Genometric analysis of quantitative traits

数量性状的基因组分析

• 批准号: 10025110
• 负责人: alexander f wilson
• 金额: $ 179.75万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10025110
• 关键词: Address; Adult; Alleles; Blood; Case-Control Studies; Caucasians; Collaborations; Computer Simulation; Computer software; Craniosynostosis; DNA Markers; Data; Data Set; Dependence; Elements; Embryo; Extramural Activities; Family; Fishes; Follow-Up Studies; Frequencies; GRP gene; Genetic; Genetic Heterogeneity; Genetic Models; Genome; Goals; Heritability; Heterogeneity; Individual; Iowa; Ireland; Justice; Linear Regressions; Linkage Disequilibrium; Luciferases; Measurement; Meta-Analysis; Metabolism; Methodology; Methods; Microscopy; Midbrain structure; Modeling; NF1 gene; National Human Genome Research Institute; Nature; Not Hispanic or Latino; Parents; Patients; Pattern; Phenotype; Property; Proteins; Publishing; Pyridoxal Phosphate; Quantitative Genetics; Regression Analysis; Regulatory Element; Reporting; Research; Research Design; Retirement; Sampling; Single Nucleotide Polymorphism; Statistical Methods; Structure; Suggestion; Testing; Time; United States National Institutes of Health; Universities; Untranslated RNA; Update; Variant; Vitamin D; Vitamins; Work; Zebrafish; base; clinical phenotype; cohort; college; density; experimental study; follow-up; genetic analysis; genetic epidemiology; genome wide association study; genome-wide; hindbrain; insight; interest; method development; next generation sequence data; non-genetic; offspring; population based; population stratification; risk variant; simulation; software development; statistics; trait; validation studies; vector; web site

SUMMARY Administrative Note The number of intramural and extramural collaborators has been substantially reduced because of Dr. Wilsons upcoming retirement in September of 2020. The focus of the Genometrics Section over the past year has been to limit new collaborations and to complete ongoing collaborations by the summer of 2020. No new collaborations are being undertaken at this time. Effort has been focused on winding down the current research portfolio before the shutdown of the Genometrics Section next year. Methods Development Ad-hoc replication with Complementary Pairs Stability Selection (ComPaSS) Results from association studies are traditionally corroborated by replicating the findings in an independent dataset. Although replication studies may be comparable for the main trait or phenotype of interest, it is unlikely that secondary phenotypes will be comparable across studies, making replication problematic. Alternatively, there may simply not be a replication sample available because of the nature or frequency of the phenotype. In these situations, an approach based on complementary-pairs stability selection, ComPaSS-GWAS, was developed as an ad-hoc alternative to replication. In this new method, the sample is randomly split into two conditionally independent halves multiple times (resamples) and a GWAS is performed on each half in each resample. Similar in spirit to testing for association with independent discovery and replication samples, a marker is corroborated if its p-value is significant in both halves of the resample. Simulation experiments were performed for both non-genetic (null model) and genetic models. The type I error rate and power of ComPaSS-GWAS were determined and compared to the statistical properties of a traditional GWAS. Simulation results show that the type I error rate decreased as the number of resamples increased with only a small reduction in power and that these results were comparable to those from a traditional GWAS. Blood levels of vitamin pyridoxal 5-phosphate (PLP) from the TSS were used to validate this approach. The results from the validation study were compared to, and were consistent with, those obtained from previously published independent replication data and functional studies Sabourin et al. 2019. Software Development Software development and implementation has focused on three projects during the past year. In the first, the tiled regression methodology was updated in the Tiled Regression Analysis Package (TRAP). Version 2.0 of TRAP includes additional penalized regression models and is available on the NHGRI website: http://research.nhgri.nih.gov/software/TRAP. In the second project, a faster version of TRAP for quantitative traits (TR-Quant) is now available at https://research.nhgri.nih.gov/software/TRQUANT. And, in the third, software for ComPaSS-GWAS Sabourin et al. 2019 is now available at https://research.nhgri.nih.gov/software/compass-gwas. This version of ComPaSS-GWAS is limited to analysis with PLINK. Collaborations Craniosynostosis As part of an ongoing collaboration with Dr. Simeon Boyd (UC Davis) and Dr. Paul Romiti (U of Iowa) Justice et al. 2012 reported a genome-wide association study (GWAS) for non-syndromic sagittal craniosynostosis and the genome-wide associations were replicated in an independent Caucasian. Zebra fish were then used to test the expression of the previously identified conserved non-coding regulatory elements to determine if the expression of identified sequence variants differed from that of the wild type expression. Zebra fish embryos were screened with fluorescent microscopy for red and green florescent protein (RFP and GFP, respectively). Embryos demonstrating RFP/GRP expression were grown to adulthood and bred with wild type fish. Several germline transmitting founders were identified for each ZED vector construct and their progeny were screened for patterns of RFP/GFP expression, again using fluorescent microscopy. GFP expression in the fish with the risk allele (C) appears to occur in the midbrain and hindbrain, while in the fish with the wild type (T) allele, GFP expression was observed in the midbrain-hindbrain boundary. This work was featured on the cover of Genetic Epidemiology Justice et al. 2017. In our current follow-up study, this same approach has been applied to parent-offspring trios with metopic non-syndromic craniosynostosis (mNCS) using 215 non-Hispanic trios. Six variants were identified that were genome-wide significant and one of the variants was replicated in an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls. A meta-analysis of SNPs common to both the mNCS and sNCS studies identified a single SNP at the genome-wide association suggestive level of 1x10 -5. Results from a luciferase studies suggested that a fragment which encompasses this SNP acts as a repressor element. Measurement of caf-au-lait macules in NF1 patients. As part of an ongoing collaboration with Dr. Douglas Stewart (NCI), a follow-up to our genome-wide association study of modifiers for a genome-wide association analysis was performed focusing on the number of caf-au-lait macules (CALM) as a clinical phenotype modifying NF1. A borderline genome-wide significant association was identified in the discovery cohort. Although, this association was not replicated in the second cohort and a meta-analysis did not show significantly associated variants with this variant, a significant corroboration score (0.72) was obtained for this SNP in the discovery cohort using Complementary Pairs Stability Selection (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error. Other ongoing collaborations 1) The ClinSeq project (Les Biesecker, NIH/NHGRI) 2) Statistical properties of fixed and mixed effects models. Dr. Ruzong Fan, Georgetown University. 3) Genetics of traits related to vitamin D metabolism. Dr. Larry Brody, NHGRI, Dr. Barry Shane, Dr. Faith Pangilinan (Trinity College, Ireland).

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