Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

AH Beecham; NA Patsopoulos; DK Xifara; MF Davis; A Kemppinen; C Cotsapas; TS Shah; C Spencer; D Booth; A Goris; A Oturai; J Saarela; B Fontaine; B Hemmer; C Martin; F Zipp; S D'Alfonso; F Martinelli-Boneschi; B Taylor; HF Harbo; I Kockum; J Hillert; T Olsson; M Ban; JR Oksenberg; Rogier Hintzen; LF Barcellos; C Agliardi; L Alfredsson; M Alizadeh; C Anderson; R Andrews; HB Sondergaard; A Baker; G Band; SE Baranzini; N Barizzone; J Barrett; C Bellenguez; L Bergamaschi; L Bernardinelli; A Berthele; V Biberacher; TMC Binder; H Blackburn; IL Bomfim; P Brambilla; S Broadley; B Brochet; L Brundin; D Buck; H Butzkueven; SJ Caillier; W Camu; W Carpentier; P Cavalla; EG Celius; I Coman; G Comi; L Corrado; L Cosemans; I Cournu-Rebeix; BAC Cree; D Cusi; V Damotte; G Defer; SR Delgado; P Deloukas; A di Sapio; AT Dilthey; P Donnelly; B Dubois; M Duddy; S Edkins; I Elovaara; F Esposito; N Evangelou; B Fiddes; J Field; A Franke; C Freeman; IY Frohlich; D Galimberti; C Gieger; PA Gourraud; C Graetz; A Graham; V Grummel; C Guaschino; A Hadjixenofontos; H Hakonarson; C Halfpenny; G Hall; P Hall; A Hamsten; J Harley; T Harrower; C Hawkins; G Hellenthal; C Hillier; J Hobart; M Hoshi; SE Hunt; M Jagodic; I Jelcic; A Jochim; B Kendall; A Kermode; T Kilpatrick; K Koivisto; I Konidari; T Korn; H Kronsbein; C Langford; M Larsson; M Lathrop; C Lebrun-Frenay; J Lechner-Scott; MH Lee; MA Leone; V Leppa; G Liberatore; BA Lie; CM Lill; M van der Linden; J Link; F Luessi; J Lycke; F Macciardi; S Mannisto; CP Manrique; R Martin; V Martinelli; D Mason; G Mazibrada; C McCabe; IL Mero; J Mescheriakova; L Moutsianas; KM Myhr; G Nagels; R Nicholas; P Nilsson; F Piehl; M Pirinen; SE Price; H Quach; M Reunanen; W Robberecht; NP Robertson; M Rodegher; D Rog; M Salvetti; NC Schnetz-Boutaud; F Sellebjerg; RC Selter; C Schaefer; S Shaunak; Lucy Shen; S Shields; V Siffrin; M Slee; PS Sorensen; M Sorosina; M Sospedra; A Spurkland; A Strange; E Sundqvist; V Thijs; J Thorpe; A Ticca; P Tienari; Cornelia Duijn; EM Visser; Strahinja Vucic; H Westerlind; JS Wiley; A Wilkins; JF Wilson; J Winkelmann; J Zajicek; E Zindler; JL Haines; MA Pericak-Vance; AJ Ivinson; G Stewart; D Hafler; SL Hauser; A Compston; G McVean; P Jager; SJ Sawcer; JL McCauley

