bims-agalsp Biomed News
on Ageing and alternative splicing
Issue of 2023‒03‒05
five papers selected by
Dongmeng Wang
King’s College


  1. Nat Commun. 2023 Feb 28. 14(1): 1132
    iPSCORE Consortium
      The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. Here, we leverage spatiotemporal information on 966 RNA-seq cardiac samples and perform an expression quantitative trait locus (eQTL) analysis detecting eQTLs considering both eGenes and eIsoforms. We identify 2,578 eQTLs associated with a specific developmental stage-, tissue- and/or cell type. Colocalization between eQTL and GWAS signals of five cardiac traits identified variants with high posterior probabilities for being causal in 210 GWAS loci. Pulse pressure GWAS loci are enriched for colocalization with fetal- and smooth muscle- eQTLs; pulse rate with adult- and cardiac muscle- eQTLs; and atrial fibrillation with cardiac muscle- eQTLs. Fine mapping identifies 79 credible sets with five or fewer SNPs, of which 15 were associated with spatiotemporal eQTLs. Our study shows that many cardiac GWAS variants impact traits and disease in a developmental stage-, tissue- and/or cell type-specific fashion.
    DOI:  https://doi.org/10.1038/s41467-023-36638-2
  2. Prog Brain Res. 2023 ;pii: S0079-6123(22)00189-3. [Epub ahead of print]275 165-215
      This chapter utilizes genomic concepts and evolutionary perspectives to further understand the possible links between typical brain aging and neurodegenerative diseases, focusing on the two most prevalent of these: Alzheimer's disease and Parkinson's disease. Aging is the major risk factor for these neurodegenerative diseases. Researching the evolutionary and molecular underpinnings of aging helps to reveal elements of the typical aging process that leave individuals more vulnerable to neurodegenerative pathologies. Very little is known about the prevalence and susceptibility of neurodegenerative diseases in nonhuman species, as only a few individuals have been observed with these neuropathologies. However, several studies have investigated the evolution of lifespan, which is closely connected with brain size in mammals, and insights can be drawn from these to enrich our understanding of neurodegeneration. This chapter explores the relationship between the typical aging process and the events in neurodegeneration. First, we examined how age-related processes can increase susceptibility to neurodegenerative diseases. Second, we assessed to what extent neurodegeneration is an accelerated form of aging. We found that while at the phenotypic level both neurodegenerative diseases and the typical aging process share some characteristics, at the molecular level they show some distinctions in their profiles, such as variation in genes and gene expression. Furthermore, neurodegeneration of the brain is associated with an earlier onset of cellular, molecular, and structural age-related changes. In conclusion, a more integrative view of the aging process, both from a molecular and an evolutionary perspective, may increase our understanding of neurodegenerative diseases.
    Keywords:  Aging; Alzheimer's disease; Brain mass; Dementia; Evolutionary biology; Genomics; Hominin fossils; Neurodegeneration; Neurodegenerative diseases; Parkinson's disease
    DOI:  https://doi.org/10.1016/bs.pbr.2022.10.004
  3. Front Genet. 2023 ;14 1114174
      Genome-wide association study (GWAS) have identified over 1,000 loci associated with blood pressure. However, these loci only explain 6% of heritability. Transcriptome-wide association studies (TWAS) combine GWAS summary data with expression quantitative trait loci (eQTL) to provide a better approach to finding genes associated with complex traits. GWAS summary data (N = 450,584) for essential hypertension originating from European samples were subjected to Post-GWAS analysis using FUMA software and then combined with eQTL data from Genotype-Tissues Expression Project (GTEx) v8 for TWAS analysis using UTMOST, FUSION software, and then validated the results with SMR. FUMA identified 346 significant genes associated with hypertension, FUSION identified 461, and UTMOST cross-tissue analysis identified 34, of which 5 were common. SMR validation identified 3 key genes: ENPEP, USP38, and KCNK3. In previous GWAS studies on blood pressure regulation, the association of ENPEP and KCNK3 with hypertension has been established, and the association between USP38 and blood pressure regulation still needs further validation.
    Keywords:  SMR; TWAS; UTMOST; hypertension; post-gwas
    DOI:  https://doi.org/10.3389/fgene.2023.1114174
  4. BMC Genomics. 2023 Mar 01. 24(1): 92
      BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of most common diseases in the world. Recently, alternative splicing (AS) has been reported to play a key role in NAFLD processes in mammals. Ducks can quickly form fatty liver similar to human NAFLD after overfeeding and restore to normal liver in a short time, suggesting that ducks are an excellent model to unravel molecular mechanisms of lipid metabolism for NAFLD. However, how alternative splicing events (ASEs) affect the fatty liver process in ducks is still unclear.RESULTS: Here we identify 126,277 unique transcripts in liver tissue from an overfed duck (77,237 total transcripts) and its sibling control (69,618 total transcripts). We combined these full-length transcripts with Illumina RNA-seq data from five pairs of overfed ducks and control individuals. Full-length transcript sequencing provided us with structural information of transcripts and Illumina RNA-seq data reveals the expressional profile of each transcript. We found, among these unique transcripts, 30,618 were lncRNAs and 1,744 transcripts including 155 lncRNAs and 1,589 coding transcripts showed significantly differential expression in liver tissues between overfed ducks and control individuals. We also detected 27,317 ASEs and 142 of them showed significant relative abundance changes in ducks under different feeding conditions. Full-length transcript profiles together with Illumina RNA-seq data demonstrated that 10 genes involving in lipid metabolism had ASEs with significantly differential abundance in normally fed (control) and overfed ducks. Among these genes, protein products of five genes (CYP4F22, BTN, GSTA2, ADH5, and DHRS2 genes) were changed by ASEs.
