Genomic approaches for understanding the genetics of complex disease

Abstract

There are thousands of known associations between genetic variants and complex human phenotypes, and the rate of novel discoveries is rapidly increasing. Translating those associations into knowledge of disease mechanisms remains a fundamental challenge because the associated variants are overwhelmingly in noncoding regions of the genome where we have few guiding principles to predict their function. Intersecting the compendium of identified genetic associations with maps of regulatory activity across the human genome has revealed that phenotype-associated variants are highly enriched in candidate regulatory elements. Allele-specific analyses of gene regulation can further prioritize variants that likely have a functional effect on disease mechanisms; and emerging high-throughput assays to quantify the activity of candidate regulatory elements are a promising next step in that direction. Together, these technologies have created the ability to systematically and empirically test hypotheses about the function of noncoding variants and haplotypes at the scale needed for comprehensive and systematic follow-up of genetic association studies. Major coordinated efforts to quantify regulatory mechanisms across genetically diverse populations in increasingly realistic cell models would be highly beneficial to realize that potential.

Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease

“…By extending the exome with noncoding conserved elements, we gain the opportunity to identify regulatory variants, which are suggested to be major contributors to complex diseases [76].…”

The developmental biology of genetic Notch disorders

“…Further efforts into understanding the transcriptional control of Notch genes, and the transcriptional machinery of the Notch signaling pathway itself, will be essential for deciphering how non-protein-coding mutations affect gene regulation and impact on disease. Mutations in DNA encoding noncoding RNAs (Makrythanasis and Antonarakis, 2013) and in regulatory elements, including enhancers and insulators, are gaining recognition as causes of Mendelian disorders (Chong et al, 2015;Lowe and Reddy, 2015). Identifying all Notch-associated genetic conditions will require continued improvements in whole-genome sequencing and analysis, standardization of patient phenotyping, and global sharing of genomic and phenotypic data.…”

Study Human Genetics & Relations with complex diseases

“…However, translating the associations into epistemology of human disease mechanisms has fundamental challenges due to the fact that information and knowledge of noncoding regions of the human genome in both technical experiments and bioinformatics theories are still relatively exile [7][8]. Thus, studies in the area are nowadays especially active and trying to formation of interdisciplinary innovative techniques which will stand for the upcoming challenges that would be disease detection, disease diagnosis and gene expression profile.…”