Identification of genetic variants controlling RNA editing and their effect on RNA structure stabilization


Post-transcriptional modification of RNA (RNA editing, RNAe) results in differences between the RNA transcript and the genomic DNA sequence (RDD). Enzymatic modification of adenosine to inosine (A2I) by ADAR is the most studied type of RNAe. However, few genetic association studies with A2I RNAe events have been conducted. Some studies have analyzed the inter-population RNAe-QTL diversity in humans, but the sample size of these studies was limited. Other types of RNA and DNA differences have been reported but are largely understudied. Here, we report a comprehensive analysis of all types of RDD, based on two independent datasets. We found that A2I was by far the most observed type of RDD. Moreover, manual curation suggests that A2I is likely the only enzymatically driven RNAe type observed in blood derived DNA, all other non-A2I RDD could either be attributed to sequencing and processing artifacts, or are a result of somatic DNA rearrangements. We then conducted an in-cis genetic association study and identified 472 genetic associations (RNAe-QTL), that were replicated in both datasets. We confirm the potential effect of the RNAe-QTL on RNA structure by showing that allele specific RNAe occurs in heterozygotes. Although the generally assumed function of RNAe is to destabilize double stranded RNA structure, we found clear evidence for the potential additional involvement of RNAe in maintaining RNA hairpin that has been altered by the RNAe-QTL. Our study confirms, in two independent datasets, the potential role of RNAe in maintaining RNA structure in the presence of genetic variation.

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Fig. 1: Schematic view of the study design.
Fig. 2: Characteristics of detected A2I and non-A2I.
Fig. 3: Effect of the RNAe-QTL on the RNA secondary structure. Three other cases are provided in Fig S4–S6.
Fig. 4: Allele specific RNA editing (ASE).

Data availability

Complete summary statistics for genetic association with RNAe level in both datasets, Gauvadis and QMDiab, are available at


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We thank the staff of the HMC dermatology department and of WCM-Q for their contribution to QMDiab. We thank Laurent Abel from the human genetics of infectious diseases lab for the scientific discussions. Finally, we are grateful to all study participants of QMDiab for their invaluable contributions to this study.


This work was supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation. The statements made herein are solely the responsibility of the authors.

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Correspondence to Aziz Belkadi or Karsten Suhre.

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Belkadi, A., Thareja, G., Halama, A. et al. Identification of genetic variants controlling RNA editing and their effect on RNA structure stabilization. Eur J Hum Genet 28, 1753–1762 (2020).

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