Conditional regression results for 5′TNFSF4 variants in four groups.

<p>Conditional analyses in SNPTESTv2 Case Control. Continuous covariate within a clustering framework. P values selected using additional model and a frequentist paradigm.</p

SLE-associated <i>rs2205960</i> predicted to be part of a decameric motif for NF-κB p65 (RELA).

<p><i>A</i>. Degeneracy within the core 10-base motif is illustrated at all positions apart from position 7 which is non-degenerate by the stacked letters at each position. The relative height of each letter is proportional to its over-enrichment in the motif. A dashed line is boxed around <i>rs2205960-T</i>, this SLE-associated allele is predicted to form the 8^th nucleotide in the motif. Predictions were made using the non-degenerate set of matrix profiles in the Jaspar Core database. <i>B</i>. Altering the <i>rs2205960</i> allele from <i>-T</i> to <i>-G</i> decreases the binding affinity for NF-κB p65 by over 10%. <i>C</i>. Binding of NF-κB at <i>rs2205960</i>, suggested by genome-wide ChIP-seq ENCODE data. Profiles were generated for lymphoblatoid cell lines and stored in the UCSC genome database.</p

Single marker association results for East Asian (As), European (Eur) and Hispanic (Hisp) SLE-control cohorts.

<p>Variants in bold are imputed using 1000 Genomes phase 1 (v3).</p

Fine scale maps of recombination rate inferred from East Asian, European, Hispanic and African-American control phased chromosomes.

<p>1568 randomly assigned chromosomes from each group were tested using <i>Rhomap</i>, from the LDHAT2.0 package. The fine-scale map of recombination rate (4Ner/kb) was inferred across 200 kb of chromosome 1q25 encompassing <i>TNFSF4</i> gene and extended 5′ and 3′ regions.</p

LD plots at <i>TNFSF4</i> locus in four populations.

<p>This section of chromosome 1q25.1 encompasses the <i>TNFSF4</i> gene and upstream region as defined by custom algorithm in Haploview 4.2. The measure of LD was used to depict 57 SNPs common to all cohorts, post QC and 1000 genomes imputation. The pair-wise correlations between <i>TNFSF4</i> markers is illustrated in these plots by the correlation coefficient R²(where r² = 0 = no correlation, white; 02<1, gradations of grey; R² = 1 = complete correlation, black). The <i>TNFSF4</i> gene is positioned above the plots relative to haplotype blocks (black triangles) and grey ticks indicate SNP locations to scale.</p

Haplotype Bifurcation Diagrams of <i>TNFSF4_risk</i> and <i>TNFSF4_non-</i>_<b>risk</b> for Four Populations.

<p>Plots are constructed using phased haplotypes for a. <i>East Asians</i>, b. <i>Europeans</i>, c. <i>Hispanics</i> and d. <i>African-Americans</i> and illustrate breakdown of LD with increasing distances from a core proximal <i>TNFSF4</i> SNP and are approximately to scale. The core is located at the <i>TNFSF4</i> gene-5′ boundary (black circle) and is selected as the most proximal 5′ marker, <i>rs1234314</i>, in each population. Gene location is depicted to scale; we have additionally labelled each plot to show the location of <i>rs1234317</i> and <i>rs2205960</i>, the best-associated markers from the meta-analysis.</p

Single marker association at <i>TNFSF4</i> locus in <i>A</i>. East Asian, <i>B</i>. European, <i>C</i>. Hispanic, <i>D</i>. African-American SLE-control populations.

<p>The strength of the association (-log10uncorrected<i>P</i>) of markers across 240 kb of chromosome 1q25. This regional plot depicts <i>TNFSF4</i> association with SLE versus chromosomal position (kb) in East Asians, Europeans, Hispanics and African-American populations. The most associated variants in each group are labelled, as is the best-associated meta-analysis SNP <i>rs2205960</i>. Markers are colour-coded for their correlation coefficient (r²) values according to the legend.</p

Best evidence meta-analysis of the association P value for <i>TNFSF4</i> SNPs.

<p>The first three columns list SNP characteristics, the next six columns list meta-analysis results including allele frequencies (FREQ1) and two-tailed P value for the nominal SNP association, conditioned on rs2205960, rs1234314 or conditioned on both rs1234314+rs2205960.</p

Confirmation of <i>TNFSF4</i> start site and splice variants.

<p>5′ RACE analysis was used to map the <i>TNFSF4</i> transcription start site. Three out of four putative splice variants modelled by the Aceview tool in the UCSC genome browser were validated in a European individual. Splice variants a. and b. are protein coding, whilst variant c. is transcribed but not translated.</p

Population demographics and imputation reference data for SLE-control cohorts post QC filtering.

<p>Numbers after filtering for duplicates, FDRs, HWE, missingness and major ancestry. post SNPs with INFO scores <0.7 excluded, SNPS with HWE<0.01 excluded.</p