Introduction: We aimed to investigate whether the effect size of the
systemic lupus erythematosus (SLE) risk alleles varies across European
subpopulations.
Methods: European SLE patients (n = 1,742) and ethnically matched
healthy controls (n = 2,101) were recruited at 17 centres from 10
different countries. Only individuals with self-reported ancestry from
the country of origin were included. In addition, participants were
genotyped for top ancestry informative markers and for 25 SLE associated
SNPs. The results were used to compare effect sizes between the Central
Eureopan and Southern European subgroups.
Results: Twenty of the 25 SNPs showed independent association with SLE,
These SNPs showed a significant bias to larger effect sizes in the
Southern subgroup, with 15/20 showing this trend (P = 0.019) and a
larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well
as a larger difference in the number of risk alleles (2.06 vs. 1.63, P =
0.027) between SLE patients and controls than for Central Europeans.
This bias was reflected in a very significant difference in the
cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 x 10(-32)). Effect
size bias was accompanied by a lower number of SLE risk alleles in the
Southern subjects, both patients and controls, the difference being more
marked between the controls (P = 1.1 x 10(-8)) than between the Southern
and Central European patients (P = 0.016). Seven of these SNPs showed
significant allele frequency clines.
Conclusion: Our findings showed a bias to larger effect sizes of SLE
loci in the Southern Europeans relative to the Central Europeans
together with clines of SLE risk allele frequencies. These results
indicate the need to study risk allele clines and the implications of
the polygenic model of inheritance in SLE