Genome-Wide Association Study of Maternal and Inherited Loci for Conotruncal Heart Defects

Abstract

Conotruncal and related heart defects (CTDs) are a group of serious and relatively common birth defects. Although both maternal and inherited genotypes are thought to play a role in the etiology of CTDs, few specific genetic risk factors have been identified. To determine whether common variants acting through the genotype of the mother (e.g. via an in utero effect) or the case are associated with CTDs, we conducted a genome-wide association study of 750 CTD case-parent triads, with follow-up analyses in 358 independent triads. Log-linear analyses were used to assess the association of CTDs with the genotypes of both the mother and case. No association achieved genomewide significance in either the discovery or combined (discovery+follow-up) samples. However, three loci with p-values suggestive of association (p<10−5) in the discovery sample had p-values <0.05 in the follow-up sample and p-values in the combined data that were lower than in the discovery sample. These included suggestive association with an inherited intergenic variant at 20p12.3 (rs6140038, combined p = 1.0×10−5) and an inherited intronic variant in KCNJ4 at 22q13.1 (rs2267386, combined p = 9.8×10−6), as well as with a maternal variant in SLC22A24 at 11q12.3 (rs11231379, combined p = 4.2×10−6). These observations suggest novel candidate loci for CTDs, including loci that appear to be associated with the risk of CTDs via the maternal genotype, but further studies are needed to confirm these associations.

Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects

“…15 Individuals of all races/ethnicities were eligible to participate. All subjects provided informed consent under a protocol approved by the CHOP Institutional Review Board for the Protection of Human Subjects.…”

“…15, 17 For the analyses presented here, data for all cohorts were imputed (or re-imputed) using data from the 1,000 Genomes Project reference data. 27 Given differences in the timing of the availability of data from CHOP and PCGC, data from these two sources were imputed separately.…”

“…For example, genome-wide significant and/or suggestive associations have been reported for conotruncal defects (CTDs), 15 tetralogy of Fallot, 16 left ventricular obstructive tract defects (LVOTDs) 17 and septal defects. 18–20 Most of the reported associations have yet to be independently replicated.…”

TBX1 loss‑of‑function mutation contributes to congenital conotruncal defects

“…It occurs in ~1% of live births and accounts for ~30% of birth defect-related mortalities (1). Conotruncal heart defect (CTD), a subset of serious and relatively common CHD, is defined as a defect of the cardiac outflow tracts or great arteries and includes tetralogy of Fallot (TOF), transposition of the great arteries (TGA), persistent truncus ateriosus, interrupted aortic arch (IAA), double outlet right ventricle (DORV), ventricular septal defect (VSD) and pulmonary atresia (PA) (2). It is estimated that CTD occurs in 1 out of every 1,000 live births, accounting for ~1/3 of all CHD cases.…”

“…If surgery to repair CTD is not performed, patients experience a reduced quality of life, decreased performance during exercise and delayed brain development. CTD may also induce pulmonary hypertension, cardiac enlargement, ventricular dysfunction, heart failure, cardiac arrhythmia and even sudden mortality (2)(3)(4). Advances in therapeutic strategies to treat patients with CTD have resulted in more neonates with CTD surviving into adulthood; however, morbidity and mortality rates remain high in such survivors (5)(6)(7)(8).…”