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"Good enough solutions" and the genetics of complex diseases.

Publication ,  Journal Article
Weiss, JN; Karma, A; MacLellan, WR; Deng, M; Rau, CD; Rees, CM; Wang, J; Wisniewski, N; Eskin, E; Horvath, S; Qu, Z; Wang, Y; Lusis, AJ
Published in: Circ Res
August 3, 2012

In this Emerging Science Review, we discuss a systems genetics strategy, which we call gene module association study (GMAS), as a novel approach complementing genome-wide association studies (GWAS), to understand complex diseases by focusing on how genes work together in groups rather than singly. The first step is to characterize phenotypic differences among a genetically diverse population. The second step is to use gene expression microarray (or other high-throughput) data from the population to construct gene coexpression networks. Coexpression analysis typically groups 20 000 genes into 20 to 30 modules containing tens to hundreds of genes, whose aggregate behavior can be represented by the module's "eigengene." The third step is to correlate expression patterns with phenotype, as in GWAS, only applied to eigengenes instead of single nucleotide polymorphisms. The goal of the GMAS approach is to identify groups of coregulated genes that explain complex traits from a systems perspective. From an evolutionary standpoint, we hypothesize that variability in eigengene patterns reflects the "good enough solution" concept, that biological systems are sufficiently complex so that many possible combinations of the same elements (in this case eigengenes) can produce an equivalent output, that is, a "good enough solution" to accomplish normal biological functions. However, when faced with environmental stresses, some "good enough solutions" adapt better than others, explaining individual variability to disease and drug susceptibility. If validated, GMAS may imply that common polygenic diseases are related as much to group interactions between normal genes, as to multiple gene mutations.

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

August 3, 2012

Volume

111

Issue

4

Start / End Page

493 / 504

Location

United States

Related Subject Headings

  • Systems Biology
  • Reproducibility of Results
  • Phenotype
  • Oligonucleotide Array Sequence Analysis
  • Inheritance Patterns
  • Humans
  • Genomics
  • Genome-Wide Association Study
  • Genetic Variation
  • Genetic Predisposition to Disease
 

Citation

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Weiss, J. N., Karma, A., MacLellan, W. R., Deng, M., Rau, C. D., Rees, C. M., … Lusis, A. J. (2012). "Good enough solutions" and the genetics of complex diseases. Circ Res, 111(4), 493–504. https://doi.org/10.1161/CIRCRESAHA.112.269084
Weiss, James N., Alain Karma, W Robb MacLellan, Mario Deng, Christoph D. Rau, Colin M. Rees, Jessica Wang, et al. “"Good enough solutions" and the genetics of complex diseases.Circ Res 111, no. 4 (August 3, 2012): 493–504. https://doi.org/10.1161/CIRCRESAHA.112.269084.
Weiss JN, Karma A, MacLellan WR, Deng M, Rau CD, Rees CM, et al. "Good enough solutions" and the genetics of complex diseases. Circ Res. 2012 Aug 3;111(4):493–504.
Weiss, James N., et al. “"Good enough solutions" and the genetics of complex diseases.Circ Res, vol. 111, no. 4, Aug. 2012, pp. 493–504. Pubmed, doi:10.1161/CIRCRESAHA.112.269084.
Weiss JN, Karma A, MacLellan WR, Deng M, Rau CD, Rees CM, Wang J, Wisniewski N, Eskin E, Horvath S, Qu Z, Wang Y, Lusis AJ. "Good enough solutions" and the genetics of complex diseases. Circ Res. 2012 Aug 3;111(4):493–504.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

August 3, 2012

Volume

111

Issue

4

Start / End Page

493 / 504

Location

United States

Related Subject Headings

  • Systems Biology
  • Reproducibility of Results
  • Phenotype
  • Oligonucleotide Array Sequence Analysis
  • Inheritance Patterns
  • Humans
  • Genomics
  • Genome-Wide Association Study
  • Genetic Variation
  • Genetic Predisposition to Disease