TY - JOUR
T1 - Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients
AU - James, Tojo
AU - Lindén, Magdalena
AU - Morikawa, Hiromasa
AU - Fernandes, Sunjay Jude
AU - Ruhrmann, Sabrina
AU - Huss, Mikael
AU - Brandi, Maya
AU - Piehl, Fredrik
AU - Jagodic, Maja
AU - Tegner, Jesper
AU - Khademi, Mohsen
AU - Olsson, Tomas
AU - Gomez-Cabrero, David
AU - Kockum, Ingrid
N1 - KAUST Repository Item: Exported on 2020-12-16
Acknowledgements: We thank all patients who have been willing to contribute with their blood samples and make this study possible. We acknowledge International Multiple Sclerosis Genetics consortium (IMSGC) for supplying genotypes from ImmunoChip and MS replication chip used in this study. We acknowledge the Science for Life Laboratory in Stockholm for bioinformatic support in the form of a collaborative project. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under project b2011139. We thank the Julian Knight group for sharing genotype and expression data from primary B cells and monocytes. We are grateful to Shahin Aeinehband for performing a part of the cell sorting, and to Izaura Lima Bomfim and Jenny Link for HLA imputation. This work was supported by grants from the Knut and Alice Wallenberg Foundation and the Swedish Association of Persons with Neurological Disabilities (Neuroförbundet), and an Astra Zeneca Science for Life grant.
PY - 2018/1/8
Y1 - 2018/1/8
N2 - Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as Multiple Sclerosis (MS). Since a large proportion of expression
quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells (PBMCs) from MS patients (n=145) to identify eQTLs in regions centered on 109 MS risk SNPs and seven associated HLA variants. We identified 77 statistically significant
eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalised with the disease association signal. Since many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the
eQTLs were replicated and characterized in at least one major PBMC derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared to noninflammatory neurological diseases patients. In addition, we found two SNPs to be significantly
associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.
AB - Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as Multiple Sclerosis (MS). Since a large proportion of expression
quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells (PBMCs) from MS patients (n=145) to identify eQTLs in regions centered on 109 MS risk SNPs and seven associated HLA variants. We identified 77 statistically significant
eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalised with the disease association signal. Since many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the
eQTLs were replicated and characterized in at least one major PBMC derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared to noninflammatory neurological diseases patients. In addition, we found two SNPs to be significantly
associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.
UR - http://hdl.handle.net/10754/626756
UR - https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddy001/4792999
UR - http://www.scopus.com/inward/record.url?scp=85043454952&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddy001
DO - 10.1093/hmg/ddy001
M3 - Article
AN - SCOPUS:85043454952
VL - 27
SP - 912
EP - 928
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 5
ER -