TY - JOUR
T1 - Heritability of 596 lipid species and genetic correlation with cardiovascular traits in the Busselton Family Heart Study
AU - Cadby, Gemma
AU - Melton, Phillip E.
AU - McCarthy, Nina S.
AU - Giles, Corey
AU - Mellett, Natalie A.
AU - Huynh, Kevin
AU - Hung, Joseph
AU - Beilby, John
AU - Dubé, Marie Pierre
AU - Watts, Gerald F.
AU - Blangero, John
AU - Meikle, Peter J.
AU - Moses, Eric K.
N1 - Funding Information:
This research was supported by the National Health and Medical Research Council of Australia (Project Grant APP1101320; P.J.M. was the recipient of Senior Research Fellowship APP1042095). This work was also supported in part by the Victorian Government’s Operational Infrastructure Support Program. The authors acknowledge the generous support for the 1994/1995 Busselton Health Study follow-up from Healthway, Western Australia, and The Great Wine Estates of the Margaret River region of Western Australia. Support from the Royal Perth Hospital Medical Research Foundation is also gratefully acknowledged. M-P.D. is an author on a patent pertaining to pharmacogenomics-guided CETP inhibition and has a minor equity interest in DalCor. All other authors declare that they have no conflicts of interest with the contents of this article. Manuscript received 20 December 2019 and in revised form 12 February 2020. Published, JLR Papers in Press, February 14, 2020 DOI https://doi.org/10.1194/jlr.RA119000594
Publisher Copyright:
© 2020 Cadby et al.
PY - 2020/4
Y1 - 2020/4
N2 - CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2: 0.06-0.50) and all lipid classes were significantly heritable (h2: 0.14-0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2 = 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg = 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64-0.82), and HDL-C and alkenylphosphatidylcholine species (rg: 0.45-0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genomewide SNP and whole-genome sequencing data.
AB - CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2: 0.06-0.50) and all lipid classes were significantly heritable (h2: 0.14-0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2 = 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg = 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64-0.82), and HDL-C and alkenylphosphatidylcholine species (rg: 0.45-0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genomewide SNP and whole-genome sequencing data.
KW - Cardiovascular disease
KW - Lipidomics
KW - Lipids
UR - http://www.scopus.com/inward/record.url?scp=85082978933&partnerID=8YFLogxK
U2 - 10.1194/jlr.RA119000594
DO - 10.1194/jlr.RA119000594
M3 - Article
C2 - 32060071
AN - SCOPUS:85082978933
SN - 0022-2275
VL - 61
SP - 537
EP - 545
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 4
ER -
