Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene.
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.
Jakkula
Eveliina
E
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Leppä
Virpi
V
Sulonen
Anna-Maija
AM
Varilo
Teppo
T
Kallio
Suvi
S
Kemppinen
Anu
A
Purcell
Shaun
S
Koivisto
Keijo
K
Tienari
Pentti
P
Sumelahti
Marja-Liisa
ML
Elovaara
Irina
I
Pirttilä
Tuula
T
Reunanen
Mauri
M
Aromaa
Arpo
A
Oturai
Annette Bang
AB
Søndergaard
Helle Bach
HB
Harbo
Hanne F
HF
Mero
Inger-Lise
IL
Gabriel
Stacey B
SB
Mirel
Daniel B
DB
Hauser
Stephen L
SL
Kappos
Ludwig
L
Polman
Chris
C
De Jager
Philip L
PL
Hafler
David A
DA
Daly
Mark J
MJ
Palotie
Aarno
A
Saarela
Janna
J
Peltonen
Leena
L
D000483:Alleles; D020029:Base Pairing / Q000235:genetics; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D050796:STAT3 Transcription Factor / Q000235:genetics*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human