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Prioritization of Osteoporosis-Associated Genome-wide Association Study (GWAS) Single-Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics.

ABSTRACT: Genetic risk factors for osteoporosis, a prevalent disease associated with aging, have been examined in many genome-wide association studies (GWASs). A major challenge is to prioritize transcription-regulatory GWAS-derived variants that are likely to be functional. Given the critical role of epigenetics in gene regulation, we have used an unusual epigenetics-based and transcription-based approach to identify some of the credible regulatory single-nucleotide polymorphisms (SNPs) relevant to osteoporosis from 38 reported bone mineral density (BMD) GWASs. Using Roadmap databases, we prioritized SNPs based upon their overlap with strong enhancer or promoter chromatin preferentially in osteoblasts relative to 12 heterologous cell culture types. We also required that these SNPs overlap open chromatin (Deoxyribonuclease I [DNaseI]-hypersensitive sites) and DNA sequences predicted to bind to osteoblast-relevant transcription factors in an allele-specific manner. From >50,000 GWAS-derived SNPs, we identified 14 novel and credible regulatory SNPs (Tier-1 SNPs) for osteoporosis risk. Their associated genes, BICC1, LGR4, DAAM2, NPR3, or HMGA2, are involved in osteoblastogenesis or bone homeostasis and regulate cell signaling or enhancer function. Four of these genes are preferentially expressed in osteoblasts. BICC1, LGR4, and DAAM2 play important roles in canonical Wnt signaling, a pathway critical for bone formation and repair. The transcription factors predicted to bind to the Tier-1 SNP-containing DNA sequences also have bone-related functions. We present evidence that some of the Tier-1 SNPs exert their effects on BMD risk indirectly through little-studied long noncoding RNA (lncRNA) genes, which may, in turn, control the nearby bone-related protein-encoding gene. Our study illustrates a method to identify novel BMD-related causal regulatory SNPs for future study and to prioritize candidate regulatory GWAS-derived SNPs, in general. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

SUBMITTER: Zhang X

PROVIDER: S-EPMC8101624 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The projected rise in global ambient temperature by 3-5 °C by the end of this century, along with unpredicted heat waves during critical crop growth stages, can drastically reduce grain yield and will pose a great food security challenge. It is therefore important to identify wheat genetic resources able to withstand high temperatures, discover genes underpinning resilience to higher temperatures, and deploy such genetic resources in wheat breeding to develop heat-tolerant cultivars. In this study, 180 accessions of synthetic hexaploid wheats (SHWs) were evaluated under normal and late wheat growing seasons (to expose them to higher temperatures) at three locations (Islamabad, Bahawalpur, and Tando Jam), and data were collected on 11 morphological and yield-related traits. The diversity panel was genotyped with a 50 K SNP array to conduct genome-wide association studies (GWASs) for heat tolerance in SHW. A known heat-tolerance locus, TaHST1, was profiled to identify different haplotypes of this locus in SHWs and their association with grain yield and related traits in SHWs. There was a 36% decrease in grain yield (GY), a 23% decrease in thousand-grain weight (TKW), and an 18% decrease in grains per spike (GpS) across three locations in the population due to the heat stress conditions. GWASs identified 143 quantitative trait nucleotides (QTNs) distributed over all 21 chromosomes in the SHWs. Out of these, 52 QTNs were associated with morphological and yield-related traits under heat stress, while 15 of them were pleiotropically associated with multiple traits. The heat shock protein (HSP) framework of the wheat genome was then aligned with the QTNs identified in this study. Seventeen QTNs were in proximity to HSPs on chr2B, chr3D, chr5A, chr5B, chr6D, and chr7D. It is likely that QTNs on the D genome and those in proximity to HSPs may carry novel alleles for heat-tolerance genes. The analysis of TaHST1 indicated that 15 haplotypes were present in the SHWs for this locus, while hap1 showed the highest frequency of 25% (33 SHWs). These haplotypes were significantly associated with yield-related traits in the SHWs. New alleles associated with yield-related traits in SHWs could be an excellent reservoir for breeding deployment.

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Prioritization of Osteoporosis-Associated Genome-wide Association Study (GWAS) Single-Nucleotide Polymorphisms (SNPs) Using Epigenomics and Transcriptomics.

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