Inclusion of endophenotypes in a standard GWAS facilitate a detailed mechanistic understanding of genetic elements that control blood lipid levels

Zhang, Qianqian; Cai, Zexi; Lhomme, Marie; Sahana, Goutam; Lesnik, Philippe; Guérin, Maryse; Fredholm, Merete; Karlskov-Mortensen, Peter

doi:10.1038/s41598-020-75612-6

Cited by 9 publications

(8 citation statements)

References 88 publications

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“…In this study a genome wide association study (GWAS) on ketosis resistance in Chinese Holstein cattle was performed, finding out that genes explaining largest variance portions were all involved in either insulin or lipid metabolism. Several other SNPs and genes mostly located on chromosomes 6, 14, and 20 were found to have a significant genetic association with milk BHB concentration in dairy cows [168].…”

Section: Genomic Information To Prevent Metabolic Dysfunctionsmentioning

confidence: 96%

The Transition Period Updated: A Review of the New Insights into the Adaptation of Dairy Cows to the New Lactation

Mezzetti

Cattaneo

Passamonti

et al. 2021

Dairy

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Recent research on the transition period (TP) of dairy cows has highlighted the pivotal role of immune function in affecting the severity of metabolic challenges the animals face when approaching calving. This suggests that the immune system may play a role in the etiology of metabolic diseases occurring in early lactation. Several studies have indicated that the roots of immune dysfunctions could sink way before the “classical” TP (e.g., 3 weeks before and 3 weeks after calving), extending the time frame deemed as “risky” for the development of early lactation disorders at the period around the dry-off. Several distressing events occurring during the TP (i.e., dietary changes, heat stress) can boost the severity of pre-existing immune dysfunctions and metabolic changes that physiologically affect this phase of the lactation cycle, further increasing the likelihood of developing diseases. Based on this background, several operational and nutritional strategies could be adopted to minimize the detrimental effects of immune dysfunctions on the adaptation of dairy cows to the new lactation. A suitable environment (i.e., optimal welfare) and a balanced diet (which guarantees optimal nutrient partitioning to improve immune functions in cow and calf) are key aspects to consider when aiming to minimize TP challenges at the herd level. Furthermore, several prognostic behavioral and physiological indicators could help in identifying subjects that are more likely to undergo a “bad transition”, allowing prompt intervention through specific modulatory treatments. Recent genomic advances in understanding the linkage between metabolic disorders and the genotype of dairy cows suggest that genetic breeding programs aimed at improving dairy cows’ adaptation to the new lactation challenges (i.e., through increasing immune system efficiency or resilience against metabolic disorders) could be expected in the future. Despite these encouraging steps forward in understanding the physiological mechanisms driving metabolic responses of dairy cows during their transition to calving, it is evident that these processes still require further investigation, and that the TP—likely extended from dry-off—continues to be “the final frontier” for research in dairy sciences.

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Section: Genomic Information To Prevent Metabolic Dysfunctionsmentioning

confidence: 96%

The Transition Period Updated: A Review of the New Insights into the Adaptation of Dairy Cows to the New Lactation

Mezzetti

Cattaneo

Passamonti

et al. 2021

Dairy

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“…Our findings in mice support future studies on the precise roles of torsinA and its activators in human lipid metabolism and conditions such as SLD. A study in pigs has tentatively linked serum TG concentrations to polymorphisms in the gene encoding LAP1 ( 29 ). An intronic variant in TOR1B encoding torsinB, a paralogue of torsinA, has been linked to SLD in humans ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of hepatic lipid metabolism by torsinA and its activators

Hernandez-Ono,

Zhao,

Murray

et al. 2024

JCI Insight

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Depletion of torsinA from hepatocytes leads to reduced liver triglyceride secretion and marked hepatic steatosis. TorsinA is an atypical ATPase that lacks intrinsic activity unless it is bound to its activator, lamina-associated polypeptide 1 (LAP1) or luminal domain–like LAP1 (LULL1). We previously demonstrated that depletion of LAP1 from hepatocytes has more modest effects on liver triglyceride secretion and steatosis development than depletion of torsinA. We now show that depletion of LULL1 alone does not significantly decrease triglyceride secretion or cause steatosis. However, simultaneous depletion of both LAP1 and LULL1 leads to defective triglyceride secretion and marked steatosis similar to that observed with depletion of torsinA. Depletion of both LAP1 and torsinA from hepatocytes generated phenotypes similar to those observed with only torsinA depletion, implying that the 2 proteins act in the same pathway in liver lipid metabolism. Our results demonstrate that torsinA and its activators dynamically regulate hepatic lipid metabolism.

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“…The pig GWAS data of 44 traits was described previously 76,77 (Supplementary Table 9). First, we filtered out all SNPs with minor allele frequency below 0.5%, with a large deviation from Hardy-Weinberg proportions (P< 1.0 −6 ), or with a R2 value of the imputation accuracy estimated by Minimac4 of less than 0.4.…”

Section: Gwas and Eqtl Signal Enrichment Of Chromatin Statementioning

confidence: 99%

Pig genome functional annotation enhances biological interpretations of complex traits and comparative epigenomics

Zhou

Pan

Yao

et al. 2021

Preprint

Self Cite

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The functional annotation of livestock genomes is crucial for understanding the molecular mechanisms that underpin complex traits of economic importance, adaptive evolution and comparative genomics. Here, we provide the most comprehensive catalogue to date of regulatory elements in the pig (Sus scrofa) by integrating 223 epigenomic and transcriptomic data sets, representing 14 biologically important tissues. We systematically describe the dynamic epigenetic landscape across tissues by functionally annotating 15 different chromatin states and defining their tissue-specific regulatory activities. We demonstrate that genomic variants associated with complex traits and adaptive evolution in pig are significantly enriched in active promoters and enhancers. Furthermore, we reveal distinct tissue-specific regulatory selection between Asian and European pig domestication processes. Compared with human and mouse epigenomes, we show that porcine regulatory elements are more conserved in DNA sequence, under both rapid and slow evolution, than those under neutral evolution across pig, mouse, and human. Finally, we provide novel biological insights on tissue-specific regulatory conservation and demonstrate that, depending on the traits, mouse or pig might be more appropriate biomedical models for different complex traits and diseases in humans through integrating comparative epigenomes with 47 human genome-wide association studies.

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Inclusion of endophenotypes in a standard GWAS facilitate a detailed mechanistic understanding of genetic elements that control blood lipid levels

Cited by 9 publications

References 88 publications

The Transition Period Updated: A Review of the New Insights into the Adaptation of Dairy Cows to the New Lactation

The Transition Period Updated: A Review of the New Insights into the Adaptation of Dairy Cows to the New Lactation

Dynamic regulation of hepatic lipid metabolism by torsinA and its activators

Pig genome functional annotation enhances biological interpretations of complex traits and comparative epigenomics

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