TOP-LD: A tool to explore linkage disequilibrium with TOPMed whole-genome sequence data,American Journal of Human Genetics

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TOP-LD: A tool to explore linkage disequilibrium with TOPMed whole-genome sequence data
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2022-05-02 , DOI: 10.1016/j.ajhg.2022.04.006
Le Huang ₁ , Jonathan D Rosen ₂ , Quan Sun ₂ , Jiawen Chen ₂ , Marsha M Wheeler ₃ , Ying Zhou ₄ , Yuan-I Min ₅ , Charles Kooperberg ₄ , Matthew P Conomos ₆ , Adrienne M Stilp ₆ , Stephen S Rich ₇ , Jerome I Rotter ₈ , Ani Manichaikul ₇ , Ruth J F Loos ₉ , Eimear E Kenny ₁₀ , Thomas W Blackwell ₁₁ , Albert V Smith ₁₁ , Goo Jun ₁₂ , Fritz J Sedlazeck ₁₃ , Ginger Metcalf ₁₃ , Eric Boerwinkle ₁₄ , , Laura M Raffield ₁₅ , Alex P Reiner ₁₆ , Paul L Auer ₁₇ , Yun Li ₁₈

Affiliation

Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Department of Biostatistics, University of Washington, Seattle, WA 98105, USA.
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY 10029, USA.
TOPMed Informatics Research Center, University of Michigan, Department of Biostatistics, Ann Arbor, MI 48109, USA.
Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Current publicly available tools that allow rapid exploration of linkage disequilibrium (LD) between markers (e.g., HaploReg and LDlink) are based on whole-genome sequence (WGS) data from 2,504 individuals in the 1000 Genomes Project. Here, we present TOP-LD, an online tool to explore LD inferred with high-coverage (∼30×) WGS data from 15,578 individuals in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. TOP-LD provides a significant upgrade compared to current LD tools, as the TOPMed WGS data provide a more comprehensive representation of genetic variation than the 1000 Genomes data, particularly for rare variants and in the specific populations that we analyzed. For example, TOP-LD encompasses LD information for 150.3, 62.2, and 36.7 million variants for European, African, and East Asian ancestral samples, respectively, offering 2.6- to 9.1-fold increase in variant coverage compared to HaploReg 4.0 or LDlink. In addition, TOP-LD includes tens of thousands of structural variants (SVs). We demonstrate the value of TOP-LD in fine-mapping at the GGT1 locus associated with gamma glutamyltransferase in the African ancestry participants in UK Biobank. Beyond fine-mapping, TOP-LD can facilitate a wide range of applications that are based on summary statistics and estimates of LD. TOP-LD is freely available online.

中文翻译：

TOP-LD：利用 TOPMed 全基因组序列数据探索连锁不平衡的工具

目前公开的工具可以快速探索标记之间的连锁不平衡 (LD)（例如 HaploReg 和 LDlink），这些工具基于 1000 基因组计划中 2,504 名个体的全基因组序列 (WGS) 数据。在这里，我们介绍了 TOP-LD，这是一种在线工具，用于探索利用 NHLBI 精准医学跨组学 (TOPMed) 计划中 15,578 名个体的高覆盖率 (∼30×) WGS 数据推断出的 LD。与当前的 LD 工具相比，TOP-LD 提供了重大升级，因为 TOPMed WGS 数据比 1000 个基因组数据提供了更全面的遗传变异表示，特别是对于罕见变异和我们分析的特定人群。例如，TOP-LD 分别包含欧洲、非洲和东亚祖先样本 150.3、62.2 和 3670 万个变异的 LD 信息，与 HaploReg 4.0 或 LDlink 相比，变异覆盖率提高了 2.6 至 9.1 倍。此外，TOP-LD 还包括数以万计的结构变体 (SV)。我们证明了 TOP-LD 在英国生物银行非洲血统参与者中与 γ 谷氨酰转移酶相关的GGT1位点精细定位中的价值。除了精细映射之外，TOP-LD 还可以促进基于 LD 的汇总统计和估计的广泛应用。 TOP-LD 可在线免费获取。

更新日期：2022-05-02

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