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X-chromosome variants are associated with aldosterone producing adenomas

  • Dutta, Ravi Kumar1, 1
  • Larsson, Malin1
  • Arnesen, Thomas2, 3, 3
  • Heie, Anette2, 3
  • Walz, Martin4
  • Alesina, Piero4
  • Gimm, Oliver1
  • Söderkvist, Peter1
  • 1 Linköping University, Linköping, 58183, Sweden , Linköping (Sweden)
  • 2 Haukeland University Hospital, Bergen, Norway , Bergen (Norway)
  • 3 University of Bergen, Bergen, Norway , Bergen (Norway)
  • 4 Klinikum Essen-Mitte, Essen, Germany , Essen (Germany)
Published Article
Scientific Reports
Springer Nature
Publication Date
May 18, 2021
DOI: 10.1038/s41598-021-89986-8
Springer Nature


Aldosterone-producing adenomas (APAs) are a major cause of primary aldosteronism (PA) and are characterized by constitutively producing aldosterone, which leads to hypertension. Several mutations have been identified in ion channels or ion channel-associated genes that result in APAs. To date, no studies have used a genome-wide association study (GWAS) approach to search for predisposing loci for APAs. Thus, we investigated Scandinavian APA cases (n = 35) and Swedish controls (n = 60) in a GWAS and discovered a susceptibility locus on chromosome Xq13.3 (rs2224095, OR = 7.9, 95% CI = 2.8–22.4, P = 1 × 10–7) in a 4-Mb region that was significantly associated with APA. Direct genotyping of sentinel SNP rs2224095 in a replication cohort of APAs (n = 83) and a control group (n = 740) revealed persistently strong significance (OR = 6.1, 95% CI = 3.5–10.6, p < 0.0005). We sequenced an adjacent gene, MAGEE1, of the sentinel SNP and identified a rare variant in one APA, p.Gly327Glu, which is complementary to other mutations in our primary cohort. Expression quantitative trait loci (eQTL) were investigated on the X-chromosome, and 24 trans-eQTL were identified. Some of the genes identified by trans-eQTL point towards a novel mechanistic explanation for the association of the SNPs with APAs. In conclusion, our study provides further insights into the genetic basis of APAs.

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