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Genome-wide association study identifies variants in HORMAD2 associated with tonsillectomy
  1. Bjarke Feenstra1,
  2. Peter Bager1,
  3. Xueping Liu1,
  4. Henrik Hjalgrim1,2,
  5. Ellen A Nohr3,
  6. David M Hougaard4,
  7. Frank Geller1,
  8. Mads Melbye1,5,6
  1. 1Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
  2. 2Department of Haematology, Rigshospitalet, Copenhagen, Denmark
  3. 3Research Unit of Gynaecology & Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
  4. 4Danish Centre for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark
  5. 5Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  6. 6Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
  1. Correspondence to Bjarke Feenstra, Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, Copenhagen S DK-2300, Denmark; fee{at}


Background Inflammation of the tonsils is a normal response to infection, but some individuals experience recurrent, severe tonsillitis and massive hypertrophy of the tonsils in which case surgical removal of the tonsils may be considered.

Objective To identify common genetic variants associated with tonsillectomy.

Methods We used tonsillectomy information from Danish health registers and carried out a genome-wide association study comprising 1464 patients and 12 019 controls of Northwestern European ancestry, with replication in an independent sample set of 1575 patients and 1367 controls.

Results The variant rs2412971, intronic in HORMAD2 at chromosome 22q12.2, was robustly associated with tonsillectomy (OR=1.22; p=1.48×10–9) and is highly correlated with SNPs previously found to be associated with IgA nephropathy, Crohn's disease (CD) and early onset inflammatory bowel disease (IBD). The risk allele for tonsillectomy corresponded to increased risk of IgA nephropathy and decreased risk of CD and IBD. We further performed lookup analyses of the top SNP for outcomes related to tonsillectomy in the combined discovery and replication sample and found that rs2412971 was associated with acute tonsillitis (OR=1.19; p=7.82×10–4), chronic disease of the tonsils (OR=1.19; p=2.32×10–6) and appendectomy (OR=1.18; p=1.13×10–3).

Conclusions We identified and replicated a genetic association at 22q12.2 with tonsillectomy. Further functional investigation is required to illuminate whether the molecular mechanisms underlying the genetic association involve general lymphoid hyper-reaction throughout the mucosa-associated lymphoid tissue system.

  • Tonsillectomy
  • Mucosa-associated lymphoid tissue
  • Genome-wide association study
  • IgA nephropathy
  • Inflammatory bowel disease

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  • Contributors BF, PB and MM conceived and designed the project. PB and BF planned and performed register data acquisition and phenotypic characterisation. XL, BF and FG carried out the statistical genetics and bioinformatics analyses. BF, PB, XL, HH, FG and MM discussed and interpreted results. EAN contributed samples. DMH performed sampling and genotyping. BF wrote the first draft of the manuscript. All authors contributed to the final manuscript.

  • Funding This research has been conducted using the Danish National Biobank resource. The Danish National Biobank is supported by the Novo Nordisk Foundation. The study was partly based on samples from the Danish National Birth Cohort, which was established with the support of a major grant from the Danish National Research Foundation with additional support from the Danish Pharmacists' Fund, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies. Grant support for the present study was obtained from the Novo Nordisk Foundation (12955). BF and PB are supported by Oak Foundation fellowships. XL is supported by the Nordic Center of Excellence in Health-Related e-Sciences.

  • Competing interests None declared.

  • Patient consent No.

  • Ethics approval The study was approved by the Scientific Ethics Committee for the Capital City Region (Copenhagen), the Danish Data Protection Agency and the Danish National Birth Cohort steering committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We will be committed to collaborating with other groups interested in using the data from our study. Statens Serum Institut is a governmental institution and a solution for a public repository for Danish GWAS data is currently worked on. When this solution is ready, the GWAS summary statistics from the study will be made directly available to interested researchers.