rs117614539 (MAPKAPK5): IBD and Brain eQTL Variant

Key takeaways

• rs117614539 sits in a genomic region containing MAPKAPK5 (mitogen-activated protein kinase-activated protein kinase 5, a stress-response signaling enzyme) and ADAM1B (ADAM metallopeptidase domain 1B)
• The alternate allele reduces expression of NAA25 (N-alpha-acetyltransferase 25, a protein-modification enzyme) in two brain regions - the nucleus accumbens and the cortex - based on GTEx v11 eQTL data from 953 donors
• Tobacco smoke has been found to modify genetic variant associations with inflammatory bowel disease (IBD) risk, with effects running in opposite directions for Crohn's disease versus ulcerative colitis for some variants
• This locus was examined in large-scale UK Biobank studies of blood and urine biomarkers involving more than 360,000 participants
• Current evidence for specific trait associations at this locus is preliminary, and no direct replication of rs117614539-specific associations is confirmed in the available study text

What the research says A systematic genetic analysis of 35 blood and urine biomarkers in 363,228 UK Biobank individuals identified 1,857 associated loci containing 3,374 fine-mapped associations, providing a large-scale map of variants with effects on laboratory measurements. A meta-analysis drawing on 55 immunochip datasets from 19,735 IBD patients found 64 variants whose association with IBD was modified by tobacco smoking behavior (interaction p < 5.0 x 10-5), with approximately 45% located near previously established IBD loci and genes regulating mucosal barrier function and immune tolerance, and with smoking showing opposite-direction effects on Crohn's disease versus ulcerative colitis for some of those variants. A newer Bayesian GWAS method applied to 405,088 UK Biobank samples identified 4.97% more quantitative trait associations and 3.25% more binary disease associations than a leading existing method, with replicated gains in independent cohorts Biobank Japan and FinnGen.

Reported associations

• Blood and urine biomarkers: This locus was analyzed in a comprehensive UK Biobank GWAS of 35 laboratory measurements (n=363,228 across five population groups) that identified 1,857 loci at Bonferroni-corrected significance (p < 5 x 10-9 for imputed and directly genotyped variants); specific effect sizes for this variant were not detailed in the available study text
• Inflammatory bowel disease, gene-smoking interaction: A meta-analysis of 55 immunochip datasets from 19,735 IBD patients (10,856 Crohn's disease and 8,879 ulcerative colitis) found 64 SNPs whose IBD associations were modified by smoking behavior; approximately 45% were located within 1 Mb of previously established IBD loci, near genes involved in mucosal barrier function and immune tolerance; smoking modified risk in opposite directions for Crohn's disease versus ulcerative colitis for some of these variants
• NAA25 brain expression (eQTL): GTEx v11 data from 953 donors shows the alternate allele is associated with reduced expression of NAA25 in the nucleus accumbens basal ganglia (p=1.1 x 10-4) and cortex (p=7.6 x 10-6), both meeting FDR < 0.05 GTEx Portal

Evidence quality The biomarker GWAS used 363,228 UK Biobank individuals across five population groups with LD score regression intercepts between 0.999 and 1.137, confirming well-controlled population structure, and applied strict Bonferroni multiple-testing correction (p < 5 x 10-9). The IBD gene-smoking study drew on 55 immunochip datasets with 19,735 cases, applied a Wald test interaction threshold (p < 5.0 x 10-5) alongside Cochrane Q heterogeneity testing to confirm consistent effect directions across datasets, and validated key gene-smoking interactions in mouse models of Il10 and Nod2 deficiency. The Quickdraws GWAS covered 405,088 UK Biobank samples with replication in Biobank Japan and FinnGen. The GTEx eQTL associations for NAA25 meet FDR < 0.05 across two brain regions (953 donors). No direct replication of rs117614539-specific associations is confirmed in the available study text, and the evidence should be considered preliminary.

Tissue-specific expression effects

• NAA25: Reduced expression in brain nucleus accumbens basal ganglia and brain cortex in carriers of the alternate allele, based on GTEx v11 cis-eQTL analysis (FDR < 0.05, 953 donors) GTEx Portal

Lifestyle considerations

• Tobacco smoking (lifestyle, mixed, low): Studies of gene-environment interactions in IBD found that tobacco smoke modifies associations between genetic variants and disease risk, with effects running in opposite directions for Crohn's disease versus ulcerative colitis.