WEHI Wednesday Seminar hosted by Dr Hamish King

Dr Viacheslav Kriachkov

Research Officer – King Laboratory, Genetics and Gene Regulation division, WEHI

Deciphering the genetic causes of autoimmunity: from non-coding GWAS variants to target genes

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Genome-wide association studies have discovered thousands of genetic variants associated with different autoimmune diseases, and yet the underlying molecular pathways have remained elusive. Over 90% of the identified genetic risk loci are in non-coding regions of the genome, which makes it challenging to predict the downstream gene regulatory consequences (if any) and their contribution to disease.

Here, we experimentally identified the gene targets for hundreds of non-coding autoimmune risk loci that contain fine-mapped genetic variants from over 30 different autoimmune traits, including lupus, multiple sclerosis, type I diabetes, Crohn’s disease, etc. To achieve that, we performed the first high-throughput CRISPR activation screen coupled with single-cell RNA-seq in human germinal centre B cells – a highly relevant cellular context for autoimmune disease. Our results revealed complex regulatory networks between autoimmune risk loci and their target genes, including scenarios where a single locus regulated multiple genes, and many examples of long-range enhancer regulation such as the locus with rs78037977 variant (type I diabetes, vitiligo) which is 460 kb away from its target gene TNFSF4 (OX40L). Furthermore, we performed massive parallel reporter assay (MPRA) and prime editing in primary B cells and found several non-coding autoimmune variants that control gene expression, including rs74405933 (G>A, rheumatoid arthritis) that showed a positive correlation with CD83 levels.

By experimentally identifying novel genes associated with autoimmunity and providing additional evidence to already reported ones, this work offers key functional insights into the development of autoimmune disease. In addition, our study provides a framework to simultaneously interrogate multiple non-coding genetic variants linked to other complex diseases like neurodegenerative and developmental disorders as well as various cancers.

All welcome!