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Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis


Infantile hypertrophic pyloric stenosis (IHPS) is a severe condition characterized by hypertrophy of the pyloric sphincter muscle. We conducted a genome-wide association study (GWAS) on 1,001 surgery-confirmed cases and 2,401 controls from Denmark. The six most strongly associated loci were tested in a replication set of 796 cases and 876 controls. Three SNPs reached genome-wide significance. One of these SNPs, rs11712066 (odds ratio (OR) = 1.61; P = 1.5 × 10−17) at 3p25.1, is located 150 kb upstream of MBNL1, which encodes a factor that regulates splicing transitions occurring shortly after birth. The second SNP, rs573872 (OR = 1.41; P = 4.3 × 10−12), maps to an intergenic region at 3p25.2 approximately 1.3 Mb downstream of MBNL1. The third SNP, rs29784 (OR = 1.42; P = 1.5 × 10−15) at 5q35.2, is 64 kb downstream of NKX2-5, which is involved in development of cardiac muscle tissue and embryonic gut development.

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Figure 1: Manhattan plot of the IHPS GWAS.
Figure 2: Regional association plots for three confirmed newly identified IHPS loci.


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This study was supported in part by grants from the Lundbeck Foundation (R34-A3931), the Novo Nordisk Foundation and the Danish Medical Research Council (271-06-0628). The GWAS data for the control samples were generated for our study of preterm birth within the Gene, Environment Association Studies (GENEVA) consortium, with funding provided through the US National Institutes of Health (NIH) Genes, Environment and Health Initiative (GEI; U01HG004423). Assistance with genotype cleaning and general study coordination for the preterm birth project were provided by the GENEVA Coordinating Center (U01HG004446). Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438).

Author information




B.F., F.G. and M.M. wrote the first draft of the manuscript. B.F. and F.G. analyzed the data. M.V.H. and D.M.H. performed the experiments. C.K., S.G., J.C.M. and H.A.B. contributed by collecting phenotype data, providing genotype data and/or giving advice on the interpretation of results. B.F., F.G. and M.M. planned and supervised the work. All authors contributed to writing the final manuscript.

Corresponding authors

Correspondence to Bjarke Feenstra or Mads Melbye.

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Competing interests

Statens Serum Institut has filed a priority patent application at the Danish Patent and Trademark Office on the use of genetic profiling to identify newborns at risk of IHPS that contains subject matter drawn from the work published here. B.F., F.G. and M.M. are listed on the patent application.

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Supplementary Note, Supplementary Tables 1–7 and Supplementary Figures 1–4 (PDF 1960 kb)

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Feenstra, B., Geller, F., Krogh, C. et al. Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis. Nat Genet 44, 334–337 (2012).

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