetic traits are those that fall between simple Mendelising traits and the quantitative (continuously varying) traits traditionally studied by the methods of quantitative genetics.

  • Many disease traits are complex genetic systems of this sort.

  • The contribution of classical genetics (including quantitative genetics) to the study of most disease traits has been modest.

  • In contrast, recent molecular methods including allele sharing, quantitative trait locus mapping and allelic association studies show more promise.

  • Genome‐wide allelic association studies have provided a wealth of new insight and considerable support for the ‘common disease–common variant’ model of disease aetiology.

  • However, rare genetic variants may also be important for the aetiology of some diseases including psychiatric ones.

  • Because of the social and political ramifications of genetic explanations, care must be taken in imputing genetic etiologies to diseases.

Keywords: genetic disease; genetic aetiology; genome‐wide association studies; common disease–common variant; complex traits; polygenic traits; genomics; genetic reductionism

References

Bucan M, Abrahams BS, Wang K et al. (2009) Genome‐wide analyses of exonic copy number variants in a family based study point to novel autism susceptibility genes. PLoS Genetics 5: e1000536.

Cirulli ET and Goldstein DB (2010) Uncovering the roles of rare variants in common disease through whole‐genome sequencing. Nature Reviews Genetics 11: 415–425.

Clarke AJ and Cooper DN (2010) GWAS: heritability missing in action? European Journal of Human Genetics 18: 859–861.

Cooper GM and Shendure J (2011) Needles in stacks of needles: finding disease‐causal variants in a wealth of genomic data. Nature Review Genetics 12: 628–640.

Dror AA and Avraham KB (2009) Hearing loss: mechanisms revealed by genetics and cell biology. Annual Review of Genetics 43: 41–437.

Engel E and Antonarakis SE (2002) Genetic Imprinting and Uniparental Disomy in Medicine: Clinical and Molecular Aspects. New York, NY: Wiley‐Liss.

Fisher RA (1918) The correlation between relatives on the supposition of Mendelian inheritance. Transactions of the Royal Society of Edinburgh 52: 399–433.

Hogben L (1933) Nature and Nurture. New York, NY: WW Norton.

Jiang YJ, Bressler J and Beaudet AL (2004) Epigenetics and human disease. Annual Review of Genomics and Human Genetics 5: 479–510.

Lander ES (2010) Initial impact of the sequencing of the human genome. Nature 470: 187–197.

Lander ES and Schork NJ (1994) Genetic dissection of complex traits. Science 265: 2037–2048.

Laubichler M and Sarkar S (2002) Flies, genes, and brains: Oskar Vogt, Nikolai Timoféeff‐Ressovsky, and the origin of the concepts of penetrance and expressivity. In: Parker LS and Ankeny R (eds) Medical Genetics, Conceptual Foundations and Classic Questions, pp. 63–85. Dordrecht: Kluwer.

Manolio TA, Collins FS, Cox NJ et al. (2009) Finding the missing heritability of complex diseases. Nature 461: 747–753.

McClellan J and King MC (2010) Genetic heterogeneity in human disease. Cell 141: 210–217.

Moldin S (1999) Summary of research. Biological Psychiatry 45: 559–602.

Nelkin D and Tancredi L (1989) Dangerous Diagnostics: The Social Power of Biological Information. New York, NY: Basic Books.

Nilsson‐Ehle H (1914) Vilka erfarenheter hava hittills vunnits rörande möjligheten av växters acklimatisering? Kunglig Landtbruks‐Akademiens. Handlinger och Tidskrift 53: 537–572.

Reich DE and Lander ES (2001) On the allelic spectrum of human diseases. Trends in Genetics 17: 502–510.

Rice G, Anderson C, Risch N and Ebers G (1999) Male homosexuality: absence of linkage to microsatellite markers at Xq28. Science 284: 665–667.

Risch N and Botstein D (1996) A manic‐depressive history. Nature Genetics 12: 351–353.

Sarkar S (1998) Genetics and Reductionism. New York, NY: Cambridge University Press.

Sarkar S (1999) From the Reaktionsnorm to the adaptive norm: the norm of reaction, 1909–1960. Biology and Philosophy 14: 235–252.

Visscher PM (2008) Sizing up human height variation. Nature Genetics 40: 489–490.

Vogt O (1926) Psychiatrisch wichtige Tatsachen der zoologisch–botanischen Systematik. Journal für Psychologie und Neurologie 101: 805–832.

Walsh T and King MC (2007) The genes of inherited breast cancer. Cancer Cell 11: 103–105.

Walsh T, McClellan JM, McCarthy SE et al. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320: 539–543.

Weatherall DJ (1991) The New Genetics and Clinical Practice. Oxford, UK: Oxford University Press.

Woltereck R (1909) Weitere experimentelle Untersuchungen über Artveränderung, speziell über das Wesen quantitativer Artunterschiede bei Daphnien. Verhandlungen der deutschen zoologischen Gesellschaft 19: 110–173.

Yang J, Benyamin B, McEvoy BP et al. (2010) Common SNPs explain a large proportion of the heritability for human height. Nature Genetics 42: 565–569.

Further Reading

Keller EF (2010) The Mirage of a Space between Nature and Nurture. Durham, NC: Duke University Press.

Kitcher P (1996) The Lives to Come: The Genetic Revolution and Human Possibilities. New York, NY: Simon & Schuster.

Ott J (1991) Analysis of Human Genetic Linkage, 2nd edn. Baltimore: Johns Hopkins Press.

Sarkar S (2004) Molecular Models of Life. Cambridge, MA: MIT Press.

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Sarkar, Sahotra(Apr 2012) Complex Genetic Systems and Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005887.pub2]