doi:10.1038/ng.2770

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

AH Beecham, NA Patsopoulos, DK Xifara, MF Davis, A Kemppinen, C Cotsapas, TS Shah, C Spencer, D Booth, A Goris, A Oturai, J Saarela, B Fontaine, B Hemmer, C Martin, F Zipp, S D'Alfonso, F Martinelli-Boneschi, B Taylor, HF HarboI Kockum, J Hillert, T Olsson, M Ban, JR Oksenberg, Rogier Hintzen, LF Barcellos, C Agliardi, L Alfredsson, M Alizadeh, C Anderson, R Andrews, HB Sondergaard, A Baker, G Band, SE Baranzini, N Barizzone, J Barrett, C Bellenguez, L Bergamaschi, L Bernardinelli, A Berthele, V Biberacher, TMC Binder, H Blackburn, IL Bomfim, P Brambilla, S Broadley, B Brochet, L Brundin, D Buck, H Butzkueven, SJ Caillier, W Camu, W Carpentier, P Cavalla, EG Celius, I Coman, G Comi, L Corrado, L Cosemans, I Cournu-Rebeix, BAC Cree, D Cusi, V Damotte, G Defer, SR Delgado, P Deloukas, A di Sapio, AT Dilthey, P Donnelly, B Dubois, M Duddy, S Edkins, I Elovaara, F Esposito, N Evangelou, B Fiddes, J Field, A Franke, C Freeman, IY Frohlich, D Galimberti, C Gieger, PA Gourraud, C Graetz, A Graham, V Grummel, C Guaschino, A Hadjixenofontos, H Hakonarson, C Halfpenny, G Hall, P Hall, A Hamsten, J Harley, T Harrower, C Hawkins, G Hellenthal, C Hillier, J Hobart, M Hoshi, SE Hunt, M Jagodic, I Jelcic, A Jochim, B Kendall, A Kermode, T Kilpatrick, K Koivisto, I Konidari, T Korn, H Kronsbein, C Langford, M Larsson, M Lathrop, C Lebrun-Frenay, J Lechner-Scott, MH Lee, MA Leone, V Leppa, G Liberatore, BA Lie, CM Lill, M van der Linden, J Link, F Luessi, J Lycke, F Macciardi, S Mannisto, CP Manrique, R Martin, V Martinelli, D Mason, G Mazibrada, C McCabe, IL Mero, J Mescheriakova, L Moutsianas, KM Myhr, G Nagels, R Nicholas, P Nilsson, F Piehl, M Pirinen, SE Price, H Quach, M Reunanen, W Robberecht, NP Robertson, M Rodegher, D Rog, M Salvetti, NC Schnetz-Boutaud, F Sellebjerg, RC Selter, C Schaefer, S Shaunak, Lucy Shen, S Shields, V Siffrin, M Slee, PS Sorensen, M Sorosina, M Sospedra, A Spurkland, A Strange, E Sundqvist, V Thijs, J Thorpe, A Ticca, P Tienari, Cornelia Duijn, EM Visser, Strahinja Vucic, H Westerlind, JS Wiley, A Wilkins, JF Wilson, J Winkelmann, J Zajicek, E Zindler, JL Haines, MA Pericak-Vance, AJ Ivinson, G Stewart, D Hafler, SL Hauser, A Compston, G McVean, P Jager, SJ Sawcer, JL McCauley

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

1118 Citations (Scopus)

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Original language	Undefined/Unknown
Pages (from-to)	1353-+
Journal	Nature Genetics
Volume	45
Issue number	11
DOIs	https://doi.org/10.1038/ng.2770
Publication status	Published - 2013

Research programs

EMC MM-04-44-02
EMC NIHES-01-64-02

Access to Document

10.1038/ng.2770

http://hdl.handle.net/1765/59795

Cite this

Beecham, AH., Patsopoulos, NA., Xifara, DK., Davis, MF., Kemppinen, A., Cotsapas, C., Shah, TS., Spencer, C., Booth, D., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B., ... McCauley, JL. (2013). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nature Genetics, 45(11), 1353-+. https://doi.org/10.1038/ng.2770

@article{eb4fb3fbf977494682b833846758c28e,

title = "Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis",

abstract = "Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.",

author = "AH Beecham and NA Patsopoulos and DK Xifara and MF Davis and A Kemppinen and C Cotsapas and TS Shah and C Spencer and D Booth and A Goris and A Oturai and J Saarela and B Fontaine and B Hemmer and C Martin and F Zipp and S D'Alfonso and F Martinelli-Boneschi and B Taylor and HF Harbo and I Kockum and J Hillert and T Olsson and M Ban and JR Oksenberg and Rogier Hintzen and LF Barcellos and C Agliardi and L Alfredsson and M Alizadeh and C Anderson and R Andrews and HB Sondergaard and A Baker and G Band and SE Baranzini and N Barizzone and J Barrett and C Bellenguez and L Bergamaschi and L Bernardinelli and A Berthele and V Biberacher and TMC Binder and H Blackburn and IL Bomfim and P Brambilla and S Broadley and B Brochet and L Brundin and D Buck and H Butzkueven and SJ Caillier and W Camu and W Carpentier and P Cavalla and EG Celius and I Coman and G Comi and L Corrado and L Cosemans and I Cournu-Rebeix and BAC Cree and D Cusi and V Damotte and G Defer and SR Delgado and P Deloukas and {di Sapio}, A and AT Dilthey and P Donnelly and B Dubois and M Duddy and S Edkins and I Elovaara and F Esposito and N Evangelou and B Fiddes and J Field and A Franke and C Freeman and IY Frohlich and D Galimberti and C Gieger and PA Gourraud and C Graetz and A Graham and V Grummel and C Guaschino and A Hadjixenofontos and H Hakonarson and C Halfpenny and G Hall and P Hall and A Hamsten and J Harley and T Harrower and C Hawkins and G Hellenthal and C Hillier and J Hobart and M Hoshi and SE Hunt and M Jagodic and I Jelcic and A Jochim and B Kendall and A Kermode and T Kilpatrick and K Koivisto and I Konidari and T Korn and H Kronsbein and C Langford and M Larsson and M Lathrop and C Lebrun-Frenay and J Lechner-Scott and MH Lee and MA Leone and V Leppa and G Liberatore and BA Lie and CM Lill and {van der Linden}, M and J Link and F Luessi and J Lycke and F Macciardi and S Mannisto and CP Manrique and R Martin and V Martinelli and D Mason and G Mazibrada and C McCabe and IL Mero and J Mescheriakova and L Moutsianas and KM Myhr and G Nagels and R Nicholas and P Nilsson and F Piehl and M Pirinen and SE Price and H Quach and M Reunanen and W Robberecht and NP Robertson and M Rodegher and D Rog and M Salvetti and NC Schnetz-Boutaud and F Sellebjerg and RC Selter and C Schaefer and S Shaunak and Lucy Shen and S Shields and V Siffrin and M Slee and PS Sorensen and M Sorosina and M Sospedra and A Spurkland and A Strange and E Sundqvist and V Thijs and J Thorpe and A Ticca and P Tienari and Cornelia Duijn and EM Visser and Strahinja Vucic and H Westerlind and JS Wiley and A Wilkins and JF Wilson and J Winkelmann and J Zajicek and E Zindler and JL Haines and MA Pericak-Vance and AJ Ivinson and G Stewart and D Hafler and SL Hauser and A Compston and G McVean and P Jager and SJ Sawcer and JL McCauley",

