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

View ORCID ProfileMay E. Montasser, Stella Aslibekyan, Vinodh Srinivasasainagendra, Hemant K. Tiwari, Amit Patki, View ORCID ProfileMinoo Bagheri, View ORCID ProfileJames Perry, View ORCID ProfileKathleen A. Ryan, View ORCID ProfileDonna K. Arnett, View ORCID ProfileAmber L. Beitelshees, Marguerite Ryan Irvin, Jeffrey R O’connell
doi: https://doi.org/10.1101/2021.05.21.445208
May E. Montasser
1Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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  • For correspondence: mmontass@som.umaryland.edu
Stella Aslibekyan
2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Vinodh Srinivasasainagendra
2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Hemant K. Tiwari
2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Amit Patki
2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Minoo Bagheri
2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
3Department of Cardiovascular Medicine, Vanderbilt University Medical center, Nashville, TN, USA
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James Perry
1Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Kathleen A. Ryan
1Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Donna K. Arnett
4Department of Epidemiology, University of Kentucky, Lexington, KY, USA
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Amber L. Beitelshees
1Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Marguerite Ryan Irvin
2Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Jeffrey R O’connell
1Division of Endocrinology, Diabetes and Nutrition and Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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ABSTRACT

Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and new 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 novel biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a GWAS of 355 lipid species in 650 individuals from the Old Order Amish founder population including 127 lipid species not previously tested. 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 GLPTD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus on chromosome 2 and estriol with SLC22A8/A24 locus on chromosome 11. Our results show the power of founder populations to discover novel biology due to genetic drift that can increase an allele found in only a few subjects in even large samples such as UKBiobank to dozens in even samples as small as 650.

Competing Interest Statement

MEM reports funding from Regeneron Pharmaceutical unrelated to this work SA reports employment and equity in 23andMe, Inc. No competing interests for all other authors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 23, 2021.
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Leveraging a founder population to identify novel rare-population genetic determinants of lipidome
May E. Montasser, Stella Aslibekyan, Vinodh Srinivasasainagendra, Hemant K. Tiwari, Amit Patki, Minoo Bagheri, James Perry, Kathleen A. Ryan, Donna K. Arnett, Amber L. Beitelshees, Marguerite Ryan Irvin, Jeffrey R O’connell
bioRxiv 2021.05.21.445208; doi: https://doi.org/10.1101/2021.05.21.445208
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Leveraging a founder population to identify novel rare-population genetic determinants of lipidome
May E. Montasser, Stella Aslibekyan, Vinodh Srinivasasainagendra, Hemant K. Tiwari, Amit Patki, Minoo Bagheri, James Perry, Kathleen A. Ryan, Donna K. Arnett, Amber L. Beitelshees, Marguerite Ryan Irvin, Jeffrey R O’connell
bioRxiv 2021.05.21.445208; doi: https://doi.org/10.1101/2021.05.21.445208

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