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Abstract
Background Strong evidence supports Epstein-Barr virus (EBV) being an original cause for most cases of both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). The Million Veteran Program (MVP) data reduces artifacts from technical processing and Veteran life experience providing a basis for disease comparisons. We compared SLE to MS to find define the similar and different genetic variants that alter risk for these disorders.
Methods Cases had the relevant concept code twice. Cutaneous and systemic lupus (C/SLE) cases were combined. After removing 44 concept codes (inflammatory conditions, labs), controls were tested against: I. MS, II. S/CLE, conditioned on age and sex. Additional case and control GWAS analyses: III. C/SLE versus MS (C/SLEvsMS), IV. C/SLE or MS versus controls (C/SLEorMS); and V. Men versus women from C/SLEvsMS. The 106 and 11 known SLE loci in non-Hispanic whites and blacks (European (EA) and admixed African (AA) ancestries), respectively, were evaluated in S/CLE, MS, C/SLEvsMS, and C/SLE&MS.
Results Only European ancestry provided pertinent results at -log_p>7.3 (figure 1). S/CLE had 1,396 and MS had 2,815 cases (20 shared) with 352,354 controls. The S/CLE and MS GWASs confirm known MS loci at HLA-DRB5 and for S/CLE at NCF2, STAT4, C4B, IKZF1, IRF5, ITGAM. We find three kinds of results: 1. Disease specific (separate genetic mechanisms): NCF2, HLA-DRB5, C4B, IRF5, ITGAM; 2. Neutral (a similar contribution from both disorders): STAT4, TNFAIP3; and 3.
Accentuated (opposing risk alleles in S/CLE and MS): R3HDM1 (-log_p=9.1), overlapping an established SLE locus (-log_p>7.3).
Conclusions This novel approach has the potential to identify the similarities and differences in genetic mechanisms between phenotypes. Power to establish MS associations at -log_p>7.3 outside of HLA is inadequate in the available MVP data release. Some S/CLE loci appear to be disease specific and may not be involved in MS pathogenesis. Opposing alleles increase risk of S/CLE and MS at R3HDM1, perhaps involving lactase expression and the microbiome in pathogenesis. These data are consistent with R3HDM1, STAT4 and TNFAIP3 being involved in genetic mechanisms responsible for both S/CLE and MS.
Comparative GWAS Analysis Between Lupus (SLE or CLE) and Multiple Sclerosis (MS), non-Hispanic White (European Ancestry (EU)) in the Million Veteran Program (MVP). lA. Lupus cases (n=1396) on left, MS cases (n=2815) on right, with both GWAS conducted with matching controls (n=352,354) excluding 44 concepts for autoimmune or immune mediated conditions, as well as positive relevant lab results. 1B. On the left, GWAS of Lupus as cases using MS as controls. On right, GWAS of those with either Lupus or MS combined (n=4191), compared to controls excluding the 44 concepts used in lA.
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