We have mapped a locus on chromosome 7p22.3-7p15.3 spanning a 22.4 Mb region for ulcerative colitis (UC) by whole genome linkage analyses of a large Danish family. The family represent three generations with UC segregating as an autosomal dominant trait with variable expressivity. The whole-genome scan resulted in a logarithm of odds score (LOD score) of Z = 3.31, and a whole genome sequencing (WGS) of two affected excluded disease-causing mutations in the protein coding genes. Two rare heterozygote variants, rs182281985:G>A and rs541426369:G>A, both with low allele frequencies (MAF A:0.0001, gnomAD ver3.1.2), were found in clusters of ChiP-seq transcription factors binding sites close to the AHR (aryl hydrocarbon receptor) gene and the UC associated SNP rs1077773:G>A. Testing the two SNPs in a promoter reporter assay for regulatory activity revealed that rs182281985:G>A influenced the AHR promoter. These results suggest a regulatory region that include rs182281985:G>A close to the UC GWAS SNP rs1077773:G>A and further demonstrate evidence that the AHR gene on the 7p-tel region is a candidate susceptible gene for UC.
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The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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We thank all family members for their participation in this study and Annemette Friis Mikkelsen and Marianne Lauridsen is thanked for excellent technical assistance and Rigshospitalets Microarray Center for the genotyping. HE was supported by the Danish Medical Research Council (22-02-0208), CBB by the Innovation Fund Denmark (0603-00320B), JTT and JBO received funding from Region Zealand and Roskilde University.
The authors declare no competing interests.
The study protocols adhered to the tenets of the Declaration of Helsinki and the ARVO statement on human subjects and approved by the Danish National Committee on Health Research Ethics in 2019 (H-19019167).
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Eiberg, H., Olsson, J.B., Bak, M. et al. A family with ulcerative colitis maps to 7p21.1 and comprises a region with regulatory activity for the aryl hydrocarbon receptor gene. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01298-9