Project Summary/Abstract
Congenital heart defects (CHDs) are the leading causes of infant morbidity and mortality attributable to
birth defects, affecting about 1% of all live births. The majority of CHDs are thought to be caused by a complex
interplay among maternal genes, fetal genes and maternal environmental exposures. However, the disease
etiology is largely unknown, and few strategies are available to reduce the burden of disease. To understand the
genetic susceptibility of CHDs, most studies have evaluated individual genetic variants or maternal
environmental factors one at a time. Less attention has been given to the identification of complex interactions
among them. In this proposed project, we will focus on the identification of gene-by-gene (GXG) or gene-by-
environment (GXE) interactions that may jointly influence CHD risk. The findings will shed light on various types
of interactions during embryogenesis: 1) GXG interactions between maternal and fetal genes; 2) GXG
interactions within maternal or fetal genes; and 3) complex interactions among maternal genes, fetal genes and
maternal environmental exposures. The discovery process of GXG and GXE interactions is enhanced by the
development of innovative biostatistical approaches and their application to samples from the National Birth
Defect Prevention Study (NBDPS). In the proposed projects, we will use datasets from an ongoing genome-wide
association study (GWAS) of CHDs, including ~1,000 case mother-father-infant triads and ~1,000 control
mother-infant dyads (5,000 subjects in total) who are participants of NBDPS. Each sample is genotyped for
approximately 5 million single nucleotide polymorphisms (SNPs) throughout the genome. The proposed project
will be initiated by an early stage new investigator, who have developed novel biostatistical approaches for the
GXG or GXE discovery process, and has applied these approaches to identify and replicate statistically
significant GXG interactions predisposing to various complex human diseases, such as nicotine dependence,
cannabis dependence, type II diabetes, small for gestational age and congenital heart defects. The proposed
project is further enhanced by assembling a research team of senior scientists with complementary and
extensive expertise in the field. The findings ultimately will provide insights into the underlying pathophysiological
and etiological processes that result in CHDs, and more importantly, can provide a foundation for more precise
preconceptional counseling and interventions.