A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Madireddy, L; Patsopoulos, NA; Cotsapas, C; Bos, SD; Beecham, A; McCauley, J; Kim, K; Jia, X; Santaniello, A; Caillier, SJ; Andlauer, TFM; Barcellos, LF; Berge, T; Bernardinelli, L; Martinelli-Boneschi, F; Booth, DR; Briggs, F; Celius, EG; Comabella, M; Comi, G; Cree, BAC; D'Alfonso, S; Dedham, K; Duquette, P; Efthimios, D; Esposito, F; Fontaine, B; Gasperi, C; Goris, A; Dubois, B; Gourraud, PA; Hadjigeorgiou, G; Haines, J; Hawkins, C; Hemmer, B; Hintzen, R; Horakova, D; Isobe, N; Kalra, S; Kira, Ji; Khalil, M; Kockum, I; Lill, CM; Lincoln, MR; Luessi, F; Martin, R; Oturai, A; Palotie, A; Pericak-Vance, MA; Henry, R; Saarela, J; Ivinson, A; Olsson, T; Taylor, BV; Stewart, GJ; Harbo, HF; Compston, A; Hauser, SL; Hafler, DA; Zipp, F; De Jager, P; Sawcer, S; Oksenberg, JR; Baranzini, SE

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A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Citation

Madireddy, L and Patsopoulos, NA and Cotsapas, C and Bos, SD and Beecham, A and McCauley, J and Kim, K and Jia, X and Santaniello, A and Caillier, SJ and Andlauer, TFM and Barcellos, LF and Berge, T and Bernardinelli, L and Martinelli-Boneschi, F and Booth, DR and Briggs, F and Celius, EG and Comabella, M and Comi, G and Cree, BAC and D'Alfonso, S and Dedham, K and Duquette, P and Efthimios, D and Esposito, F and Fontaine, B and Gasperi, C and Goris, A and Dubois, B and Gourraud, PA and Hadjigeorgiou, G and Haines, J and Hawkins, C and Hemmer, B and Hintzen, R and Horakova, D and Isobe, N and Kalra, S and Kira, Ji and Khalil, M and Kockum, I and Lill, CM and Lincoln, MR and Luessi, F and Martin, R and Oturai, A and Palotie, A and Pericak-Vance, MA and Henry, R and Saarela, J and Ivinson, A and Olsson, T and Taylor, BV and Stewart, GJ and Harbo, HF and Compston, A and Hauser, SL and Hafler, DA and Zipp, F and De Jager, P and Sawcer, S and Oksenberg, JR and Baranzini, SE, A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis, Nature Communications, 10 Article 2236. ISSN 2041-1723 (2019) [Refereed Article]

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DOI: doi:10.1038/s41467-019-09773-y

Abstract

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

Item Details

Item Type:	Refereed Article
Research Division:	Biomedical and Clinical Sciences
Research Group:	Neurosciences
Research Field:	Central nervous system
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Taylor, BV (Professor Bruce Taylor)
ID Code:	133624
Year Published:	2019
Web of Science^® Times Cited:	21
Deposited By:	Menzies Institute for Medical Research
Deposited On:	2019-07-04
Last Modified:	2020-08-12
Downloads:	9 View Download Statistics

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