Heritability of 596 lipid species and genetic correlation with cardiovascular traits in the Busselton Family Heart Study

Abstract

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 genome-wide SNP and whole-genome sequencing data. 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 genome-wide SNP and whole-genome sequencing data. CVD is the leading cause of death globally, accounting for approximately 31% of all deaths in 2015 (1Roth G.A. Johnson C. Abajobir A. Abd-Allah F. Abera S.F. Abyu G. Ahmed M. Aksut B. Alam T. Alam K. et al.Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015.J. Am. Coll. Cardiol. 2017; 70: 1-25Crossref PubMed Scopus (1674) Google Scholar). Cardiometabolic traits associated with CVD include the standard lipid profile (“clinical lipids”), such as elevated LDL-C and triglycerides, and lowered HDL-C, and other factors such as elevated BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP) (2Ford E.S. Li C. Zhao G. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US.J. Diabetes. 2010; 2: 180-193Crossref PubMed Scopus (313) Google Scholar). These traits are heritable, with the heritability of each trait dependent on the study type and sample used to measure heritability (3Elks C.E. den Hoed M. Zhao J.H. Sharp S.J. Wareham N.J. Loos R.J.F. Ong K.K. Variability in the heritability of body mass index: a systematic review and meta-regression.Front. Endocrinol. (Lausanne). 2012; 3: 29Crossref PubMed Scopus (322) Google Scholar). Typical reported heritabilities for clinical lipid traits are in the range of 0.30 to 0.70 (4Pilia G. Chen W-M. Scuteri A. Orrú M. Albai G. Dei M. Lai S. Usala G. Lai M. Loi P. et al.Heritability of cardiovascular and personality traits in 6,148 Sardinians.PLoS Genet. 2006; 2: e132Crossref PubMed Scopus (361) Google Scholar, 5Benyamin B. Sorensen T.I. Schousboe K. Fenger M. Visscher P.M. Kyvik K.O. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?.Diabetologia. 2007; 50: 1880-1888Crossref PubMed Scopus (91) Google Scholar, 6Elder S.J. Lichtenstein A.H. Pittas A.G. Roberts S.B. Fuss P.J. Greenberg A.S. McCrory M.A. Bouchard Jr., T.J. Saltzman E. Neale M.C. Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome.J. Lipid Res. 2009; 50: 1917-1926Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 7Vattikuti S. Guo J. Chow C.C. Heritability and genetic correlations explained by common SNPs for metabolic syndrome traits.PLoS Genet. 2012; 8: e1002637Crossref PubMed Scopus (152) Google Scholar, 8van Dongen J. Willemsen G. Chen W.M. de Geus E.J. Boomsma D.I. Heritability of metabolic syndrome traits in a large population-based sample.J. Lipid Res. 2013; 54: 2914-2923Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 9Zaitlen N. Kraft P. Patterson N. Pasaniuc B. Bhatia G. Pollack S. Price A.L. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits.PLoS Genet. 2013; 9: e1003520Crossref PubMed Scopus (220) Google Scholar), while blood pressure and obesity-related traits tend to vary between 0.20 and 0.50 (4Pilia G. Chen W-M. Scuteri A. Orrú M. Albai G. Dei M. Lai S. Usala G. Lai M. Loi P. et al.Heritability of cardiovascular and personality traits in 6,148 Sardinians.PLoS Genet. 2006; 2: e132Crossref PubMed Scopus (361) Google Scholar, 5Benyamin B. Sorensen T.I. Schousboe K. Fenger M. Visscher P.M. Kyvik K.O. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?.Diabetologia. 2007; 50: 1880-1888Crossref PubMed Scopus (91) Google Scholar, 6Elder S.J. Lichtenstein A.H. Pittas A.G. Roberts S.B. Fuss P.J. Greenberg A.S. McCrory M.A. Bouchard Jr., T.J. Saltzman E. Neale M.C. Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome.J. Lipid Res. 2009; 50: 1917-1926Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 7Vattikuti S. Guo J. Chow C.C. Heritability and genetic correlations explained by common SNPs for metabolic syndrome traits.PLoS Genet. 2012; 8: e1002637Crossref PubMed Scopus (152) Google Scholar, 8van Dongen J. Willemsen G. Chen W.M. de Geus E.J. Boomsma D.I. Heritability of metabolic syndrome traits in a large population-based sample.J. Lipid Res. 2013; 54: 2914-2923Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 10van Rijn M.J. Schut A.F. Aulchenko Y.S. Deinum J. Sayed-Tabatabaei F.A. Yazdanpanah M. Isaacs A. Axenovich T.I. Zorkoltseva I.V. Zillikens M.C. et al.Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes.J. Hypertens. 