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.
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
Eveliina
E
Jakkula
Virpi
V
Leppä
Anna-Maija
AM
Sulonen
Teppo
T
Varilo
Suvi
S
Kallio
Anu
A
Kemppinen
Shaun
S
Purcell
Keijo
K
Koivisto
Pentti
P
Tienari
Marja-Liisa
ML
Sumelahti
Irina
I
Elovaara
Tuula
T
Pirttilä
Mauri
M
Reunanen
Arpo
A
Aromaa
Annette Bang
AB
Oturai
Helle Bach
HB
Søndergaard
Hanne F
HF
Harbo
Inger-Lise
IL
Mero
Stacey B
SB
Gabriel
Daniel B
DB
Mirel
Stephen L
SL
Hauser
Ludwig
L
Kappos
Chris
C
Polman
Philip L
PL
De Jager
David A
DA
Hafler
Mark J
MJ
Daly
Aarno
A
Palotie
Janna
J
Saarela
Leena
L
Peltonen
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