Genome-wide significant association with seven novel multiple sclerosis risk loci

CM Lill; F Luessi; A Alcina; EA Sokolova; N Ugidos; B de la Hera; L Guillot-Noel; S (Sunny) Malhotra; E Reinthaler; BMM Schjeide; Julia Mescheriakova; A Mashychev; I Wohlers; DA Akkad; O Aktas; I Alloza; A Antiguedad; R Arroyo; I Astobiza; P Blaschke; AN Boyko; M Buttmann; A Chan; T Dorner; JT Epplen; OO Favorova; M Fedetz; O Fernandez; A Garcia-Martinez; LA Gerdes; C Graetz; HP Hartung; S Hoffjan; G Izquierdo; DS Korobko; A Kroner; C Kubisch; T Kumpfel; L Leyva; P Lohse; NA Malkova; X Montalban; EV Popova; P Rieckmann; AS Rozhdestvenskii; C Schmied; IV Smagina; EY Tsareva; A Winkelmann; UK Zettl; H Binder; I Cournu-Rebeix; Rogier Hintzen; A Zimprich; M Comabella; B Fontaine; E Urcelay; K Vandenbroeck; M Filipenko; F Matesanz; F Zipp; L Bertram

doi:10.1136/jmedgenet-2015-103442

Genome-wide significant association with seven novel multiple sclerosis risk loci

CM Lill, F Luessi, A Alcina, EA Sokolova, N Ugidos, B de la Hera, L Guillot-Noel, S (Sunny) Malhotra, E Reinthaler, BMM Schjeide, Julia Mescheriakova, A Mashychev, I Wohlers, DA Akkad, O Aktas, I Alloza, A Antiguedad, R Arroyo, I Astobiza, P BlaschkeAN Boyko, M Buttmann, A Chan, T Dorner, JT Epplen, OO Favorova, M Fedetz, O Fernandez, A Garcia-Martinez, LA Gerdes, C Graetz, HP Hartung, S Hoffjan, G Izquierdo, DS Korobko, A Kroner, C Kubisch, T Kumpfel, L Leyva, P Lohse, NA Malkova, X Montalban, EV Popova, P Rieckmann, AS Rozhdestvenskii, C Schmied, IV Smagina, EY Tsareva, A Winkelmann, UK Zettl, H Binder, I Cournu-Rebeix, Rogier Hintzen, A Zimprich, M Comabella, B Fontaine, E Urcelay, K Vandenbroeck, M Filipenko, F Matesanz, F Zipp, L Bertram

Neurology

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

34 Citations (Scopus)

Abstract

Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5x10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03x10(-12)), CD28 (rs6435203, p=1.35x10(-9)), LPP (rs4686953, p=3.35x10(-8)), ETS1 (rs3809006, p=7.74x10(-9)), DLEU1 (rs806349, p=8.14x10(-12)), LPIN3 (rs6072343, p=7.16x10(-12)) and IFNGR2 (rs9808753, p=4.40x10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

Original language	English
Pages (from-to)	848-855
Number of pages	8
Journal	Journal of Medical Genetics
Volume	52
Issue number	12
DOIs	https://doi.org/10.1136/jmedgenet-2015-103442
Publication status	Published - 2015

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EMC MM-02-72-02

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10.1136/jmedgenet-2015-103442

http://hdl.handle.net/1765/85268

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Lill, CM., Luessi, F., Alcina, A., Sokolova, EA., Ugidos, N., de la Hera, B., Guillot-Noel, L., Malhotra, S., Reinthaler, E., Schjeide, BMM., Mescheriakova, J., Mashychev, A., Wohlers, I., Akkad, DA., Aktas, O., Alloza, I., Antiguedad, A., Arroyo, R., Astobiza, I., ... Bertram, L. (2015). Genome-wide significant association with seven novel multiple sclerosis risk loci. Journal of Medical Genetics, 52(12), 848-855. https://doi.org/10.1136/jmedgenet-2015-103442

@article{7b023596de5748a09ddd50b8e818b214,

title = "Genome-wide significant association with seven novel multiple sclerosis risk loci",

abstract = "Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5x10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03x10(-12)), CD28 (rs6435203, p=1.35x10(-9)), LPP (rs4686953, p=3.35x10(-8)), ETS1 (rs3809006, p=7.74x10(-9)), DLEU1 (rs806349, p=8.14x10(-12)), LPIN3 (rs6072343, p=7.16x10(-12)) and IFNGR2 (rs9808753, p=4.40x10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.",

author = "CM Lill and F Luessi and A Alcina and EA Sokolova and N Ugidos and {de la Hera}, B and L Guillot-Noel and Malhotra, {S (Sunny)} and E Reinthaler and BMM Schjeide and Julia Mescheriakova and A Mashychev and I Wohlers and DA Akkad and O Aktas and I Alloza and A Antiguedad and R Arroyo and I Astobiza and P Blaschke and AN Boyko and M Buttmann and A Chan and T Dorner and JT Epplen and OO Favorova and M Fedetz and O Fernandez and A Garcia-Martinez and LA Gerdes and C Graetz and HP Hartung and S Hoffjan and G Izquierdo and DS Korobko and A Kroner and C Kubisch and T Kumpfel and L Leyva and P Lohse and NA Malkova and X Montalban and EV Popova and P Rieckmann and AS Rozhdestvenskii and C Schmied and IV Smagina and EY Tsareva and A Winkelmann and UK Zettl and H Binder and I Cournu-Rebeix and Rogier Hintzen and A Zimprich and M Comabella and B Fontaine and E Urcelay and K Vandenbroeck and M Filipenko and F Matesanz and F Zipp and L Bertram",

