Feasibility Of Genome-wide Association Studies Research Articles

Abstract OT3-4-04: InVite: an observational pilot study evaluating the feasibility of genome-wide association studies using self-reported data from patients with metastatic breast cancer treated with bevacizumab

Abstract Background: Personalized healthcare tailors treatments to patients and their disease characteristics through the use of genetics and other biomarkers. Genetic differences among individuals may explain variations in drug treatment response, including side effects. With such information physicians could make more informed decisions about drugs and dosing for a given individual, thereby improving patient care. Although there has been some success, to a large extent genetic variation related to drug response remains unexplained. Bevacizumab, a humanized monoclonal antibody against the angiogenic factor VEGF, has demonstrated activity in patients with metastatic breast cancer (MBC). The InVite study will evaluate the feasibility of performing genomewide association studies using self-reported information collected via an online platform from patients with MBC who have been treated with bevacizumab. Using novel methodology in a convenient, user-friendly, and scientifically rigorous format, InVite ultimately aims to identify potential pharmacogenetic associations in this patient population. Trial design: InVite is a pilot, non-interventional, observational, web-based, prospective cohort study designed to collect patient-reported safety, efficacy, and genetic data from patients with MBC treated with bevacizumab. Data on demographics, breast cancer disease status, cancer treatment history, bevacizumab-related outcomes, and certain safety events will be collected directly from patients entirely via online surveys. Patients will be asked to complete surveys at the time of enrollment and then every 3 months for 1 year after enrollment. A saliva sample for DNA collection will be gathered using an at-home kit. Evaluations of data quality and collection feasibility will be conducted intermittently. There will be an optional substudy to allow for blood sample collection for DNA analysis. Eligibility criteria: ≥18 years of age, residing in the US, locally recurrent breast cancer or MBC, currently being or having been treated with bevacizumab starting on or before Dec 31, 2011, fluent in English, and access to a computer with an internet connection. Specific aims: The primary objective is to assess the feasibility of recruiting subjects and collecting biospecimens and self-reported data online. The secondary objective is to characterize the patient population. Exploratory objectives include analyzing potential associations between genetic polymorphisms and 1) bevacizumab-induced hypertension, the most common bevacizumab-related adverse event, and 2) patient-reported time-to-progression. Statistical methods: Baseline demographics, clinical and treatment characteristics of enrolled patients will be summarized. Each polymorphism genotyped will be tested for association with the defined endpoint using appropriate statistical modeling. Present and target accrual: Accrual as of May 23, 2012 is 82 patients. Target accrual is 1000 patients. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-4-04.

Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

BackgroundThe ideal malaria parasite populations for initial mapping of genomic regions contributing to phenotypes such as drug resistance and virulence, through genome-wide association studies, are those with high genetic diversity, allowing for numerous informative markers, and rare meiotic recombination, allowing for strong linkage disequilibrium (LD) between markers and phenotype-determining loci. However, levels of genetic diversity and LD in field populations of the major human malaria parasite P. vivax remain little characterized.ResultsWe examined single-nucleotide polymorphisms (SNPs) and LD patterns across a 100-kb chromosome segment of P. vivax in 238 field isolates from areas of low to moderate malaria endemicity in South America and Asia, where LD tends to be more extensive than in holoendemic populations, and in two monkey-adapted strains (Salvador-I, from El Salvador, and Belem, from Brazil). We found varying levels of SNP diversity and LD across populations, with the highest diversity and strongest LD in the area of lowest malaria transmission. We found several clusters of contiguous markers with rare meiotic recombination and characterized a relatively conserved haplotype structure among populations, suggesting the existence of recombination hotspots in the genome region analyzed. Both silent and nonsynonymous SNPs revealed substantial between-population differentiation, which accounted for ~40% of the overall genetic diversity observed. Although parasites clustered according to their continental origin, we found evidence for substructure within the Brazilian population of P. vivax. We also explored between-population differentiation patterns revealed by loci putatively affected by natural selection and found marked geographic variation in frequencies of nucleotide substitutions at the pvmdr-1 locus, putatively associated with drug resistance.ConclusionThese findings support the feasibility of genome-wide association studies in carefully selected populations of P. vivax, using relatively low densities of markers, but underscore the risk of false positives caused by population structure at both local and regional levels.See commentary: http://www.biomedcentral.com/1741-7007/8/90

Recombination Hotspots and Population Structure in Plasmodium falciparum

Understanding the influences of population structure, selection, and recombination on polymorphism and linkage disequilibrium (LD) is integral to mapping genes contributing to drug resistance or virulence in Plasmodium falciparum. The parasite's short generation time, coupled with a high cross-over rate, can cause rapid LD break-down. However, observations of low genetic variation have led to suggestions of effective clonality: selfing, population admixture, and selection may preserve LD in populations. Indeed, extensive LD surrounding drug-resistant genes has been observed, indicating that recombination and selection play important roles in shaping recent parasite genome evolution. These studies, however, provide only limited information about haplotype variation at local scales. Here we describe the first (to our knowledge) chromosome-wide SNP haplotype and population recombination maps for a global collection of malaria parasites, including the 3D7 isolate, whose genome has been sequenced previously. The parasites are clustered according to continental origin, but alternative groupings were obtained using SNPs at 37 putative transporter genes that are potentially under selection. Geographic isolation and highly variable multiple infection rates are the major factors affecting haplotype structure. Variation in effective recombination rates is high, both among populations and along the chromosome, with recombination hotspots conserved among populations at chromosome ends. This study supports the feasibility of genome-wide association studies in some parasite populations.

The Genetic Dissection of Complex Traits in a Founder Population

We estimated broad heritabilities (H(2)) and narrow heritabilities (h(2)) and conducted genomewide screens, using a novel association-based mapping approach for 20 quantitative trait loci (QTLs) among the Hutterites, a founder population that practices a communal lifestyle. Heritability estimates ranged from.21 for diastolic blood pressure (DBP) to.99 for whole-blood serotonin levels. Using a multipoint method to detect association under a recessive model we found evidence of major QTLs for six traits: low-density lipoprotein (LDL), triglycerides, lipoprotein (a) (Lp[a]), systolic blood pressure (SBP), serum cortisol, and whole-blood serotonin. Second major QTLs for Lp(a) and for cortisol were identified using a single-point method to detect association under a general two-allele model. The heritabilities for these six traits ranged from.37 for triglycerides to.99 for serotonin, and three traits (LDL, SBP, and serotonin) had significant dominance variances (i.e., H(2) > h(2)). Surprisingly, there was little correlation between measures of heritability and the strength of association on a genomewide screen (P>.50), suggesting that heritability estimates per se do not identify phenotypes that are influenced by genes with major effects. The present study demonstrates the feasibility of genomewide association studies for QTL mapping. However, even in this young founder population that has extensive linkage disequilibrium, map densities <<5 cM may be required to detect all major QTLs.