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

被引:14
|
作者
Fadista, Joao [1 ,2 ]
Skotte, Line [1 ]
Geller, Frank [1 ]
Bybjerg-Grauholm, Jonas [3 ]
Gortz, Sanne [1 ]
Romitti, Paul A. [4 ]
Caggana, Michele [5 ]
Kay, Denise M. [5 ]
Matsson, Hans [6 ,7 ]
Boyd, Heather A. [1 ]
Hougaard, David M. [3 ]
Nordenskjold, Agneta [6 ,7 ,8 ]
Mills, James L. [9 ]
Melbye, Mads [1 ,10 ,11 ]
Feenstra, Bjarke [1 ]
机构
[1] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark
[2] Lund Univ, Diabet Ctr, Dept Clin Sci, SE-21428 Malmo, Sweden
[3] Statens Serum Inst, Danish Ctr Neonatal Screening, Dept Congenital Disorders, DK-2300 Copenhagen, Denmark
[4] Univ Iowa, Dept Epidemiol, Coll Publ Hlth, Iowa City, IA USA
[5] New York State Dept Hlth, Wadsworth Ctr, Div Genet, Albany, NY USA
[6] Karolinska Inst, Dept Womens & Childrens Hlth, SE-17177 Stockholm, Sweden
[7] Karolinska Inst, Ctr Mol Med, SE-17177 Stockholm, Sweden
[8] Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Pediat Surg, SE-17177 Stockholm, Sweden
[9] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Intramural Populat Hlth Res, NIH, Bethesda, MD USA
[10] Univ Copenhagen, Dept Clin Med, Copenhagen, Denmark
[11] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA
基金
英国医学研究理事会; 瑞典研究理事会;
关键词
LD SCORE REGRESSION; SMOOTH-MUSCLE; HERITABILITY; STOMACH; RISK; MALFORMATIONS; HAPLOTYPE; VARIANTS; GENOTYPE; CHILDREN;
D O I
10.1093/hmg/ddy347
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of similar to 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 x 10(-8)), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 x 10(-15)], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 x 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.
引用
收藏
页码:332 / 340
页数:9
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