Genetic Association Studies

Disorders found to be associated with changes in the sequence of a single gene have been associated with an increased risk of preterm birth, often as a result of a predisposition to polyhydramnios in pregnancies with fetuses with changes in the sequence of that single gene. Among these conditions are myotonic dystrophy, Ehlers-Danlos syndrome, Smith-Lemli-Opitz syndrome, and neurofibromatosis. However, like many other complex human diseases, such as obesity, hypertension, diabetes, and asthma, preterm birth is a complex trait and possesses the following features: non-Mendelian transmission, the involvement of multiple genes, and gene-gene and gene-environment interactions. Research on the genetics of preterm birth thus faces significant challenges. The approaches available for the identification of genes that may be associated with a particular trait include positional cloning, the identification of positional candidate genes, whole-genome association analysis, and functional candidate gene analysis. Positional cloning requires extended pedigrees or sibling pairs. It has been successful for the analysis of disease transmitted by Mendelian genetics but has not been so successful for the study of more complex diseases and conditions. The identification of positional candidate genes requires linkage information, which is not possible for the genetic analysis of preterm birth. Scanning of the whole genome requires the identification of more than 100,000 single-nucleotide polymorphism (SNPs), which are single-base-pair substitutions in the DNA sequence; but this procedure is costly. The functional candidate gene approach, that is, the study of carefully selected candidate genes associated with major pathogenic pathways of preterm birth, is feasible and is commonly used. Relevant genetic association studies are summarized below.

One characteristic of the human genome with medical and social relevance is that each person's genome, except those of monozygotic twins, is unique. A persons' genotype represents the blending of parental genotypes. In addition, the human genome undergoes natural mutation. On average, the DNA sequences of two unrelated humans vary by millions of bases. Nearly all human genes are capable of causing disease if they are altered substantially. Mutations known to cause disease have been identified in about 1,000 genes. About 90 percent of all DNA sequence variations occur as SNPs (Brookes, 1999). The human genome contains about 10 million SNPs. A haplotype, on the other hand, represents a considerably longer sequence of nucleotides (an average of 25,000 nucleotides, which are the building blocks of DNA and genes), as well as any variants, that tend to be inherited together. Analysis of both SNPs and haplotypes is thus necessary to identify the genetic factors associated with complex diseases and syndromes, including preterm birth.

Two organizations have focused on the analysis of SNPs to identify the genes that may be associated with particular diseases and syndromes. The SNP Consortium Ltd. is a nonprofit foundation whose mission was to identify up to 300,000 SNPs distributed evenly throughout the human genome and to make the information related to those SNPs available to the public without intellectual property restrictions. Eventually, however, the SNP Consortium Ltd. discovered many more SNPs (1.5 million in total) than it had originally planned (SNP Consortium Ltd., 2005). The National Institute of Environmental Health Sciences initiated the Environmental Genome Project (EGP) in 1998 to identify polymorphisms in the genes involved in environment-induced diseases (Olden and Wilson, 2000). In addition to the identification of polymorphisms,

EGP aims to characterize the functions of these polymorphisms and supports epidemiological studies of gene-environment interactions.

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