A Case-Case Genome-Wide Association Study of Trisomy 21

The Centers for Disease Control and Prevention (CDC) estimates that about 6,000 babies are born with Down syndrome (DS) each year in the United States—that is one out of every 691 babies, making it the most common birth defect in humans. It is a genetic disorder that results from being born with an extra chromosome 21 (trisomy 21). In addition to mental retardation and abnormal physical development, DS individuals can also suffer from physiological abnormalities such as heart defects and leukemia. They experience Alzheimer-like symptoms, accelerated aging, and their average age at death is at 49 years old. The majority of trisomy 21 cases occurred due to maternal meiotic nondisjunction (NDJ). There are two types of NDJ: M1 NDJ and M2 NDJ, nondisjunction in the meiosis I and meiosis II stages respectively. The two types differ in their etiology: maternal age, recombination pattern, and environmental factors. This thesis is a pilot study using genome-wide association analysis to locate genes that may be responsible for the meiotic error. This study has public health significance because it identifies potential genes associated with DS susceptibility. It will help enable us to tease apart the susceptibility of NDJ into its individual liability factors. Genotype data from 134 Caucasian mothers of maternal NDJ cases were examined using the Cochran-Armitage test for trend. Two genes were identified to potentially be associated with the difference in NDJ error: SNX13 and PRPS1L1. The data were also used to test known genes responsible for altered recombination and Alzheimer’s disease and we found suggestive associations between NDJ and RNF212, a gene thought to be associated with meiotic recombination rate, and between NDJ and PSEN1, an Alzheimer’s disease-related gene