year = "2013",

doi = "10.1038/ng.2770",

language = "Undefined/Unknown",

volume = "45",

pages = "1353--+",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Sondergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, Franke, A, Freeman, C, Frohlich, IY, Galimberti, D, Gieger, C, Gourraud, PA, Graetz, C, Graham, A, Grummel, V, Guaschino, C, Hadjixenofontos, A, Hakonarson, H, Halfpenny, C, Hall, G, Hall, P, Hamsten, A, Harley, J, Harrower, T, Hawkins, C, Hellenthal, G, Hillier, C, Hobart, J, Hoshi, M, Hunt, SE, Jagodic, M, Jelcic, I, Jochim, A, Kendall, B, Kermode, A, Kilpatrick, T, Koivisto, K, Konidari, I, Korn, T, Kronsbein, H, Langford, C, Larsson, M, Lathrop, M, Lebrun-Frenay, C, Lechner-Scott, J, Lee, MH, Leone, MA, Leppa, V, Liberatore, G, Lie, BA, Lill, CM, van der Linden, M, Link, J, Luessi, F, Lycke, J, Macciardi, F, Mannisto, S, Manrique, CP, Martin, R, Martinelli, V, Mason, D, Mazibrada, G, McCabe, C, Mero, IL, Mescheriakova, J, Moutsianas, L, Myhr, KM, Nagels, G, Nicholas, R, Nilsson, P, Piehl, F, Pirinen, M, Price, SE, Quach, H, Reunanen, M, Robberecht, W, Robertson, NP, Rodegher, M, Rog, D, Salvetti, M, Schnetz-Boutaud, NC, Sellebjerg, F, Selter, RC, Schaefer, C, Shaunak, S, Shen, L, Shields, S, Siffrin, V, Slee, M, Sorensen, PS, Sorosina, M, Sospedra, M, Spurkland, A, Strange, A, Sundqvist, E, Thijs, V, Thorpe, J, Ticca, A, Tienari, P, Duijn, C, Visser, EM, Vucic, S, Westerlind, H, Wiley, JS, Wilkins, A, Wilson, JF, Winkelmann, J, Zajicek, J, Zindler, E, Haines, JL, Pericak-Vance, MA, Ivinson, AJ, Stewart, G, Hafler, D, Hauser, SL, Compston, A, McVean, G, Jager, P, Sawcer, SJ & McCauley, JL 2013, 'Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis', Nature Genetics, vol. 45, no. 11, pp. 1353-+. https://doi.org/10.1038/ng.2770

