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Missing heritability of complex diseases: case solved?

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  • 1Inserm, Univ Brest, EFS, CHU Brest, UMR 1078, GGB (Génétique, Génomique fonctionnelle et Biotechnologies), Faculté de Médecine, Bâtiment E-IBRBS 2ieme étage, 22 avenue Camille Desmoulins, 29200, Brest Cedex 3, France. emmanuelle.genin@inserm.fr.

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Summary
This summary is machine-generated.

The "missing heritability" problem in genetics, where identified gene variants explained little of inherited traits, is re-examined. This study questions if the problem was ill-defined, exploring the success of strategies like larger genome-wide association studies (GWAS).

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Area of Science:

  • Genetics
  • Genomics
  • Complex Trait Genetics

Background:

  • Large-scale genome-wide association studies (GWAS) initially identified few gene variants linked to common complex diseases.
  • A significant gap, termed "missing heritability," existed between heritability estimated from family studies and that explained by identified variants.
  • This discrepancy prompted various hypotheses and research strategies to uncover the underpield genetic contributions.

Purpose of the Study:

  • To evaluate the success of different strategies in resolving the "missing heritability" problem.
  • To critically assess whether the "missing heritability" concept itself was accurately defined.
  • To explore the genetic architecture of complex traits using specific examples.

Main Methods:

  • Review of findings from large-scale genome-wide association studies (GWAS).
  • Analysis of hypotheses proposed to explain the "missing heritability" gap.
  • Examination of novel research strategies, including increased sample sizes and analysis of rare/structural variants.

Main Results:

  • Initial GWAS efforts identified variants explaining a small fraction of trait heritability, significantly less than family-based estimates.
  • Strategies like increasing GWAS sample sizes and searching for rare variants have yielded some progress but not fully resolved the gap for many traits.
  • The effectiveness of these strategies varies across different complex traits.

Conclusions:

  • The "missing heritability" problem highlights the complexity of genetic contributions to common diseases.
  • Further research is needed to fully understand the genetic basis of complex traits, potentially requiring refined methodologies and theoretical frameworks.
  • Re-evaluation of the "missing heritability" concept suggests it may have been an oversimplification of complex genetic architectures.