Molecular Genetics
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21690
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Browsing Molecular Genetics by Author "Barber, Robert"
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Item Case-Case Genome-Wide Association Study of Age-Related Cancer and Alzheimer’s Disease(2017-03-14) Barber, Robert; Phillips, Nicole R.; Olmstead, KeeganBackground: Research over the past five years has strengthened in support of an inverse epidemiological correlation between Alzheimer’s disease (AD) and cancer--individuals with cancer are less likely to develop AD and those with AD have reduced cancer risk. Since cancer is characterized by uncontrolled cell division, and AD by neuronal death (and limited neuronal regeneration), this inverse relationship may point to dysregulation in some common underlying pathways. Here, we aim to investigate the genetic underpinnings of this unique relationship which have not been fully explored, using a unique case-case genome-wide association study (GWAS) design between an AD and cancer cohort. Hypothesis: We hypothesize that suggestive association signals will be observed when comparing the AD to cancer group, with the most interesting signals being those that are stronger when comparing cases-to-cases than when comparing cases-to-controls. Methods: Genome-wide SNP data for AD, Cancer, and Control groups were created using two publically available datasets: Breast Cancer (BrCa) and Prostate Cancer (PCa) Cohort Consortium and Alzheimer’s Disease Neuroimaging Initiative. Breast and prostate cancer were combined to form the Cancer group, which according to Cancer Research UK, are the most prevalent forms of adult and elderly cancers. All samples were typed with the Illumina Human610-Quad BeadChip. Rigorous data management and quality control measures were taken: group matching, updating map location, permutations test, sex check and filtering of low genotyping individuals and loci as well as loci with HWE issues. Three association analyses were performed: AD–Control, Cancer–Control, and AD–Cancer. Results: After matching for age, gender, and Caucasian ethnicity 492 individuals were included in the AD group (Avg age: 75 years, 37% female), 691 individuals in Cancer group (Avg age: 67.7 years, 37% female), and 1150 individuals in the combined Control group (avg age: 71 years, 37% female). Association analysis of the AD–Cancer study indicated one marker, rs2075650, as significant at p -8. Initial analysis also indicated possible clustering of significant SNPs on chromosomes 8 and 11. Conclusions: Case-case GWAS provides a novel means for identifying novel loci involved in the dichotomous relationship of risk of AD and risk of BrCa/PCa. These signals may point to critical genomic regions involved in age-related pathologies of cancer and AD.Item Genetic Differentiation of Hispanic Populations Using Ancestry Informative Markers(2017-03-14) Cross, Deanna; Chakraborty, Ranajit; Planz, John; Eisenberg, Arthur; Barber, Robert; Setser, CasandraHypothesis: There are at least 10,500 unidentified human remains in the US as of August 2015, with 2,041 of presumed Hispanic origin (NamUs 2015). Conventional DNA analysis identifies an individual through comparison with reference profiles. For those with no reference, panels of ancestry informative single nucleotide polymorphisms (SNPs) exist (Kidd 2014, Seldin 2009), but they focus on global differentiation and are not useful for ancestry determination of admixed populations (e.g. Hispanics). We hypothesize that a small panel of SNPs ascertained from appropriate populations with great genetic differentiation can distinguish ancestry within Hispanic populations. Materials: This bioinformatics study uses the Genomic Origins and Ancestry in Latinos (GOAL) data set of 250 individuals with ancestry from Columbia, Cuba, Dominican Republic, Haiti, Honduras, or Puerto Rico, genotyped using the Affymetrix 6.0 chip to develop an informative Hispanic SNP panel. Methods: Starting with 897,336 SNPs, we trimmed to 531,878 SNPs using linkage disequilibrium of 0.7. We then calculated pairwise FST for each SNP with each population pair using PLINK software (Haiti excluded). SNPs that met the 0.15 threshold for the four comparisons were included in a 1217 SNP panel. We used STRUCTURE to visualize population separation. To determine if a smaller SNP set could be utilized while retaining information, we used the SNPs with the top ten mean FST values from each population plus five extra to try to distinguish Cuba vs. Dominican Republic for a condensed panel of 56 SNPs. Additionally, we combined 1000 Genomes and GOAL data to verify whether the countries differentiate ancestrally or geographically. Results: STRUCTURE analysis showed Honduras was easily distinguished from other countries in the 1217 and 56 SNP panels. Other countries were also separated based on contribution from ancestral populations; however, the separation was less than ideal. Notably, Honduras contributed 71% of the SNPs in the 1217 panel. When analyzed with 1000 Genomes data, Honduras separated with the Chinese population for K=1-3, but was the first GOAL population to separate from the ancestral line. Conclusions: Utilizing an efficient SNP panel consistently separated Honduras from other populations demonstrating proof of concept. Greater separation of country of origin may be seen with a larger data set and alternative selection of each population’s number of SNPs by a cumulative mean FST threshold.