Abstract
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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References
Ranells, J.D., Carver, J.D. & Kirby, R.S. Infantile hypertrophic pyloric stenosis: epidemiology, genetics, and clinical update. Adv. Pediatr. 58, 195–206 (2011).
Mitchell, L.E. & Risch, N. The genetics of infantile hypertrophic pyloric stenosis. A reanalysis. Am. J. Dis. Child. 147, 1203–1211 (1993).
Krogh, C. et al. Familial aggregation and heritability of pyloric stenosis. J. Am. Med. Assoc. 303, 2393–2399 (2010).
Chung, E. Infantile hypertrophic pyloric stenosis: genes and environment. Arch. Dis. Child. 93, 1003–1004 (2008).
Schechter, R., Torfs, C.P. & Bateson, T.F. The epidemiology of infantile hypertrophic pyloric stenosis. Paediatr. Perinat. Epidemiol. 11, 407–427 (1997).
MacMahon, B. The continuing enigma of pyloric stenosis of infancy: a review. Epidemiology 17, 195–201 (2006).
Honein, M.A. et al. Infantile hypertrophic pyloric stenosis after pertussis prophylaxis with erythromcyin: a case review and cohort study. Lancet 354, 2101–2105 (1999).
Pisacane, A. et al. Breast feeding and hypertrophic pyloric stenosis: population based case-control study. Br. Med. J. 312, 745–746 (1996).
Chakraborty, R. The inheritance of pyloric stenosis explained by a multifactorial threshold model with sex dimorphism for liability. Genet. Epidemiol. 3, 1–15 (1986).
Panteli, C. New insights into the pathogenesis of infantile pyloric stenosis. Pediatr. Surg. Int. 25, 1043–1052 (2009).
Falconer, D.S. The inheritance of liability to certain diseases, estimated from the incidence among relatives. Ann. Hum. Genet. 29, 51–76 (1965).
1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
Myers, R.M. et al. A user's guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol. 9, e1001046 (2011).
Visel, A., Rubin, E.M. & Pennacchio, L.A. Genomic views of distant-acting enhancers. Nature 461, 199–205 (2009).
Pfeufer, A. et al. Genome-wide association study of PR interval. Nat. Genet. 42, 153–159 (2010).
Ho, T.H. et al. Muscleblind proteins regulate alternative splicing. EMBO J. 23, 3103–3112 (2004).
Pan, Q., Shai, O., Lee, L.J., Frey, B.J. & Blencowe, B.J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40, 1413–1415 (2008).
Bland, C.S. et al. Global regulation of alternative splicing during myogenic differentiation. Nucleic Acids Res. 38, 7651–7664 (2010).
Kalsotra, A. et al. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart. Proc. Natl. Acad. Sci. USA 105, 20333–20338 (2008).
Lin, X. et al. Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Hum. Mol. Genet. 15, 2087–2097 (2006).
Fu, Y., Yan, W., Mohun, T.J. & Evans, S.M. Vertebrate tinman homologues XNkx2-3 and XNkx2-5 are required for heart formation in a functionally redundant manner. Development 125, 4439–4449 (1998).
Reamon-Buettner, S.M. & Borlak, J. NKX2–5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD). Hum. Mutat. 31, 1185–1194 (2010).
Kasahara, H., Bartunkova, S., Schinke, M., Tanaka, M. & Izumo, S. Cardiac and extracardiac expression of Csx/Nkx2.5 homeodomain protein. Circ. Res. 82, 936–946 (1998).
Smith, D.M. & Tabin, C.J. BMP signalling specifies the pyloric sphincter. Nature 402, 748–749 (1999).
Smith, D.M., Nielsen, C., Tabin, C.J. & Roberts, D.J. Roles of BMP signaling and Nkx2.5 in patterning at the chick midgut-foregut boundary. Development 127, 3671–3681 (2000).
Self, M., Geng, X. & Oliver, G. Six2 activity is required for the formation of the mammalian pyloric sphincter. Dev. Biol. 334, 409–417 (2009).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).
Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).
So, H.C., Gui, A.H., Cherny, S.S. & Sham, P.C. Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet. Epidemiol. 35, 310–317 (2011).
Li, Y., Willer, C.J., Ding, J., Scheet, P. & Abecasis, G.R. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).
Acknowledgements
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).
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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.
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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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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). https://doi.org/10.1038/ng.1067
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DOI: https://doi.org/10.1038/ng.1067
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