PT  - JOURNAL ARTICLE
AU  - Abhishek K. Sarkar
AU  - Lucas D. Ward
AU  - Manolis Kellis
TI  - Functional enrichments of disease variants across thousands of independent loci in eight diseases
AID  - 10.1101/048066
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 048066
4099  - http://biorxiv.org/content/early/2016/04/11/048066.short
4100  - http://biorxiv.org/content/early/2016/04/11/048066.full
AB  - For most complex traits, known genetic associations only explain a small fraction of the narrow sense heritability prompting intense debate on the genetic basis of complex traits. Joint analysis of all common variants together explains much of this missing heritability and reveals that large numbers of weakly associated loci are enriched in regulatory regions, but fails to identify specific regions or biological pathways. Here, we use epigenomic annotations across 127 tissues and cell types to investigate weak regulatory associations, the specific enhancers they reside in, their downstream target genes, their upstream regulators, and the biological pathways they disrupt in eight common diseases. We show weak associations are significantly enriched in disease-relevant regulatory regions across thousands of independent loci. We develop methods to control for LD between weak associations and overlap between annotations. We show that weak non-coding associations are additionally enriched in relevant biological pathways implicating additional downstream target genes and upstream disease-specific master regulators. Our results can help guide the discovery of biologically meaningful, but currently undetectable regulatory loci underlying a number of common diseases.