Genome-wide meta-analysis identifiesBARX1andEML4-MTA3as new loci associated with infantile hypertrophic pyloric stenosis
Year: 2018
Type: review
Study design: Observational Study
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 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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddy347
Institutions: Statens Serum Institut, Lund University, University of Iowa, New York State Department of Health, Wadsworth Center, Karolinska Institutet, Karolinska University Hospital, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, University of Copenhagen, Stanford Medicine, Stanford University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: Oak Foundation, Sundhed og Sygdom, Det Frie Forskningsråd, Kommunfullmäktige, Stockholms Stad, Novo Nordisk, Vetenskapsrådet, Novo Nordisk Fonden, Centers for Disease Control and Prevention, Medical Research Council, National Institute of Environmental Health Sciences, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
OpenAlex ID: W2895096903