2007; 25: 565-570Crossref PubMed Scopus (72) Google Scholar). Clinical lipid measures such as total cholesterol, LDL-C, and HDL-C reflect the cholesterol component of the lipoprotein particles, which are complex mixtures of phospholipids, sphingolipids, free cholesterol, cholesteryl esters, and triglycerides (referred to as triacylglycerol (TG) species in the mass spectrometric measurements), together with a range of proteins (11Mundra P.A. Shaw J.E. Meikle P.J. Lipidomic analyses in epidemiology.Int. J. Epidemiol. 2016; 45: 1329-1338Crossref PubMed Scopus (16) Google Scholar). These lipid classes contain potentially thousands of individual molecular species that make up the human lipidome, which can now be measured using established low-cost high-throughput methods (12Weir J.M. Wong G. Barlow C.K. Greeve M.A. Kowalczyk A. Almasy L. Comuzzie A.G. Mahaney M.C. Jowett J.B. Shaw J. et al.Plasma lipid profiling in a large population-based cohort.J. Lipid Res. 2013; 54: 2898-2908Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar). Lipids are transported through plasma as lipoproteins for exchange between the liver, intestine, and peripheral tissues. Their composition and abundance are likely to reflect underlying metabolic processes influenced by the environment, diet, and genetics (11Mundra P.A. Shaw J.E. Meikle P.J. Lipidomic analyses in epidemiology.Int. J. Epidemiol. 2016; 45: 1329-1338Crossref PubMed Scopus (16) Google Scholar). The individual species comprising the lipidome may represent novel predictors of CVD risk, particularly if measured in longitudinal cohort studies where causality may potentially be inferred (11Mundra P.A. Shaw J.E. Meikle P.J. Lipidomic analyses in epidemiology.Int. J. Epidemiol. 2016; 45: 1329-1338Crossref PubMed Scopus (16) Google Scholar, 13Alshehry Z.H. Mundra P.A. Barlow C.K. Mellette N.A. Wong G. McConville M.J. Simes J. Tonkin A.M. Sullivan D.R. Barnes E.H. et al.Plasma lipidomic profiles improve on traditional risk factors for the prediction of cardiovascular events in type 2 diabetes mellitus.Circulation. 2016; 134: 1637-1650Crossref PubMed Scopus (118) Google Scholar). Owing to their close proximity to an individual's metabolic state, genetic investigations into these lipid species may provide insight into CVD risk and prediction, that through the genetic of the clinical lipid This is particularly the for lipid species that are with as the for can be to the species that are heritable and between the circulating lipidome and CVD traits insight into CVD and novel Meikle et P.J. Wong G. Barlow C.K. J.M. M.J. B. L. Kowalczyk A. et al.Plasma lipidomic of and PubMed Scopus Google lipid classes and lipids associated with disease with a lipid and lipid species from the and and lipid species from plasma were associated with with P.J. N.A. C. M. A.L. et phospholipids, cholesterol syndrome from Am. Heart 8: PubMed Scopus (16) Google Scholar). the and cardiovascular events were associated with lipid species to the and lipid classes C. M. P. K. M. T. B. K. A. et al.Plasma lipid composition and risk of cardiovascular 2013; 8: PubMed Scopus Google Scholar). et A. S. J. A. A. M. et profiling novel for Genet. PubMed Scopus Google significant between disease and of which were associated in an for traditional CVD risk the of lipid species to a CVD events for CVD events from to and CVD deaths from to Z.H. Mundra P.A. Barlow C.K. Mellette N.A. Wong G. McConville M.J. Simes J. Tonkin A.M. Sullivan D.R. Barnes E.H. et al.Plasma lipidomic profiles improve on traditional risk factors for the prediction of cardiovascular events in type 2 diabetes mellitus.Circulation. 2016; 134: 1637-1650Crossref PubMed Scopus (118) Google Scholar). were in a study of from a population-based with the of lipid species in a traditional risk the by and for CVD events and CVD P.A. Barlow C.K. P.J. Barnes E.H. A. P. Sullivan D.R. Z.H. N.A. K. et plasma lipidomic profiling lipids that cardiovascular events in 3: PubMed Scopus Google Scholar). studies estimated the heritability of the lipidome and genetic correlation with CVD traits. a study of from the Family Heart Study C. M. Jr., Wong G. J.M. Barlow C.K. M. et plasma lipidome is associated with cardiovascular risk factors and Genet. PubMed Scopus Google Scholar), all lipid species were significantly heritable, with a median heritability of This study lipid species associated with risk of cardiovascular and other risk such as type 2 and a study of et P. M. J. P. S. J. et of human plasma lipidome and to cardiovascular PubMed Scopus Google estimated heritabilities of lipid species between and genetic correlations were observed between and diacylglycerol lipid classes and the clinical lipid measure of triglycerides = 0.88). et A. J. M. J. A. A. N. et study of plasma the genetic correlation between lipid species from and classes and genetic correlations between lipid species and clinical lipids triglycerides, LDL-C, total body and These studies that the human lipidome is heritable and the genetic that between the plasma lipidome and CVD traits. 