European population substructure correlates with systemic lupus erythematosus endophenotypes in North Americans of European descent

Abstract

Previous work has demonstrated that Northern and Southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. In this study, 1855 SLE cases of European descent were genotyped for 4965 single-nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished Northern from Southern European ancestry, PC2 differentiated Eastern from Western European ancestry and PC3 delineated Ashkenazi Jewish ancestry. Compared with Northern European ancestry, Southern European ancestry was associated with autoantibody production (odds ratio (OR)=1.40, 95% confidence interval (CI) 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.

Figure 1

Principal components analysis (PCA) shows European population substructure. (a) Panel 1a plots principal component (PC) 2 against PC1. (b) Panel 1b plots PC3 against PC1. (c) Panel 1c identifies homogenous clusters (northern European, southern European, Ashkenazi Jewish) defined by PC1 and PC3. Points on the graphs represent individual study participants; individuals are color coded according to SLE status and grandparental country of origin, AJA=Ashkenazi Jewish ancestry, EEUR=Eastern European. Population genetic substructure was determined using PCA of 4965 single nucleotide polymorphisms (SNPs) in EIGENSTRAT (Cambridge, MA). Of these SNPs, 2617 were informative for European population substructure and the remainder were informative for continental ancestry (187 SNPs) or East Asian substructure (2161 SNPs). These SNPs are distributed throughout the autosomal genome and exclude regions of extended linkage disequilibrium (inversion regions and the major histocompatibility complex region). Additionally, pairs of SNPs with r² >0.5 in European population groups, SNPs not in Hardy-Weinberg equilibrium, and SNPs missing in >10% of participants were excluded. To improve PC differentiation and interpretation, we also included a set of 2398 controls genotyped for the same set of SNPs. Controls were adults of self-reported European ancestry enrolled in the New York Cancer Project who did not have SLE. Information on grandparental country of origin was collected for controls, and controls with all 4 grandparents from a single European country or region or who shared a single ethnic identity were used for PC interpretation. Prior to PCA, we screened the study population for non-European ancestry using a set of 187 ancestry informative markers included in the SNP panel. We used STRUCTURE, a program that applies a model based, non-hierarchical clustering method for individual ancestry estimation. Participants with >10% non-European ancestry were excluded prior to PCA to determine European substructure. Participants were also excluded for outlying PC values (>6 standard deviations from the mean).

Figure 2

Correlation coefficients for SLE manifestations. We used the Spearman rank correlation coefficient, which does not require a normal distribution of values for a variable, to assess the correlation between pairs of SLE manifestations included in the American College of Rheumatology classification criteria for SLE and also for specific autoantibodies. Shading reflects the strength and direction of the correlation between SLE phenotypes. *p<0.01; ds-DNA=anti-double stranded DNA antibody, ACL=anti-cardiolipin antibody, ANA=anti-nuclear antibody