Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility

Maxime Rotival (1)

1 Génétique Evolutive Humaine - Human Evolutionary Genetics

Over the last 10 years, genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for autoimmune diseases. However, despite increasing power for the detection of both common and rare coding variants affecting disease susceptibility, a large fraction of disease heritability has remained unexplained. In addition, a majority of the identified loci are located in noncoding regions, and translation of disease-associated loci into new biological insights on the etiology of immune disorders has been lagging. This highlights the need for a better understanding of noncoding variation and new strategies to identify causal genes at disease loci. In this review, I will first detail the molecular basis of gene expression and review the various mechanisms that contribute to alter gene activity at the transcriptional and post-transcriptional level. I will then review the findings from 10 years of functional genomics studies regarding the genetics on gene expression, in particular in the context of infection. Finally, I will discuss the extent to which genetic variants that modulate gene expression at transcriptional and post-transcriptional level contribute to disease susceptibility and present strategies to leverage this information for the identification of causal mechanisms at disease loci in the era of whole genome sequencing.

Mots clés: rare variants; GWAS; immune response; eQTL; disease etiology; massively parallel reporter assays; regulatory elements

Domaines: Génétique des populations [q-bio.PE]; Génétique humaine

Maxime Rotival. Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility. HLA: Immune Response Genetics, 2019, 94 (3), pp.275-284. ⟨10.1111/tan.13598⟩. ⟨pasteur-02868915⟩