Leveraging histone modification heritability to understand complex disease genetics

Harvard School Of Public Health, Boston MA

Investigators

Linked publications & trials

Abstract

Project Summary (Abstract) The vast majority of common variants associated with diseases and complex traits are non-coding, making uncovering the mechanisms underlying gene regulation extremely important. Existing genomic annotations based on a variety of sequencing studies have yielded insights into the types and locations of regulatory elements. However, they fail to fully utilize the information that has been assayed and annotations methods are not being fit to maximally capture known regulatory sites. This proposal aims to investigate which functional annotations are the best indicators of regulatory activity as measured by histone modification control and apply these annotations to understand complex disease variation. Histone modifications mark important changes in chromatin state and the genetic elements that establish these modifications play a key role in regulation that propagates all the way to the protein level. Thousands of genetic variants alter their local histone modification levels, providing a perfect opportunity to train functionally relevant annotation methods. The first aim is to develop methods for partitioning heritability of many loci in a single regression when significant associations for each locus come from distinct, small genomic regions. These will be used to partition the heritability of histone modifications across functional annotations in order to better understand the elements that contribute to their genetic control. The second aim is to use histone modification heritability explained as a metric to create new functional annotations that are maximally enriched from regulatory activity. The final aim is to apply these new annotations to partition variation of complex traits and diseases. Ultimately, this project will produce 1) a detailed understanding of genetic contributors to regulation at the chromatin level 2) a set of functional annotations for a variety of cell types that are most enriched for regulatory activity, and 3) precise definitions of genomic regions that most contribute to a number of human diseases and complex traits.