Systems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species

Jha, Pooja; McDevitt, Molly T.; Gupta, Rahul; Quirós, Pedro M.; Williams, Evan G.; Gariani, Karim; Sleiman, Maroun Bou; Diserens, Leo; Jochem, Adam; Ulbrich, Arne; Coon, Joshua J.; Auwerx, Johan; Pagliarini, David J.

doi:10.1016/j.cels.2018.05.016

Cited by 59 publications

(53 citation statements)

References 36 publications

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“…Since plasma lipids associated with metabolic traits, we next tested this finding in the context of a disease. Taking advantage of the liver lipid species measured from the same cohort of mice from our companion article in this issue ( Jha et al, 2018 ), we tested whether plasma lipid species can be indicative of NAFLD, characterized by excess TAG accumulation in liver ( Kleiner et al, 2005 ). Both in humans and different mouse strains, plasma and liver TAG levels are highly variable and are not always increased in NAFLD or by HFD, indicating a complex polygenic regulation ( Browning et al, 2004 ; Johansen et al, 2011 ; Kirk et al, 1995 ; Lin et al, 2005 ; Romeo et al, 2008 ).…”

Section: Resultsmentioning

confidence: 99%

Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes

et al. 2018

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The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for ∼94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits.

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Section: Resultsmentioning

confidence: 99%

Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes

et al. 2018

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“…With the development of high-throughput molecular technologies, the collection of omics data has become routine, especially in systems genetics studies using mouse genetic populations. Contributed by research groups around the world, large-scale omics data have been collected, ranging from epigenomics [76,77], transcriptomics (data from the BXD and HMDP cohorts were partially summarized in [25,75]), proteomics [33,38,78], lipidomics [79][80][81], metabolomics [38,82], microbiome [83][84][85], as well as phenomics [25,26]. Mouse systems genetics studies often are unbiased towards the gene targets, therefore data from such studies can be reused to analyze any gene of interest for different research groups.…”

Section: Panels and Resources In Mouse Systems Geneticsmentioning

confidence: 99%

Mouse Systems Genetics as a Prelude to Precision Medicine

Auwerx

2020

Trends in Genetics

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Mouse models have been instrumental in understanding human disease biology and proposing possible new treatments. The precise control of the environment and genetic composition of mice allows more rigorous observations, but limits the generalizability and translatability of the results into human applications. In the era of precision medicine, strategies using mouse models have to be revisited to effectively emulate human populations. Systems genetics is one promising paradigm that may promote the transition to novel precision medicine strategies. Here, we review the state-of-the-art resources and discuss how mouse systems genetics helps to understand human diseases and to advance the development of precision medicine, with an emphasis on the existing resources and strategies. Promises and Problems with Precision Medicine Most complex traits and diseases, such as height, longevity, and diabetes, are heritable and influenced by various genetic factors [1], while being modulated by environmental stimuli. Due every individual's unique genetic makeup, response to drugs [2], nutrition [3], and lifestyle [4] vary considerably from person to person. This uniqueness of every human being underpins the purpose of precision medicine, which posits that disease prediction, diagnosis, and treatment for each individual is based on personal genomic variations and external environments [5]. Precision medicine is an innovative approach that takes the variability in genetics, environment, and lifestyle of each individual into account in disease prevention and treatment, and provides better prediction of effective treatments, while concurrently minimizing the possibility of drug side effects [6]. Therefore, precision medicine requires a good understanding of the genetic bases of variation in phenotypes and their interaction with the environment in health and disease. Highlights The mouse is the premier model organism for human biomedical research. So far, most of the research studies involving mouse models rely on a single or few genetic backgrounds and controlled external factors that limit the generalizability of the results. Systems genetics improves the translational potential of mouse studies in human. Systems genetics approaches in mouse panels could serve as the prototype and provide valuable insights for human precision medicine.

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“…Importantly, genetic mechanisms seem not to regulate all lipid species in a lipid class in the same way, as also observed in recent mice lipidomics studies. 41,42 Longer and more unsaturated lipid species from different lipid classes clearly display a greater genetic sharing. These observations are consistent with a previous study based on family pedigree.…”

Section: Discussionmentioning

confidence: 99%

Genetics of human plasma lipidome: Understanding lipid metabolism and its link to diseases beyond traditional lipids

Tabassum

Rämö

Ripatti

et al. 2018

Preprint

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Aim: Genetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures. Methods and Results: We performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical endpoints related to cardiometabolic, psychiatric and gastrointestinal disorders (n=456,941 individuals). SNP-based heritability for lipid species ranged from 0.10-0.54. Lipids with long-chain polyunsaturated fatty acids showed higher heritability and genetic sharing, suggesting considerable genetic regulation at acyl chains levels. We identified 35 genomic regions associated with at least one lipid species (P<5x10 -8 ), revealing 37 new SNP-lipid species pair associations e.g. new association between ABCG5/8 and CE(20:2;0). PheWAS of lipid-species-associated loci suggested new associations of BLK with obesity, FADS2 with thrombophlebitis, and BLK and SPTLC3 with gallbladder disease (false discovery rate <0.05). The association patterns of lipid-species-associated loci supplied clues to their probable roles in lipid metabolism e.g. suggestive role of SYNGR1, MIR100HG, and PTPRN2 in desaturation and/or elongation of fatty acids. At known lipid loci (FADS2, APOA5 and LPL), genetic associations provided detailed insights to their roles in lipid biology and diseases. We also show that traditional lipid measures may fail to capture lipids such as lysophospatidylcholines (LPCs) and phosphatidylcholines (PCs) that are potential disease risk factors, but are not included in routine screens. The full genome-wide association statistics are available on the web-based database (http://35.205.141.92). Conclusion:Our study reveals genetic regulation of plasma lipidome and highlights the potential of lipidomic profiling in disease gene mapping.

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Systems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species

Cited by 59 publications

References 36 publications

Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes

Genetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes

Mouse Systems Genetics as a Prelude to Precision Medicine

Genetics of human plasma lipidome: Understanding lipid metabolism and its link to diseases beyond traditional lipids

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