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Abstract
In order to better identify and understand the genetic architecture of complex traits, modern genomic methods are more focused on using the ample amount of data that has been collected over the last decade and examining the genome in different ways. However, prioritizing functional variants in this framework remains challenging. Strategies including faster and easier to use annotation and filtering methods are increasingly important for genomic analyses today. Selecting cohorts from genetically-sensitized populations or constructing a cohort from those with the extreme phenotypes of a complex trait are other strategies to maximize the ability to detect susceptibility variants. In this dissertation, I employ these strategies to study primary ovarian insufficiency (POI) in a cohort of women with a fragile X premutation (PM) and to study atrioventricular septal defects (AVSD) in a cohort of individuals with Down syndrome (DS). Both of these groups have these co-occurring traits at a much higher frequency than the general population - women with a PM are at a 20-fold increased risk for POI and individuals with DS are at a >2000 increased risk for AVSD.
POI, which affects 1% of women in the general population, is a condition characterized by symptoms of early menopause and is a leading cause of infertility. About 20% of women who carry a PM, a CGG repeat expansion in the range of 55-200 repeats in the 5’UTR of the X-linked FMR1 gene, are diagnosed with fragile X-associated POI (FXPOI). We hypothesize that there are genetic modifiers that contribute to the age of onset and severity of FXPOI. In order to test this, we conducted a case/control study among women with a PM taken from the extremes of the distribution of age at onset of FXPOI/menopause (onset before age 35 and after age 50). We compared whole genome sequencing (WGS) data in an untargeted way and examining candidate genes that are involved in the underlying mechanism of PM-associated disorders. Top ranked genes were then screened using the Drosophila model as a high-throughput, whole organism functional screen to gain further evidence of their involvement in ovarian dysfunction.
AVSDs are a rare and severe form of congenital heart defects (CHD) and require surgery soon after birth. In general, CHDs occur in almost 1% of infants in the general population; AVSD occurs in about 1/10,000. Most genetic studies of CHD examine all forms, although there is strong evidence of etiological heterogeneity. We took the same strategy as above and identified a genetically-sensitized population to increase the ability to identify risk variants of AVSD. About 20% of infants with Down syndrome, or trisomy 21, are born with an AVSD, an enormous increase in frequency over the general population. Thus, we based our study on 702 individuals with DS who did and did not have an AVSD, again, drawing from those with the extremes of heart development. We used available whole exome sequencing, WGS, and/or array-based imputation data and took a variety of statistical approaches to examine risk-associated genes and pathways and to examine the contribution of many common variants of small effect size using polygenic risk score (PRS) methods.
Results from both studies that combined multiple statistical approaches of genetic data based on extreme phenotypes within genetically-sensitized cohorts proved successful. Identified candidate genes can now be moved to mammalian model systems to test for functional involvement. These studies benefit not only those with increased risk (i.e., women with a PM or people with DS), but may also be translated to those with idiopathic forms of the disorders.
