TY - JOUR

T1 - TOP-LD

T2 - A tool to explore linkage disequilibrium with TOPMed whole-genome sequence data

AU - Huang, Le

AU - Rosen, Jonathan D.

AU - Sun, Quan

AU - Chen, Jiawen

AU - Wheeler, Marsha M.

AU - Zhou, Ying

AU - Min, Yuan I.

AU - Kooperberg, Charles

AU - Conomos, Matthew P.

AU - Stilp, Adrienne M.

AU - Rich, Stephen S.

AU - Rotter, Jerome I.

AU - Manichaikul, Ani

AU - Loos, Ruth J.F.

AU - Kenny, Eimear E.

AU - Blackwell, Thomas W.

AU - Smith, Albert V.

AU - Jun, Goo

AU - Sedlazeck, Fritz J.

AU - Metcalf, Ginger

AU - Boerwinkle, Eric

AU - Raffield, Laura M.

AU - Reiner, Alex P.

AU - Auer, Paul L.

AU - Li, Yun

AU - NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

N1 - Publisher Copyright: © 2022 The Authors

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2022.04.006

DO - 10.1016/j.ajhg.2022.04.006

M3 - Journal article

C2 - 35504290

AN - SCOPUS:85131100015

VL - 109

SP - 1175

EP - 1181

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -