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

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

doi:10.1038/s41467-019-09773-y

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

L Madireddy
, NA Patsopoulos
, C Cotsapas
, SD Bos
, A Beecham
, J McCauley
, K Kim
, XM Jia
, A Santaniello
, SJ Caillier
, TFM Andlauer
, LF Barcellos
, T Berge
, L Bernardinelli
, F Martinelli-Boneschi
, DR Booth
, F Briggs
, EG Celius
, M Comabella
, G Comi

BAC Cree, Sandra D'ALFONSO, K Dedham, P Duquette, D Efthimios, F Esposito, B Fontaine, C Gasperi, A Goris, B Dubois, PA Gourraud, G Hadjigeorgiou, J Haines, C Hawkins, B Hemmer, R Hintzen, D Horakova, N Isobe, S Kalra, J Kira, M Khalil, I Kockum, CM Lill, MR Lincoln, F Luessi, R Martin, A Oturai, A Palotie, MA Pericak-Vance, R Henry, J Saarela, A Ivinson, T Olsson, BV Taylor, GJ Stewart, HF Harbo, A Compston, SL Hauser, DA Hafler, F Zipp, P De Jager, S Sawcer, JR Oksenberg, SE Baranzini

Department of Health Sciences

Research output: Contribution to journal › Article › peer-review

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 intraindividual 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.

Original language	English
Pages (from-to)	2236
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09773-y
Publication status	Published - 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Gene Expression Regulation
Genes, Regulator
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Multiple Sclerosis
Polymorphism, Single Nucleotide
Systems Biology

Access to Document

10.1038/s41467-019-09773-y

http://hdl.handle.net/11579/112443

Cite this

Madireddy, L., Patsopoulos, NA., Cotsapas, C., Bos, SD., Beecham, A., McCauley, J., Kim, K., Jia, XM., Santaniello, A., Caillier, SJ., Andlauer, TFM., Barcellos, LF., Berge, T., Bernardinelli, L., Martinelli-Boneschi, F., Booth, DR., Briggs, F., Celius, EG., Comabella, M., ... Baranzini, SE. (2019). A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis. Nature Communications, 10(1), 2236. https://doi.org/10.1038/s41467-019-09773-y

@article{50ad908d6b6b472fb70ed7170c31dd5d,

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

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 intraindividual 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.",

keywords = "Gene Expression Regulation, Genes, Regulator, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Systems Biology, Gene Expression Regulation, Genes, Regulator, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Systems Biology",

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

year = "2019",

doi = "10.1038/s41467-019-09773-y",

language = "English",

volume = "10",

pages = "2236",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Madireddy, L, Patsopoulos, NA, Cotsapas, C, Bos, SD, Beecham, A, McCauley, J, Kim, K, Jia, XM, 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, J, 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 2019, 'A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis', Nature Communications, vol. 10, no. 1, pp. 2236. https://doi.org/10.1038/s41467-019-09773-y

TY - JOUR

T1 - A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

AU - Madireddy, L

AU - Patsopoulos, NA

AU - Cotsapas, C

AU - Bos, SD

AU - Beecham, A

AU - McCauley, J

AU - Kim, K

AU - Jia, XM

AU - Santaniello, A

AU - Caillier, SJ

AU - Andlauer, TFM

AU - Barcellos, LF

AU - Berge, T

AU - Bernardinelli, L

AU - Martinelli-Boneschi, F

AU - Booth, DR

AU - Briggs, F

AU - Celius, EG

AU - Comabella, M

AU - Comi, G

AU - Cree, BAC

AU - D'ALFONSO, Sandra

AU - Dedham, K

AU - Duquette, P

AU - Efthimios, D

AU - Esposito, F

AU - Fontaine, B

AU - Gasperi, C

AU - Goris, A

AU - Dubois, B

AU - Gourraud, PA

AU - Hadjigeorgiou, G

AU - Haines, J

AU - Hawkins, C

AU - Hemmer, B

AU - Hintzen, R

AU - Horakova, D

AU - Isobe, N

AU - Kalra, S

AU - Kira, J

AU - Khalil, M

AU - Kockum, I

AU - Lill, CM

AU - Lincoln, MR

AU - Luessi, F

AU - Martin, R

AU - Oturai, A

AU - Palotie, A

AU - Pericak-Vance, MA

AU - Henry, R

AU - Saarela, J

AU - Ivinson, A

AU - Olsson, T

AU - Taylor, BV

AU - Stewart, GJ

AU - Harbo, HF

AU - Compston, A

AU - Hauser, SL

AU - Hafler, DA

AU - Zipp, F

AU - De Jager, P

AU - Sawcer, S

AU - Oksenberg, JR

AU - Baranzini, SE

PY - 2019

Y1 - 2019

N2 - 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 intraindividual 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.

AB - 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 intraindividual 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.

KW - Gene Expression Regulation

KW - Genes, Regulator

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Multiple Sclerosis

KW - Polymorphism, Single Nucleotide

KW - Systems Biology

KW - Gene Expression Regulation

KW - Genes, Regulator

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Multiple Sclerosis

KW - Polymorphism, Single Nucleotide

KW - Systems Biology

UR - https://iris.uniupo.it/handle/11579/112443

U2 - 10.1038/s41467-019-09773-y

DO - 10.1038/s41467-019-09773-y

M3 - Article

SN - 2041-1723

VL - 10

SP - 2236

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

UN SDGs

Keywords

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