Genometric analysis of quantitative traits

总结 分发行政记录 由于威尔逊博士即将于2020年9月退休，正在进行的项目数量以及校内和校外合作者的数量已大幅减少。 过去一年，基因统计科的重点是完成正在进行的合作。 努力的重点是逐步减少目前的研究组合。 这是数量性状基因分析项目的最后一份年度报告。 最后一位IRTA博士后研究员Jeremy Sabourin博士在马里兰州弗雷德里克的Biostat Solutions公司任职。 基因组科学家被安排在NIH的其他同等职位。 Heejong Sung博士在弗朗西斯麦克马洪博士的指导下搬到了国家精神卫生研究所。 克里斯蒂娜·贾斯蒂斯博士和亚历克莎·索朗特博士继续留在NHGRI;贾斯蒂斯博士由菲利普·肖博士领导，索朗特女士由琼·贝利-威尔逊博士领导。 威尔逊博士将继续，兼职，作为一个特殊的志愿者，或如果批准，作为一个名誉科学家。 软件开发 目前已有三个项目的最终版本。 首先，平铺回归方法在平铺回归分析包（TRAP）中进行了更新。 TRAP 2.0版包括额外的惩罚回归模型，可在NHGRI网站上获得：http://research.nhgri.nih.gov/software/TRAP。 在第二个项目中，用于数量性状的TRAP（TR-Quant）的更快版本现在可以在https://research.nhgri.nih.gov/software/TRQUANT上获得。 第三，CompaSS-GWAS Sabourin等人2019的软件现在可以在https://research.nhgri.nih.gov/software/compass-gwas上获得。 此版本的CompPaSS-GWAS仅限于使用PLINK进行分析。 合作 颅缝 作为与Simeon Boyd博士（加州大学戴维斯分校）和Paul Romiti博士（爱荷华州大学）正在进行的合作的一部分，Justice等人于2012年报告了一项矢状面非综合征性颅缝早闭（sNCS）的全基因组关联研究（GWAS）。 同样的方法被应用到215个非西班牙裔的父母-后代三人组与异位非综合征性颅缝早闭（mNCS）。 鉴定出6种全基因组显著的变异，其中一种变异在194例无关mNCS病例和333例未受影响对照的独立非西班牙裔白色样本中复制。 对mNCS和sNCS研究共同的SNP进行的荟萃分析在1x 10 -5的全基因组关联提示水平上鉴定了单个SNP。 荧光素酶研究的结果表明，包含该SNP的片段充当阻遏元件。 这项工作最近发表在《人类遗传学》上。 NF 1患者中咖啡牛奶斑的测量。 作为与道格拉斯斯图尔特博士（NCI）正在进行的合作的一部分，我们进行了一项全基因组关联分析的修饰剂的全基因组关联研究的后续研究，重点关注咖啡牛奶斑（CALM）作为修饰NF 1的临床表型的数量。 在发现队列中确定了临界全基因组显著关联。 这种关联在第二个队列中没有重复，荟萃分析也没有显示与该变体显著相关的变体。 然而，使用互补对稳定性选择（CompaSS-GWAS）分析Sabourin，2019在发现队列中获得了该SNP的显著确证评分（0.72），表明缺乏复制可能是由于队列的异质性而不是I型错误。 这项工作在Molecular Genetic and Genomic Medicine 2020上发表。 其他正在进行的合作 1)ClinSeq项目（Les Biesecker，NIH/NHGRI） 2)固定和混合效应模型的统计特性。 范儒宗博士，乔治敦大学。 3)维生素D代谢相关性状的遗传学。 拉里·布罗迪博士，NHGRI，巴里谢恩博士，信仰潘吉利南博士（Trinity学院，爱尔兰）。 4)英国生物银行数据库中非欧洲人的心血管和代谢特征（Teri Manolio博士，NHGRI）。

SUMMARY Administrative Note The number of ongoing projects, and the number of intramural and extramural collaborators has been substantially reduced because of Dr. Wilsons upcoming retirement in September 2020. The focus of the Genometrics Section over the past year has been to complete ongoing collaborations. Effort has been focused on winding down the current research portfolio. This is the final annual report for the Genometric Analysis of Quantitative Traits project. The last post-doctoral IRTA fellow, Dr. Jeremy Sabourin has taken a position with Biostat Solutions in Frederick, MD. The Staff Scientists in the Genometrics Section have been placed in other equivalent positions at NIH. Dr. Heejong Sung has moved to the National Institute of Mental Health under the direction of Dr. Francis McMahon. Dr. Cristina Justice and Alexa Sorant remain in NHGRI; Dr. Justice under the direction of Dr. Philip Shaw, and Ms. Sorant under the direction of Dr. Joan Bailey-Wilson. Dr. Wilson will continue, part-time, as a special volunteer, or if approved, as an Emeritus Scientist. Software Development Final versions of three projects are now available. 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 sagittal non-syndromic craniosynostosis (sNCS). This same approach was applied to 215 non-Hispanic parent-offspring trios with metopic non-syndromic craniosynostosis (mNCS). 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. This work was recently published in Human Genetics. 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. This association was not replicated in the second cohort and a meta-analysis did not show significantly associated variants with this variant. However, a significant corroboration score (0.72) was obtained for this SNP in the discovery cohort using Complementary Pairs Stability Selection (ComPaSS-GWAS) analysis Sabourin, 2019 suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error. This work is in press in Molecular Genetic and Genomic Medicine 2020. 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). 4) Cardiovascular and metabolic traits in non-Europeans in the UK BioBank database (Dr. Teri Manolio, NHGRI).