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Meikle P.J. plasma of the with risk Full Text Full Text PDF PubMed Scopus (90) Google Scholar). was performed the Heart and lipids were using a Z.H. Barlow C.K. J.M. McConville M.J. Meikle P.J. for the of plasma PubMed Scopus Google and by mass as K. Barlow C.K. J.M. N.A. M. Shaw J.E. Meikle P.J. plasma of the with risk Full Text Full Text PDF PubMed Scopus (90) Google Scholar). were into a with and and 10 were in a with the of of a of lipid between 10 and Lipid was performed by mass using an to an mass The was in positive with pressure 10 was performed on a of 10 The was to and the to Lipid were and using a of and the The and of each were to total of 596 lipid were measured using multiple where were a to each lipid mass were using Lipid were by the the for each lipid species to the factors were to for in where these were K. Barlow C.K. J.M. N.A. M. Shaw J.E. Meikle P.J. plasma of the with risk Full Text Full Text PDF PubMed Scopus (90) Google Scholar). of the Busselton Study J. of the metabolic syndrome and components in the prediction of cardiovascular a cohort J. 2009; PubMed Scopus Google Scholar). this eight CVD HDL-C, LDL-C, triglycerides, total cholesterol, BMI, and waist-hip cholesterol and triglycerides were by standard methods on a from blood in HDL-C was on a after using an cholesterol and LDL-C was estimated using the of the of lipoprotein cholesterol in of the PubMed Scopus Google Scholar). and were and to were from participants the of was as of and was was performed on the the de in = and on the the = based on by in S. Neale B. K. L. J. P. de M.J. et a for whole-genome and population-based J. Genet. 2007; Full Text Full Text PDF PubMed Scopus Google the were was performed in G. M. S. J.E. J. J. et of syndrome with obesity-related traits using from the Busselton Genet. 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This is the largest lipidomic study to address the heritability of The of lipidomic profiling the to heritability the lipid to the fatty composition heritability and genetic correlations with CVD risk These an as to the between genetic and environmental risk with of which are through lipid this report that the human lipidome lipid species and lipid is significantly report the heritabilities for the largest of lipid species to species from 33 lipid in the largest sample of = to lipid classes and lipid species with CVD traits. studies CVD traits are The range of lipid species heritabilities (h2: 0.06–0.50) observed in this study for lipid species and classes was to that of studies with from to C. M. Jr., Wong G. J.M. Barlow C.K. M. et plasma lipidome is associated with cardiovascular risk factors and Genet. PubMed Scopus Google Scholar, P. M. J. P. S. J. et of human plasma lipidome and to cardiovascular PubMed Scopus Google Scholar). This and the of genetic on lipid species the of environmental positive genetic correlations between the clinical measure of triglycerides and the mass spectrometric measure of and lipid classes were to P. M. J. P. S. J. et of human plasma lipidome and to cardiovascular PubMed Scopus Google Scholar, A. J. M. J. A. A. N. et study of plasma Scholar). observed a novel positive genetic correlation between the clinical lipid triglycerides and phosphatidylglycerol species (rg: novel positive genetic correlation was observed between HDL-C and species the HDL-C positive correlations with lipid classes Genetic correlations between the species and HDL-C were with the the median genetic correlation with HDL-C the was with in the and in the the median genetic correlation with HDL-C the was with in the and in the We observed in genetic correlations between lipids in the and the median genetic correlation between LDL-C and lipid species in the was with in the the significant genetic correlations were of significant genetic correlations between lipids in the and triglycerides were while of significant genetic correlations between lipids and triglycerides were This is as these lipid classes are in that contain a the that contain and the contain species of and that these species may the positive with genetic correlations between the human lipidome