    CONCLUSIONS: This study presents an example of how to identify ASEs related to important biological processes, such as fatty liver formation, using full-length transcripts alongside Illumina RNA-seq data. Based on these data, we screened out ASEs of lipid-metabolism related genes which might respond to overfeeding. Our future ability to explore the function of genes showing AS differences between overfed ducks and their sibling controls, using genetic manipulations and co-evolutionary studies, will certainly extend our knowledge of genes related to the non-pathogenic fatty liver process.
    Keywords:  Alternative splicing; Duck; Fatty liver; Full-length transcripts sequencing
    DOI:  https://doi.org/10.1186/s12864-023-09160-4
  5. JAMA Netw Open. 2023 Mar 01. 6(3): e2248995
      Importance: A frailty index has been proposed as a measure of aging among older individuals. However, few studies have examined whether a frailty index measured at the same chronologic age at younger ages could forecast the development of new age-related conditions.Objective: To examine the association of the frailty index at 66 years of age with incident age-related diseases, disability, and death over 10 years.
    Design, Setting, and Participants: This retrospective nationwide cohort study used the Korean National Health Insurance database to identify 968 885 Korean individuals who attended the National Screening Program for Transitional Ages at 66 years of age between January 1, 2007, and December 31, 2017. Data were analyzed from October 1, 2020, to January 2022.
    Exposures: Frailty was defined using a 39-item frailty index ranging from 0 to 1.00 as robust (<0.15), prefrail (0.15-0.24), mildly frail (0.25-0.34), and moderately to severely frail (≥0.35).
    Main Outcomes and Measures: The primary outcome was all-cause death. Secondary outcomes were 8 age-related chronic diseases (congestive heart failure, coronary artery disease, stroke, type 2 diabetes, cancer, dementia, fall, and fracture) and disability qualifying for long-term care services. Cox proportional hazards regression and cause-specific and subdistribution hazards regression were used to examine hazard ratios (HRs) and 95% CIs for the outcomes until the earliest of date of death, the occurrence of relevant age-related conditions, 10 years from the screening examination, or December 31, 2019.
    Results: Among the 968 885 participants included in the analysis (517 052 women [53.4%]), the majority were classified as robust (65.2%) or prefrail (28.2%); only a small fraction were classified as mildly frail (5.7%) or moderately to severely frail (1.0%). The mean frailty index was 0.13 (SD, 0.07), and 64 415 (6.6%) were frail. Compared with the robust group, those in the moderately to severely frail group were more likely to be women (47.8% vs 61.7%), receiving medical aid insurance for low income (2.1% vs 18.9%), and less active (median, 657 [IQR, 219-1133] vs 319 [IQR, 0-693] metabolic equivalent task [min/wk]). After adjusting for sociodemographic and lifestyle characteristics, moderate to severe frailty was associated with increased rates of death (HR, 4.43 [95% CI, 4.24-4.64]) and new diagnosis of all chronic diseases, including congestive heart failure (adjusted cause-specific HR, 2.90 [95% CI, 2.67-3.15]), coronary artery disease (adjusted cause-specific HR, 1.98 [95% CI, 1.85-2.12]), stroke (adjusted cause-specific HR, 2.22 [95% CI, 2.10-2.34]), diabetes (adjusted cause-specific HR, 2.34 [95% CI, 2.21-2.47]), cancer (adjusted cause-specific HR, 1.10 [95% CI, 1.03-1.18]), dementia (adjusted cause-specific HR, 3.59 [95% CI, 3.42-3.77]), fall (adjusted cause-specific HR, 2.76 [95% CI, 2.29-3.32]), fracture (adjusted cause-specific HR, 1.54 [95% CI, 1.48-1.62]), and disability (adjusted cause-specific HR, 10.85 [95% CI, 10.00-11.70]). Frailty was associated with increased 10-year incidence of all the outcomes, except for cancer (moderate to severe frailty adjusted subdistribution HR, 0.99 [95% CI, 0.92-1.06]). Frailty at 66 years of age was associated with greater acquisition of age-related conditions (mean [SD] conditions per year for the robust group, 0.14 [0.32]; for the moderately to severely frail group, 0.45 [0.87]) in the next 10 years.
    Conclusions and Relevance: The findings of this cohort study suggest that a frailty index measured at 66 years of age was associated with accelerated acquisition of age-related conditions, disability, and death over the next 10 years. Measuring frailty at this age may offer opportunities to prevent age-related health decline.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2022.48995