期刊
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
卷 188, 期 8, 页码 2303-2314出版社
WILEY
DOI: 10.1002/ajmg.a.62759
关键词
congenital heart defects; CAPN11; GWAS; National Birth Defects Prevention Study; obstructive heart defects; SLC44A2
资金
- National Center on Birth Defects and Developmental Disabilities [5U01DD000491-05, DD09-001, DD13-003, DD18-001, 02081, 96043]
- National Institute of Child Health and Human Development [5R01HD039054-12]
- National Institutes of Health [R25 CA112355]
- Centers for Disease Control and Prevention
This study found potential associations between obstructive heart defects and specific genes, with preliminary validation in different populations.
Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for similar to 25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (N-discovery = 3978; N-replication = 2507), investigating the genetic architecture of OHDs using transmission/disequilibrium tests (TDT) in complete case-parental trios (N-discovery_TDT = 440; N-replication_TDT = 275) and case-control analyses separately in infants (N-discovery_CCI = 1635; N-replication_CCI = 990) and mothers (case status defined by infant; Ndiscovery_CCm = 1703; N-replication_CCM = 1078). In the TDT analysis, the SLC44A2 single nucleotide polymorphism (SNP) rs2360743 was significantly associated with OHD (P-discovery = 4.08 x n 10(-9); p(replication) = 2.44 x 10(-4)). A CAPN11 SNP (rs55877192) was suggestively associated with OHD (P-discovery = 1.61 x 10(-7); P-replication= 0.0016). Two other SNPs were suggestively associated (p < 1 x 10(-6)) with OHD in only the discovery sample. In the case-control analyses, no SNPs were genome-wide significant, and, even with relaxed thresholds (x(discovery) < 1 x 10(-5) and n i-replication < 0.05), only one SNP (rs188255766) in the infant analysis was associated with OHDs (P-discovery= 1.42 x 10(-6); p(replication) = 0.04). Additional SNPs with P-discovery< 1 x 10(-5) were in loci supporting previous findings but did not replicate. Overall, there was modest evidence of an association between rs2360743 and rs55877192 and OHD and some evidence validating previously published findings.
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