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

João Fadista; Line Skotte; Frank Geller; Jonas Bybjerg-Grauholm; Sanne Gørtz; Paul A Romitti; Michele Caggana; Denise M Kay; Hans Matsson; Heather A Boyd; David M Hougaard; Agneta Nordenskjöld; James L Mills; Mads Melbye; Bjarke Feenstra

doi:10.1093/hmg/ddy347

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

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

João Fadista, Line Skotte, Frank Geller, Jonas Bybjerg-Grauholm, Sanne Gørtz, Paul A Romitti, Michele Caggana, Denise M Kay, Hans Matsson, Heather A Boyd, …

Human molecular genetics, Vol.28(2), pp.332-340

01/15/2019

DOI: 10.1093/hmg/ddy347

PMCID: PMC6322072

PMID: 30281099

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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.

Genetic Predisposition to Disease

Genome-Wide Association Study

Microtubule-Associated Proteins - genetics

Pyloric Stenosis, Hypertrophic - genetics

Humans

Infant

Transcription Factors - genetics

Case-Control Studies

Homeodomain Proteins - genetics

Serine Endopeptidases - genetics

Cell Cycle Proteins - genetics

Polymorphism, Single Nucleotide

Neoplasm Proteins - genetics

Infant, Newborn

Cohort Studies

Details

Title: Subtitle: Genome-wide meta-analysis identifies BARX1 and EML4-MTA3 as new loci associated with infantile hypertrophic pyloric stenosis
Creators: João Fadista - Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden
Line Skotte - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
Frank Geller - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
Jonas Bybjerg-Grauholm - Department of Congenital Disorders, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark
Sanne Gørtz - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
Paul A Romitti - Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA
Michele Caggana - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA
Denise M Kay - Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY, USA
Hans Matsson - Department of Women's and Children's Health, and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Heather A Boyd - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
David M Hougaard - Department of Congenital Disorders, Danish Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark
Agneta Nordenskjöld - Department of Pediatric Surgery, Astrid Lindgren Children´s Hospital, Karolinska University Hospital, Stockholm, Sweden
James L Mills - Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Mads Melbye - Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
Bjarke Feenstra - Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.28(2), pp.332-340
Publisher: England
DOI: 10.1093/hmg/ddy347
PMID: 30281099
PMCID: PMC6322072
ISSN: 1460-2083
eISSN: 1460-2083
Grant note: P30 ES005605 / NIEHS NIH HHS HHSN275201100001I / NICHD NIH HHS HHSN275201100001C / NICHD NIH HHS HHSN275201100001G / NICHD NIH HHS U01 DD001035 / NCBDD CDC HHS U01 DD001223 / NCBDD CDC HHS
Language: English
Date published: 01/15/2019
Academic Unit: Epidemiology; Biostatistics
Record Identifier: 9983995051702771

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