TY - JOUR

T1 - Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

AU - Beecham, AH

AU - Patsopoulos, NA

AU - Xifara, DK

AU - Davis, MF

AU - Kemppinen, A

AU - Cotsapas, C

AU - Shah, TS

AU - Spencer, C

AU - Booth, D

AU - Goris, A

AU - Oturai, A

AU - Saarela, J

AU - Fontaine, B

AU - Hemmer, B

AU - Martin, C

AU - Zipp, F

AU - D'Alfonso, S

AU - Martinelli-Boneschi, F

AU - Taylor, B

AU - Harbo, HF

AU - Kockum, I

AU - Hillert, J

AU - Olsson, T

AU - Ban, M

AU - Oksenberg, JR

AU - Hintzen, Rogier

AU - Barcellos, LF

AU - Agliardi, C

AU - Alfredsson, L

AU - Alizadeh, M

AU - Anderson, C

AU - Andrews, R

AU - Sondergaard, HB

AU - Baker, A

AU - Band, G

AU - Baranzini, SE

AU - Barizzone, N

AU - Barrett, J

AU - Bellenguez, C

AU - Bergamaschi, L

AU - Bernardinelli, L

AU - Berthele, A

AU - Biberacher, V

AU - Binder, TMC

AU - Blackburn, H

AU - Bomfim, IL

AU - Brambilla, P

AU - Broadley, S

AU - Brochet, B

AU - Brundin, L

AU - Buck, D

AU - Butzkueven, H

AU - Caillier, SJ

AU - Camu, W

AU - Carpentier, W

AU - Cavalla, P

AU - Celius, EG

AU - Coman, I

AU - Comi, G

AU - Corrado, L

AU - Cosemans, L

AU - Cournu-Rebeix, I

AU - Cree, BAC

AU - Cusi, D

AU - Damotte, V

AU - Defer, G

AU - Delgado, SR

AU - Deloukas, P

AU - di Sapio, A

AU - Dilthey, AT

AU - Donnelly, P

AU - Dubois, B

AU - Duddy, M

AU - Edkins, S

AU - Elovaara, I

AU - Esposito, F

AU - Evangelou, N

AU - Fiddes, B

AU - Field, J

AU - Franke, A

AU - Freeman, C

AU - Frohlich, IY

AU - Galimberti, D

AU - Gieger, C

AU - Gourraud, PA

AU - Graetz, C

AU - Graham, A

AU - Grummel, V

AU - Guaschino, C

AU - Hadjixenofontos, A

AU - Hakonarson, H

AU - Halfpenny, C

AU - Hall, G

AU - Hall, P

AU - Hamsten, A

AU - Harley, J

AU - Harrower, T

AU - Hawkins, C

AU - Hellenthal, G

AU - Hillier, C

AU - Hobart, J

AU - Hoshi, M

AU - Hunt, SE

AU - Jagodic, M

AU - Jelcic, I

AU - Jochim, A

AU - Kendall, B

AU - Kermode, A

AU - Kilpatrick, T

AU - Koivisto, K

AU - Konidari, I

AU - Korn, T

AU - Kronsbein, H

AU - Langford, C

AU - Larsson, M

AU - Lathrop, M

AU - Lebrun-Frenay, C

AU - Lechner-Scott, J

AU - Lee, MH

AU - Leone, MA

AU - Leppa, V

AU - Liberatore, G

AU - Lie, BA

AU - Lill, CM

AU - van der Linden, M

AU - Link, J

AU - Luessi, F

AU - Lycke, J

AU - Macciardi, F

AU - Mannisto, S

AU - Manrique, CP

AU - Martin, R

AU - Martinelli, V

AU - Mason, D

AU - Mazibrada, G

AU - McCabe, C

AU - Mero, IL

AU - Mescheriakova, J

AU - Moutsianas, L

AU - Myhr, KM

AU - Nagels, G

AU - Nicholas, R

AU - Nilsson, P

AU - Piehl, F

AU - Pirinen, M

AU - Price, SE

AU - Quach, H

AU - Reunanen, M

AU - Robberecht, W

AU - Robertson, NP

AU - Rodegher, M

AU - Rog, D

AU - Salvetti, M

AU - Schnetz-Boutaud, NC

AU - Sellebjerg, F

AU - Selter, RC

AU - Schaefer, C

AU - Shaunak, S

AU - Shen, Lucy

AU - Shields, S

AU - Siffrin, V

AU - Slee, M

AU - Sorensen, PS

AU - Sorosina, M

AU - Sospedra, M

AU - Spurkland, A

AU - Strange, A

AU - Sundqvist, E

AU - Thijs, V

AU - Thorpe, J

AU - Ticca, A

AU - Tienari, P

AU - Duijn, Cornelia

AU - Visser, EM

AU - Vucic, Strahinja

AU - Westerlind, H

AU - Wiley, JS

AU - Wilkins, A

AU - Wilson, JF

AU - Winkelmann, J

AU - Zajicek, J

AU - Zindler, E

AU - Haines, JL

AU - Pericak-Vance, MA

AU - Ivinson, AJ

AU - Stewart, G

AU - Hafler, D

AU - Hauser, SL

AU - Compston, A

AU - McVean, G

AU - Jager, P

AU - Sawcer, SJ

AU - McCauley, JL

PY - 2013

Y1 - 2013

N2 - Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

AB - Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 x 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 x 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

U2 - 10.1038/ng.2770

DO - 10.1038/ng.2770

M3 - Article

C2 - 24076602

SN - 1061-4036

VL - 45

SP - 1353-+

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -