Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene

Eveliina Jakkula; Virpi Leppä; Anna Maija Sulonen; Teppo Varilo; Suvi Kallio; Anu Kemppinen; Shaun Purcell; Keijo Koivisto; Pentti Tienari; Marja Liisa Sumelahti; Irina Elovaara; Tuula Pirttilä; Mauri Reunanen; Arpo Aromaa; Annette Bang Oturai; Helle Bach Søndergaard; Hanne F. Harbo; Inger Lise Mero; Stacey B. Gabriel; Daniel B. Mirel; Stephen L. Hauser; Ludwig Kappos; Chris Polman; Philip L. De Jager; David A. Hafler; Mark J. Daly; Aarno Palotie; Janna Saarela; Leena Peltonen

doi:10.1016/j.ajhg.2010.01.017

Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene

Eveliina Jakkula
, Virpi Leppä
, Anna Maija Sulonen
, Teppo Varilo
, Suvi Kallio
, Anu Kemppinen
, Shaun Purcell
, Keijo Koivisto
, Pentti Tienari
, Marja Liisa Sumelahti
, Irina Elovaara
, Tuula Pirttilä
, Mauri Reunanen
, Arpo Aromaa
, Annette Bang Oturai
, Helle Bach Søndergaard
, Hanne F. Harbo
, Inger Lise Mero
, Stacey B. Gabriel
, Daniel B. Mirel

Stephen L. Hauser, Ludwig Kappos, Chris Polman, Philip L. De Jager, David A. Hafler, Mark J. Daly, Aarno Palotie, Janna Saarela, Leena Peltonen

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

208 Scopus citations

Abstract

Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10^-4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10^-10, OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

Original language	English
Pages (from-to)	285-291
Number of pages	7
Journal	American Journal of Human Genetics
Volume	86
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2010.01.017
State	Published - 12 Feb 2010
Externally published	Yes

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10.1016/j.ajhg.2010.01.017

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Jakkula, E., Leppä, V., Sulonen, A. M., Varilo, T., Kallio, S., Kemppinen, A., Purcell, S., Koivisto, K., Tienari, P., Sumelahti, M. L., Elovaara, I., Pirttilä, T., Reunanen, M., Aromaa, A., Oturai, A. B., Søndergaard, H. B., Harbo, H. F., Mero, I. L., Gabriel, S. B., ... Peltonen, L. (2010). Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene. American Journal of Human Genetics, 86(2), 285-291. https://doi.org/10.1016/j.ajhg.2010.01.017

@article{c048de4966534293a625c67ab3b5d393,

title = "Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene",

abstract = "Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10-4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10-10, OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.",

author = "Eveliina Jakkula and Virpi Lepp{\"a} and Sulonen, \{Anna Maija\} and Teppo Varilo and Suvi Kallio and Anu Kemppinen and Shaun Purcell and Keijo Koivisto and Pentti Tienari and Sumelahti, \{Marja Liisa\} and Irina Elovaara and Tuula Pirttil{\"a} and Mauri Reunanen and Arpo Aromaa and Oturai, \{Annette Bang\} and S{\o}ndergaard, \{Helle Bach\} and Harbo, \{Hanne F.\} and Mero, \{Inger Lise\} and Gabriel, \{Stacey B.\} and Mirel, \{Daniel B.\} and Hauser, \{Stephen L.\} and Ludwig Kappos and Chris Polman and \{De Jager\}, \{Philip L.\} and Hafler, \{David A.\} and Daly, \{Mark J.\} and Aarno Palotie and Janna Saarela and Leena Peltonen",

note = "Funding Information: We wish to thank all participating MS patients and families. Elli Kempas, Liisa Arala, Anne Vikman, Anne Nyberg, Minna Suvela, and Marja-Leena Sairanen are acknowledged for their invaluable assistance and technical support. We sincerely thank Ida Surakka, Samuli Ripatti, and Carl Anderson for their valuable assistance and advice in statistical analyses and Nicole Soranzo for guidance on Haplotter. The International Multiple Sclerosis Genetics Consortium (IMSGC) and Gene MSA Consortium are acknowledged for the data utilized in the replication phase. The Danish Multiple Sclerosis Society is acknowledged for supporting the Danish sample collection, and the Norwegian Bone Marrow Donor Registry is acknowledged for collaboration in establishment of the Norwegian control material. The Institute for Molecular Medicine Finland (FIMM) Technology Center (previously Finnish Genome Center) and the Broad Institute Center for Genotyping and Analysis are acknowledged for conducting genotyping on the Illumina GWA platform. The Health 2000 project is thanked for providing population-based controls for this GWAS study. This work was supported by the National Institutes of Health (grant RO1 NS 43559), the Center of Excellence for Disease Genetics of the Academy of Finland (grants 213506 and 129680), the Sigrid Juselius Foundation, the Biocentrum Helsinki Foundation, Helsinki University Central Hospital Research Foundation, the Neuropromise EU project (grant LSHM-CT-2005-018637), and The Wellcome Trust (grant 089061/Z/09/Z). The Broad Institute Center for Genotyping and Analysis is supported by the National Center for Research Resources (grant U54 RR020278). The genotyping of the Health 2000 controls was funded by the SGENE EU project (LSHM-CT-2006-037761) and Simons Foundation (R01MH71425-01A1). P.L.D.J. is a Harry Weaver Neuroscience Scholar of the National MS Society. L.P. is a member of the Board of the Orion Pharma Limited, Helsinki, Finland. ",

year = "2010",

month = feb,

day = "12",

doi = "10.1016/j.ajhg.2010.01.017",

language = "English",

volume = "86",

pages = "285--291",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Jakkula, E, Leppä, V, Sulonen, AM, Varilo, T, Kallio, S, Kemppinen, A, Purcell, S, Koivisto, K, Tienari, P, Sumelahti, ML, Elovaara, I, Pirttilä, T, Reunanen, M, Aromaa, A, Oturai, AB, Søndergaard, HB, Harbo, HF, Mero, IL, Gabriel, SB, Mirel, DB, Hauser, SL, Kappos, L, Polman, C, De Jager, PL, Hafler, DA, Daly, MJ, Palotie, A, Saarela, J & Peltonen, L 2010, 'Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene', American Journal of Human Genetics, vol. 86, no. 2, pp. 285-291. https://doi.org/10.1016/j.ajhg.2010.01.017

TY - JOUR

T1 - Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene

AU - Jakkula, Eveliina

AU - Leppä, Virpi

AU - Sulonen, Anna Maija

AU - Varilo, Teppo

AU - Kallio, Suvi

AU - Kemppinen, Anu

AU - Purcell, Shaun

AU - Koivisto, Keijo

AU - Tienari, Pentti

AU - Sumelahti, Marja Liisa

AU - Elovaara, Irina

AU - Pirttilä, Tuula

AU - Reunanen, Mauri

AU - Aromaa, Arpo

AU - Oturai, Annette Bang

AU - Søndergaard, Helle Bach

AU - Harbo, Hanne F.

AU - Mero, Inger Lise

AU - Gabriel, Stacey B.

AU - Mirel, Daniel B.

AU - Hauser, Stephen L.

AU - Kappos, Ludwig

AU - Polman, Chris

AU - De Jager, Philip L.

AU - Hafler, David A.

AU - Daly, Mark J.

AU - Palotie, Aarno

AU - Saarela, Janna

AU - Peltonen, Leena

N1 - Funding Information: We wish to thank all participating MS patients and families. Elli Kempas, Liisa Arala, Anne Vikman, Anne Nyberg, Minna Suvela, and Marja-Leena Sairanen are acknowledged for their invaluable assistance and technical support. We sincerely thank Ida Surakka, Samuli Ripatti, and Carl Anderson for their valuable assistance and advice in statistical analyses and Nicole Soranzo for guidance on Haplotter. The International Multiple Sclerosis Genetics Consortium (IMSGC) and Gene MSA Consortium are acknowledged for the data utilized in the replication phase. The Danish Multiple Sclerosis Society is acknowledged for supporting the Danish sample collection, and the Norwegian Bone Marrow Donor Registry is acknowledged for collaboration in establishment of the Norwegian control material. The Institute for Molecular Medicine Finland (FIMM) Technology Center (previously Finnish Genome Center) and the Broad Institute Center for Genotyping and Analysis are acknowledged for conducting genotyping on the Illumina GWA platform. The Health 2000 project is thanked for providing population-based controls for this GWAS study. This work was supported by the National Institutes of Health (grant RO1 NS 43559), the Center of Excellence for Disease Genetics of the Academy of Finland (grants 213506 and 129680), the Sigrid Juselius Foundation, the Biocentrum Helsinki Foundation, Helsinki University Central Hospital Research Foundation, the Neuropromise EU project (grant LSHM-CT-2005-018637), and The Wellcome Trust (grant 089061/Z/09/Z). The Broad Institute Center for Genotyping and Analysis is supported by the National Center for Research Resources (grant U54 RR020278). The genotyping of the Health 2000 controls was funded by the SGENE EU project (LSHM-CT-2006-037761) and Simons Foundation (R01MH71425-01A1). P.L.D.J. is a Harry Weaver Neuroscience Scholar of the National MS Society. L.P. is a member of the Board of the Orion Pharma Limited, Helsinki, Finland.

PY - 2010/2/12

Y1 - 2010/2/12

N2 - Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10-4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10-10, OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

AB - Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10-4 were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 × 10-10, OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

UR - https://www.scopus.com/pages/publications/76049083598

U2 - 10.1016/j.ajhg.2010.01.017

DO - 10.1016/j.ajhg.2010.01.017

M3 - Article

AN - SCOPUS:76049083598

SN - 0002-9297

VL - 86

SP - 285

EP - 291

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene

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