year = "2015",

doi = "10.1136/jmedgenet-2015-103442",

language = "English",

volume = "52",

pages = "848--855",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "12",

}

Lill, CM, Luessi, F, Alcina, A, Sokolova, EA, Ugidos, N, de la Hera, B, Guillot-Noel, L, Malhotra, S, Reinthaler, E, Schjeide, BMM, Mescheriakova, J, Mashychev, A, Wohlers, I, Akkad, DA, Aktas, O, Alloza, I, Antiguedad, A, Arroyo, R, Astobiza, I, Blaschke, P, Boyko, AN, Buttmann, M, Chan, A, Dorner, T, Epplen, JT, Favorova, OO, Fedetz, M, Fernandez, O, Garcia-Martinez, A, Gerdes, LA, Graetz, C, Hartung, HP, Hoffjan, S, Izquierdo, G, Korobko, DS, Kroner, A, Kubisch, C, Kumpfel, T, Leyva, L, Lohse, P, Malkova, NA, Montalban, X, Popova, EV, Rieckmann, P, Rozhdestvenskii, AS, Schmied, C, Smagina, IV, Tsareva, EY, Winkelmann, A, Zettl, UK, Binder, H, Cournu-Rebeix, I, Hintzen, R, Zimprich, A, Comabella, M, Fontaine, B, Urcelay, E, Vandenbroeck, K, Filipenko, M, Matesanz, F, Zipp, F & Bertram, L 2015, 'Genome-wide significant association with seven novel multiple sclerosis risk loci', Journal of Medical Genetics, vol. 52, no. 12, pp. 848-855. https://doi.org/10.1136/jmedgenet-2015-103442

TY - JOUR

T1 - Genome-wide significant association with seven novel multiple sclerosis risk loci

AU - Lill, CM

AU - Luessi, F

AU - Alcina, A

AU - Sokolova, EA

AU - Ugidos, N

AU - de la Hera, B

AU - Guillot-Noel, L

AU - Malhotra, S (Sunny)

AU - Reinthaler, E

AU - Schjeide, BMM

AU - Mescheriakova, Julia

AU - Mashychev, A

AU - Wohlers, I

AU - Akkad, DA

AU - Aktas, O

AU - Alloza, I

AU - Antiguedad, A

AU - Arroyo, R

AU - Astobiza, I

AU - Blaschke, P

AU - Boyko, AN

AU - Buttmann, M

AU - Chan, A

AU - Dorner, T

AU - Epplen, JT

AU - Favorova, OO

AU - Fedetz, M

AU - Fernandez, O

AU - Garcia-Martinez, A

AU - Gerdes, LA

AU - Graetz, C

AU - Hartung, HP

AU - Hoffjan, S

AU - Izquierdo, G

AU - Korobko, DS

AU - Kroner, A

AU - Kubisch, C

AU - Kumpfel, T

AU - Leyva, L

AU - Lohse, P

AU - Malkova, NA

AU - Montalban, X

AU - Popova, EV

AU - Rieckmann, P

AU - Rozhdestvenskii, AS

AU - Schmied, C

AU - Smagina, IV

AU - Tsareva, EY

AU - Winkelmann, A

AU - Zettl, UK

AU - Binder, H

AU - Cournu-Rebeix, I

AU - Hintzen, Rogier

AU - Zimprich, A

AU - Comabella, M

AU - Fontaine, B

AU - Urcelay, E

AU - Vandenbroeck, K

AU - Filipenko, M

AU - Matesanz, F

AU - Zipp, F

AU - Bertram, L

PY - 2015

Y1 - 2015

N2 - Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5x10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03x10(-12)), CD28 (rs6435203, p=1.35x10(-9)), LPP (rs4686953, p=3.35x10(-8)), ETS1 (rs3809006, p=7.74x10(-9)), DLEU1 (rs806349, p=8.14x10(-12)), LPIN3 (rs6072343, p=7.16x10(-12)) and IFNGR2 (rs9808753, p=4.40x10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

AB - Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5x10(-8)) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03x10(-12)), CD28 (rs6435203, p=1.35x10(-9)), LPP (rs4686953, p=3.35x10(-8)), ETS1 (rs3809006, p=7.74x10(-9)), DLEU1 (rs806349, p=8.14x10(-12)), LPIN3 (rs6072343, p=7.16x10(-12)) and IFNGR2 (rs9808753, p=4.40x10(-10)). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

U2 - 10.1136/jmedgenet-2015-103442

DO - 10.1136/jmedgenet-2015-103442

M3 - Article

C2 - 26475045

SN - 0022-2593

VL - 52

SP - 848

EP - 855

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 12

ER -

Genome-wide significant association with seven novel multiple sclerosis risk loci

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