An Amish founder population reveals rare-population genetic determinants of the human lipidome

Figures

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  Fig. 1. Heritability of the lipid species. a Histogram showing the heritability distribution for all lipid species. b Box plot for the heritability by class. Heritabilities presented as unadjusted and adjusted for 4 Amish-enriched lipid variants (APOB_rs574290415, APOC3_rs7635320314, B4GALT1_rs55156468321, TIMD4_rs89895600320). The upper, center, and lower line of the boxplot indicates third quartile (Q3), median, first quartile (Q1), respectively. The upper and lower whisker of the boxplot indicates Q3 + 1.5 * interquartile range (IQR) and Q1 − 1.5 * IQR. Outliers are suppressed from the plot for readability. ACT Acylcarnitine, CE Cholesteryl ester, Cer Ceramide, DAG Diglycerides, FA Fatty acids, GlcCer Glycosphingolipids, LPC Lysophosphatidylcholines, LPE Lysophosphatidylethanolamines, PC Phosphatidylcholines, PE Phosphatidylethanolamine, PI Phosphatidylinositol, SM Sphingomyelin, TAG Triglycerides, ST Sterols, TRAD Traditional lipids.

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  Fig. 2. Contribution of previously identified lipid GWAS variants to lpidomics variance. Heritability estimates using adjusted kinship separately (Adjusted for 4 Amish-enriched lipid variants (APOB_rs574290415, APOC3_rs7635320314, B4GALT1_rs55156468321, TIMD4_rs89895600320) and then jointly with a SNP GRM for each traditional lipid. Analysis restricted to 194 lipid species with baseline significant heritability (Kinship + 4 V heritability p-value < 0.01). The upper, center, and lower line of the boxplot indicates third quartile (Q3), median, first quartile (Q1), respectively. The upper and lower whisker of the boxplot indicates Q3 + 1.5 * interquartile range (IQR) and Q1 − 1.5 * IQR. Outliers are suppressed from the plot for readability. ACT Acylcarnitine, CE Cholesteryl ester, Cer Ceramide, DAG Diglycerides, FA Fatty acids, GlcCer Glycosphingolipids, LPC Lysophosphatidylcholines, LPE Lysophosphatidylethanolamines, PC Phosphatidylcholines, PE Phosphatidylethanolamine, PI Phosphatidylinositol, SM Sphingomyelin, TAG Triglycerides, ST Sterols.

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  Fig. 3. Lipidomic association results. a Manhattan plot for the association results of all 355 lipid species in 639 Amish subjects. Amish-enriched loci denoted in red, previously known signals denoted in blue and previously known signals with novel trait association and/or novel variant in known loci in green. Blue line marks a genome-wide suggestive threshold (5.0E-08) and red line marks a genome-wide significant threshold (4.5E-10). b GWAS results for all significantly associated lipid species in Amish-enriched loci. c GWAS results for all significantly associated lipid species in previously known loci. All p-values based on t-test using additive genetic model. CE Cholesteryl ester, Cer Ceramide, GlcCer Glycosphingolipids, PC Phosphatidylcholines, PE Phosphatidylethanolamine, SM Sphingomyelin.

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  Fig. 4. Rare-population but Amish-enriched loci. Locus zoom for 5 loci in a, chromosome 2 with SM(d34:1) b, chromosome 9 with GlcCer(d42:2) c, chromosome 11 with PE(36:2) d, chromosome 12 with SM(d32:2) and e, chromosome 17 with SM(d40:0). All p-values based on t-test using additive genetic model. GlcCer Glycosphingolipids, PE Phosphatidylethanolamine, SM Sphingomyelin.