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Beyond Exons: Linking Noncoding Heritability and Polygenicity across Complex Human Traits and Disorders.

Julian Fuhrer1, Alexey A Shadrin1,2, Timothy Hughes3

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Summary
This summary is machine-generated.

The genetic basis of complex traits varies by the number of involved genes. Highly polygenic traits, like psychiatric conditions, rely more on dispersed regulatory elements, unlike less polygenic traits.

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Area of Science:

  • Human Genetics
  • Genomics
  • Complex Trait Genetics

Background:

  • Complex traits exhibit a wide range of polygenicity, involving numerous genetic variants.
  • The relationship between polygenicity and the functional genomic distribution of heritability is not well understood.

Purpose of the Study:

  • To investigate how the functional localization of single nucleotide polymorphism (SNP) heritability differs across traits with varying degrees of polygenicity.
  • To quantify the contribution of different genomic regions and functional annotations to heritability based on polygenicity.

Main Methods:

  • Utilized a MiXeR-based framework to partition heritability across exonic, intronic, and intergenic regions for 34 complex traits.
  • Introduced a likelihood-based annotation contribution score to assess the impact of specific functional annotations on heritability.
  • Analyzed broader functional annotations, including comparative genomics, variant-effect scores, and regulatory elements (promoter, transcription, chromatin).

Main Results:

  • Exonic regions contribute a smaller fraction of heritability, with this contribution decreasing as polygenicity increases (22% in less polygenic traits to 13% in highly polygenic traits).
  • Intergenic regions show an increasing contribution to heritability with higher polygenicity, while intronic regions remain relatively stable.
  • Highly polygenic traits are associated with stronger contributions from comparative genomics and variant-effect scores, whereas less polygenic traits show stronger links to promoter, transcription, and chromatin annotations.

Conclusions:

  • The functional partitioning of heritability significantly varies with the degree of polygenicity across complex traits.
  • A shift in genetic architecture is observed, moving from gene-proximal regulatory mechanisms in less polygenic traits to numerous dispersed regulatory effects in highly polygenic traits.