title: Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs.
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 closest to the AID SNP, which was the case in nearly 50% of cases.
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Isis
authors.initials: I
authors.lastname: Ricaño-Ponce
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands; University of Groningen, University Medical Centre Groningen, Genomics Coordination Centre, Groningen, 9700 RB, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Deelen
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Luo
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Xingwang
authors.initials: X
authors.lastname: Li
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Juha
authors.initials: J
authors.lastname: Karjalainen
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Di Tommaso
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Zuzanna Agnieszka
authors.initials: ZA
authors.lastname: Borek
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Zorro
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Joyce
authors.initials: J
authors.lastname: van Meurs
authors.affiliation: Department of Internal Medicine and Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, 6525 GA, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Iris H
authors.initials: IH
authors.lastname: Jonkers
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Sebo
authors.initials: S
authors.lastname: Withoff
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Centre, Rotterdam, 3015 CE, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA; Department of Genetics and Genome Sciences, University of Connecticut Health Centre, 400 Farmington Ave, Farmington, CT 06030, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, 9700 RB, The Netherlands. Electronic address: v.kumar@umcg.nl.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D002446:Celiac Disease / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping; D016207:Cytokines / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D062085:RNA, Long Noncoding / Q000235:genetics; D022661:RNA, Untranslated
chemical_list: D016207:Cytokines; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated
keywords: Causal genes; Genome-wide association; Long non-coding RNAs; RNA-sequencing; eQTLs