Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

Montasser, May E.; Aslibekyan, Stella; Srinivasasainagendra, Vinodh; Tiwari, Hemant K.; Patki, Amit; Bagheri, Minoo; Perry, James A.; Ryan, Kathleen A.; Arnett, Donna K.; Beitelshees, Amber L.; Irvin, Marguerite R.; O’Connell, Jeffrey R.

doi:10.1101/2021.05.21.445208

Cited by 2 publications

(2 citation statements)

References 74 publications

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“…Akna, an AT-hook transcription factor (35), promotes Cd40 expression (36), indicating a role in inflammatory processes. In human genetic association studies, AKNA variants have been linked to total cholesterol (37), HDL cholesterol and ApoA1 (38), and plasma sphingolipids (39). However, no studies have mechanistically linked Akna to cholesterol or lipoprotein metabolism.…”

Section: Integration Of Mouse Lipoprotein Qtl With Human Gwasmentioning

confidence: 99%

Identification of genetic drivers of plasma lipoproteins in the Diversity Outbred mouse population

Price,

Emfinger,

Schueler

et al. 2023

Preprint

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Despite great progress in understanding lipoprotein physiology, there is still much to be learned about the genetic drivers of lipoprotein abundance, composition, and function. We used ion mobility spectrometry to survey 16 plasma lipoprotein subfractions in 500 Diversity Outbred (DO) mice maintained on a Western-style diet. We identified 21 quantitative trait loci (QTL) affecting lipoprotein abundance. To refine the QTL and link them to disease risk in humans, we asked if the human homologues of genes located at each QTL were associated with lipid traits in human genome-wide association studies (GWAS). Integration of mouse QTL with human GWAS yielded candidate gene drivers for 18 of the 21 QTL. This approach enabled us to nominate the gene encoding the neutral ceramidase,Asah2, as a novel candidate driver at a QTL on chromosome 19 for large HDL particles (HDL-2b). To experimentally validateAsah2, we surveyed lipoproteins inAsah2-/-mice. Compared to wild-type mice, femaleAsah2-/-mice showed an increase in several lipoproteins, including HDL. Our results provide insights into the genetic regulation of circulating lipoproteins, as well as mechanisms by which lipoprotein subfractions may affect cardiovascular disease risk in humans.

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Section: Integration Of Mouse Lipoprotein Qtl With Human Gwasmentioning

confidence: 99%

Identification of genetic drivers of plasma lipoproteins in the Diversity Outbred mouse population

Price,

Emfinger,

Schueler

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Genome-wide genotyping was performed with the Affymetrix GeneChip Mapping 500 K Assay at the University of Maryland Biopolymer Core Facility. QC has been described, resulting in the inclusion of 307,238 genotyped variants for imputation [42]. The genotype data were uploaded to the Michigan Imputation Server [43] where the pre-phasing was performed using Eagle v2.4 [44], and then imputation to the TOPMed Freeze 5b reference panel was performed using Minimac4 [45].…”

Section: Replication Populationmentioning

confidence: 99%

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study

et al. 2021

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Postprandial lipemia (PPL) is an important risk factor for cardiovascular disease. Inter-individual variation in the dietary response to a meal is known to be influenced by genetic factors, yet genes that dictate variation in postprandial lipids are not completely characterized. Genetic studies of the plasma lipidome can help to better understand postprandial metabolism by isolating lipid molecular species which are more closely related to the genome. We measured the plasma lipidome at fasting and 6 h after a standardized high-fat meal in 668 participants from the Genetics of Lipid-Lowering Drugs and Diet Network study (GOLDN) using ultra-performance liquid chromatography coupled to (quadrupole) time-of-flight mass spectrometry. A total of 413 unique lipids were identified. Heritable and responsive lipid species were examined for association with single-nucleotide polymorphisms (SNPs) genotyped on the Affymetrix 6.0 array. The most statistically significant SNP findings were replicated in the Amish Heredity and Phenotype Intervention (HAPI) Heart Study. We further followed up findings from GOLDN with a regional analysis of cytosine-phosphate-guanine (CpGs) sites measured on the Illumina HumanMethylation450 array. A total of 132 lipids were both responsive to the meal challenge and heritable in the GOLDN study. After correction for multiple testing of 132 lipids (α = 5 × 10−8/132 = 4 × 10−10), no SNP was statistically significantly associated with any lipid response. Four SNPs in the region of a known lipid locus (fatty acid desaturase 1 and 2/FADS1 and FADS2) on chromosome 11 had p < 8.0 × 10−7 for arachidonic acid FA(20:4). Those SNPs replicated in HAPI Heart with p < 3.3 × 10−3. CpGs around the FADS1/2 region were associated with arachidonic acid and the relationship of one SNP was partially mediated by a CpG (p = 0.005). Both SNPs and CpGs from the fatty acid desaturase region on chromosome 11 contribute jointly and independently to the diet response to a high-fat meal.

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Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

Cited by 2 publications

References 74 publications

Identification of genetic drivers of plasma lipoproteins in the Diversity Outbred mouse population

Identification of genetic drivers of plasma lipoproteins in the Diversity Outbred mouse population

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study

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