Decreased expression of CLECL1 was significantly associated with increased MS risk (Wald ratio = −0.16, P = 1.58 × 10−9) and showed clear co-localization (PP4 > 0.87). The ieQTL analysis indicated that rs7306304-A increased expression of CLECL1 with increased proportions of microglia (interaction β = −2.72, interaction P = 5.09 × 10−37; Fig. 5d), confirming a previous finding of a microglia cell type-specific cis-eQTL for CLECL1 at this MS risk locus29. This eQTL also replicates in the microglia single-cell analysis by Bryois et al.24 (eQTL β = −0.62, P = 3.2 × 10−20) with the same direction of effect. The rs7306304 SNP is in strong LD with the MS lead SNP rs7977720 (r2 = 0.84)29. CLECL1 encodes a C-type lectin-like transmembrane protein expressed at high levels in dendritic and B cells, which has been proposed to modulate immune response39. It has 20-fold higher expression in a purified microglia dataset29 than in cortical tissue, suggesting that decreased CLECL1 increases MS susceptibility through microglia-mediated immune processes in the brain.
