Genome-wide association study of conotruncal and related cardiac malformations.

摘要

Conotruncal and related cardiac malformations (CCMs) are among the most common, serious birth defects, yet the etiology of these conditions remains unknown for the majority of affected individuals. When designing etiological studies of these and other complex conditions, for which the maternal in utero environment is suspected to contribute to risk, it is critical to consider approaches that evaluate maternal genetic effects in addition to detecting inherited genetic effects. Genome wide association (GWA) studies represent a relatively new approach for identifying genetic variants that are associated with the risk of complex diseases, such as CCMs. Yet, few GWA studies have been used to examine both maternal and inherited genetic effects, perhaps partially because efficient computational platforms for such analyses are not currently publically available.;To conduct efficient GWA analyses to assess both maternal and inherited genetic effects in family-based GWA studies, a new computational platform was developed. This platform uses SAS and LEM software in combination to perform analyses using log-linear models to evaluate maternal and inherited effects in large, genome-wide datasets. The platform was evaluated using existing genome-wide association data, and was shown to perform accurately and relatively efficiently.;Using this new platform, a genome-wide association study was performed among 750 case-parent triads recruited at The Children's Hospital of Philadelphia from 1997-2007. Analyses of 2,421,290 total SNPs passing quality control were conducted to test for association with CCMs via inherited or maternal genetic effects using log-linear models under a log-additive risk model. Analyses were repeated among a subgroup of 537 non-Hispanic Caucasian triads and again in a subgroup of 362 non-Hispanic Caucasian triads in which cases had CCMs involving normally-related great vessels. Many SNPs had p-values suggestive of genome-wide significance for both inherited and maternal genetic effects. Further, several genes had multiple intronic SNPs with p -values suggestive of genome-wide significance. Thus, several potential candidates were identified for further genetic studies.