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 Harbo Hansen; 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 Harbo Hansen, Inger-Lise Mero, Stacey B Gabriel, Daniel B MirelStephen L Hauser, Ludwig Kappos, Chris Polman, Philip L De Jager, David A Hafler, Mark J Daly, Aarno Palotie, Janna Saarela, Leena Peltonen

Department of Neurology

208 Citations (Scopus)

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 x 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
Journal	American Journal of Human Genetics
Volume	86
Issue number	2
Pages (from-to)	285-91
Number of pages	7
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2010.01.017
Publication status	Published - 12 Feb 2010

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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., Hansen, H. H., 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), 285-91. https://doi.org/10.1016/j.ajhg.2010.01.017

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, AB, Søndergaard, HB, Hansen, HH, Mero, I-L, 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. 285-91. https://doi.org/10.1016/j.ajhg.2010.01.017

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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 x 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 Anna-Maija Sulonen and Teppo Varilo and Suvi Kallio and Anu Kemppinen and Shaun Purcell and Keijo Koivisto and Pentti Tienari and Marja-Liisa Sumelahti and Irina Elovaara and Tuula Pirttil{\"a} and Mauri Reunanen and Arpo Aromaa and Oturai, \{Annette Bang\} and S{\o}ndergaard, \{Helle Bach\} and Hansen, \{Hanne Harbo\} and Inger-Lise Mero 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",

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

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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 - Hansen, Hanne Harbo

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

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 x 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 x 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 - Journal article

C2 - 20159113

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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