and lipid may be genetic correlations between lipid classes and individual lipid species and measures of and and blood study of participants from population-based plasma lipids and to significant genetic correlations between blood pressure with A. J. M. J. A. A. N. et study of plasma Scholar). the lipid species the and classes the genetic correlations with and with species from and classes with in an study A. J. M. J. A. A. N. et study of plasma Scholar). with the the lipidomic in the study of individual lipid is to be methods used in the study G. G. S. Neale A. P.A. P. B. et of genetic correlation and J. Genet. Full Text Full Text PDF PubMed Scopus Google Scholar). species classes of genetic correlations with and all significant genetic correlations between species and and were while all significant genetic correlations between AC species were in the study lipid species the and classes were with while were with lipid species was with and with BMI, These are as that lipid lipid species are and may with and These genetic correlations between lipid species and CVD traits there are potentially that lipid species and CVD traits. studies CVD traits are heritable with heritability (h2: to in a sample of the Busselton Family Heart Study G. M. S. J.E. J. J. et of syndrome with obesity-related traits using from the Busselton Genet. PubMed Scopus Google and in studies of CVD traits (4Pilia G. Chen W-M. Scuteri A. Orrú M. Albai G. Dei M. Lai S. Usala G. Lai M. Loi P. et al.Heritability of cardiovascular and personality traits in 6,148 Sardinians.PLoS Genet. 2006; 2: e132Crossref PubMed Scopus (361) Google Scholar, 5Benyamin B. Sorensen T.I. Schousboe K. Fenger M. Visscher P.M. Kyvik K.O. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?.Diabetologia. 2007; 50: 1880-1888Crossref PubMed Scopus (91) Google Scholar, 6Elder S.J. Lichtenstein A.H. Pittas A.G. Roberts S.B. Fuss P.J. Greenberg A.S. McCrory M.A. Bouchard Jr., T.J. Saltzman E. Neale M.C. Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome.J. Lipid Res. 2009; 50: 1917-1926Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 7Vattikuti S. Guo J. Chow C.C. Heritability and genetic correlations explained by common SNPs for metabolic syndrome traits.PLoS Genet. 2012; 8: e1002637Crossref PubMed Scopus (152) Google Scholar, 8van Dongen J. Willemsen G. Chen W.M. de Geus E.J. Boomsma D.I. Heritability of metabolic syndrome traits in a large population-based sample.J. Lipid Res. 2013; 54: 2914-2923Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 9Zaitlen N. Kraft P. Patterson N. Pasaniuc B. Bhatia G. Pollack S. Price A.L. Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits.PLoS Genet. 2013; 9: e1003520Crossref PubMed Scopus (220) Google Scholar, 10van Rijn M.J. Schut A.F. Aulchenko Y.S. Deinum J. Sayed-Tabatabaei F.A. Yazdanpanah M. Isaacs A. Axenovich T.I. Zorkoltseva I.V. Zillikens M.C. et al.Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes.J. Hypertens. 2007; 25: 565-570Crossref PubMed Scopus (72) Google Scholar). are in study cohort with and these may be to other the heritability observed in this study are to an study of C. M. Jr., Wong G. J.M. Barlow C.K. M. et plasma lipidome is associated with cardiovascular risk factors and Genet. PubMed Scopus Google Scholar). lipid measures used this study were measured and the lipid represent a in and as such may be influenced by environmental factors that may such as diet, and other that were to into S.J. lipid and PubMed Scopus Google Scholar). lipid measures may in these are for this were the and the of lipid to be to reported M. K. K. and of molecular lipidomic of human plasma 2013; PubMed Scopus Google Scholar, M. C. S. C. G. J. of human plasma Res. PubMed Scopus Google Scholar). as were the be between the and likely on while the of associated with the human lipidome and CVD genetic variants which is a in to the genetic between the human lipidome and CVD traits. This be the of that the human lipidome is heritable and with CVD traits. We novel lipid endophenotypes that are with CVD traits to their genetic genetic of these lipidome endophenotypes may to causal genetic variants for Future work the of genome-wide SNP and whole-genome in this The the Busselton with and the study participants from the of with acylcarnitine disease diastolic blood pressure diacylglycerol genetic monohexosylceramide oxidized cholesteryl alkenylphosphatidylcholine phosphatidylglycerol systolic blood pressure triacylglycerol waist-hip

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