Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and additional insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of previously unknown biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a genome-wide association scan of 355 lipid species in 650 individuals from the Amish founder population including 127 lipid species not previously tested. To the best of our knowledge, we report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLTPD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus and estriol with SLC22A8/A24 locus. Our results show the double power of founder populations and detailed lipidome to discover novel trait-associated variants.
|State||Published - Dec 2022|
Bibliographical noteFunding Information:
We gratefully thank the Amish community, the Amish Research Clinic staff and liaisons, and the participants of the GOLDN study. We also thank Simeon I. Taylor for insightful suggestions, comments and discussions. The HAPI Heart study was supported by U01HL072515. The analysis methods and software were supported by U01HL084756 and U01HL137181. The GOLDN study was supported by the NHLBI grant U01HL072524–04 and R01HL091357.
Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Genetics of Lipid Lowering Drugs and Diet Network” (phs001359) was performed at the North West Genomics Center, University of Washington. Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center. Data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center. Library preparation and whole-genome sequencing were performed on 967 GOLDN samples by North West Genomics Center, University of Washington. The NHLBI Informatics Resource Core at the University of Michigan performed alignment, base calling, and sequence quality scoring and variant calling of all TOPMed samples using the GotCloud pipeline. Variant calling used a support vector machine (SVM) trained using known variants. Variants passing all quality filters with read depth at least 10 were delivered in BCF format and used for association analysis. Further variant QC included removing all sites in low-complexity regions, and on the X chromosome. There were 835 GOLDN samples with both lipidome and WGS data and used for the GWAS.
© 2022, The Author(s).
ASJC Scopus subject areas
- Medicine (miscellaneous)
- Biochemistry, Genetics and Molecular Biology (all)
- Agricultural and Biological Sciences (all)