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

TitleTOP-LD: A tool to explore linkage disequilibrium with TOPMed whole-genome sequence data.
Publication TypeJournal Article
Year of Publication2022
AuthorsHuang, L, Rosen, JD, Sun, Q, Chen, J, Wheeler, MM, Zhou, Y, Min, Y-I, Kooperberg, C, Conomos, MP, Stilp, AM, Rich, SS, Rotter, JI, Manichaikul, A, Loos, RJF, Kenny, EE, Blackwell, TW, Smith, AV, Jun, G, Sedlazeck, FJ, Metcalf, GA, Boerwinkle, E, Raffield, LM, Reiner, AP, Auer, PL, Li, Y
Corporate AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalAm J Hum Genet
Date Published2022 Jun 02
KeywordsAsian People, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Precision Medicine, Whole Genome Sequencing

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.

Alternate JournalAm J Hum Genet
PubMed ID35504290
PubMed Central IDPMC9247832
Grant ListMC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
R01 HL129132 / HL / NHLBI NIH HHS / United States
T32 HL129982 / HL / NHLBI NIH HHS / United States
U01 DA052713 / DA / NIDA NIH HHS / United States
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
U01 HG011720 / HG / NHGRI NIH HHS / United States
U24 AR076730 / AR / NIAMS NIH HHS / United States
R01 HL146500 / HL / NHLBI NIH HHS / United States
KL2 TR002490 / TR / NCATS NIH HHS / United States