TOP-LD: A tool to explore linkage disequilibrium with TOPMed whole-genome sequence data

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  • Le Huang
  • Jonathan D. Rosen
  • Quan Sun
  • Jiawen Chen
  • Marsha M. Wheeler
  • Ying Zhou
  • Yuan I. Min
  • Charles Kooperberg
  • Matthew P. Conomos
  • Adrienne M. Stilp
  • Stephen S. Rich
  • Jerome I. Rotter
  • Ani Manichaikul
  • Loos, Ruth
  • Eimear E. Kenny
  • Thomas W. Blackwell
  • Albert V. Smith
  • Goo Jun
  • Fritz J. Sedlazeck
  • Ginger Metcalf
  • Eric Boerwinkle
  • Laura M. Raffield
  • Alex P. Reiner
  • Paul L. Auer
  • Yun Li
  • NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume109
Issue number6
Pages (from-to)1175-1181
Number of pages7
ISSN0002-9297
DOIs
Publication statusPublished - 2022

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