Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci

• Published in: BMC medicine Vol. 19; no. 1; pp. 232 - 17
• Main Authors: Harshfield, Eric L, Fauman, Eric B, Stacey, David, Paul, Dirk S, Ziemek, Daniel, Ong, Rachel M Y, Danesh, John, Butterworth, Adam S, Rasheed, Asif, Sattar, Taniya, Zameer-Ul-Asar, Saleem, Imran, Hina, Zoubia, Ishtiaq, Unzila, Qamar, Nadeem, Mallick, Nadeem Hayat, Yaqub, Zia, Saghir, Tahir, Rizvi, Syed Nadeem Hasan, Memon, Anis, Ishaq, Mohammad, Rasheed, Syed Zahed, Memon, Fazal-Ur-Rehman, Jalal, Anjum, Abbas, Shahid, Frossard, Philippe, Saleheen, Danish, Wood, Angela M, Griffin, Julian L, Koulman, Albert
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 10.09.2021; BioMed Central; BMC
• Subjects: Apolipoprotein E; Asians - genetics; Blood; Blood & organ donations; Blood donors; Blood lipids; Cardiovascular diseases; Datasets; Environmental factors; Gaussian Graphical Modelling; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetics; Genome-Wide Association Study; Genomes; Genotype & phenotype; Health aspects; Health risks; Heart attacks; Humans; Knowledge bases (artificial intelligence); Lipidomics; Lipids; Loci; Mass spectrometry; Mass spectroscopy; Metabolic disorders; Metabolism; Metabolites; Myocardial Infarction; Network analysis; Perturbation; Polymorphism, Single Nucleotide; Principal components analysis; Quality control; Risk factors; Risk management; Scientific imaging; South Asian; Whites; Pakistan; United Kingdom > UK; Genetics; Lipidomics; South Asian; Gaussian Graphical Modelling; Network analysis
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-021-02087-1

Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.