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Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis

Fadista, João LU ; Skotte, Line; Geller, Frank; Bybjerg-Grauholm, Jonas; Gørtz, Sanne; Romitti, Paul A.; Caggana, Michele; Kay, Denise M.; Matsson, Hans and Boyd, Heather A., et al. (2019) In Human Molecular Genetics 28(2). p.332-340
Abstract

Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a... (More)

Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.

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published
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Human Molecular Genetics
volume
28
issue
2
pages
9 pages
publisher
Oxford University Press
external identifiers
  • scopus:85059503621
ISSN
0964-6906
DOI
10.1093/hmg/ddy347
language
English
LU publication?
yes
id
a8c2f552-b4e1-4ee3-8cd9-d7f9e4190496
date added to LUP
2019-01-17 14:50:43
date last changed
2019-01-18 03:00:04
@article{a8c2f552-b4e1-4ee3-8cd9-d7f9e4190496,
  abstract     = {<p>Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P &lt; 5 × 10-8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10-15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10-9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.</p>},
  author       = {Fadista, João and Skotte, Line and Geller, Frank and Bybjerg-Grauholm, Jonas and Gørtz, Sanne and Romitti, Paul A. and Caggana, Michele and Kay, Denise M. and Matsson, Hans and Boyd, Heather A. and Hougaard, David M. and Nordenskjöld, Agneta and Mills, James L. and Melbye, Mads and Feenstra, Bjarke},
  issn         = {0964-6906},
  language     = {eng},
  number       = {2},
  pages        = {332--340},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis},
  url          = {http://dx.doi.org/10.1093/hmg/ddy347},
  volume       = {28},
  year         = {2019},
}