Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs.

Journal of Autoimmunity
Isis Ricaño-PonceVinod Kumar

Abstract

Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene c...Continue Reading

References

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Citations

Mar 15, 2016·Trends in Genetics : TIG·Sebo WithoffCisca Wijmenga
Oct 5, 2017·Human Molecular Genetics·Iris H Jonkers, Cisca Wijmenga
Nov 23, 2017·Autophagy·Vojo Deretic, Beth Levine
May 23, 2018·European Journal of Gastroenterology & Hepatology·Barbara HrdlickovaVinod Kumar
Nov 8, 2018·Annals of Human Genetics·Luz María MedranoConcepción Núñez
Jan 25, 2018·Nature Reviews. Rheumatology·Guillermo BarturenMarta E Alarcón-Riquelme
Jul 18, 2020·Biomolecules·Valeria LoddeMaria Laura Idda
Mar 3, 2018·Clinical & Translational Immunology·Timothy SadlonSimon C Barry
Oct 24, 2017·Hepatology Communications·Atsushi TanakaaM Eric Gershwin
Oct 9, 2019·European Journal of Human Genetics : EJHG·Isis Ricaño-PonceCisca Wijmenga
Jan 21, 2021·Non-coding RNA·Maialen Sebastian-delaCruzIzortze Santin
May 4, 2021·Frontiers in Immunology·Parul Mehra, Andrew D Wells
Jul 1, 2021·Nature Reviews. Rheumatology·Yuriy BaglaenkoSoumya Raychaudhuri
Dec 12, 2017·Best Practice & Research. Clinical Rheumatology·Guillermo Barturen, Marta E Alarcón-Riquelme

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Datasets Mentioned

BETA
GM12878

Methods Mentioned

BETA
genotyping
RNA-seq
RNAseq
biopsies
enzyme-linked immunosorbent assay
ChIPseq

Software Mentioned

MOLGENIS
Bedtools suite
Sickle
FastQC
SHAPEIT2 Harmonizer
CASAVA
Ensembl
Immunochip analysis
intersectBed
STAR

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