Identification of a Novel SLC2A9 Gene Association with LDL-C levels and Evaluation of Polygenic Scores in a Multi-Ancestry Genome Wide Association Study

The genetic determinants of low-density lipoprotein cholesterol (LDL-C) levels in blood have been predominantly explored in European populations and remain poorly understood in Middle Eastern populations. We investigated the genetic architecture of LDL-C variation in the Middle Eastern population of Qatar. Whole genome sequencing data of 13,701 individuals (discovery; n=5939, replication; n=7762) from the population-based Qatar Biobank (QBB) cohort was used to conduct a genome-wide association study (GWAS) on serum LDL-C levels. We replicated 168 previously reported loci from the largest LDL-C GWAS conducted by the Global Lipids Genetics Consortium (GLGC), with high correlation in allele frequencies (R2=0.77) and moderate correlation in effect sizes (Beta; R2=0.53). We also performed a multi-ancestry meta-analysis with the GLGC study using MR-MEGA (Meta-Regression of Multi-Ethnic Genetic Association). The multi-ancestry meta-analysis identified one novel LDL-C-associated locus; rs10939663 (SLC2A9; genomic control-corrected P=1.25x10-8). Lastly, we developed Qatari-specific polygenic score (PGS) panels from our discovery dataset and tested their performance in the replication dataset against PGS derived from other ancestries. The multi-ancestry derived PGS (PGS000889) performed best at predicting LDL-C levels, whilst the Qatari-derived PGS panels also showed comparable performance. Overall, we report one novel gene variant associated with LDL-C levels, which may be explored further to decipher its potential role in the etiopathogenesis of cardiovascular diseases. Our findings also highlight the importance of population-based genetics in developing PGS panels for clinical utilization. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by a grant from the Qatar National Research Fund (QNRF) awarded to OMEA (PPM 03-0324-190038). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the institutional review boards of Qatar BionBank (QBB) and Hamad Bin Khalifa University (HBKU), Doha, Qatar. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data analyzed in this study are subject to the following licenses/restrictions: the raw WGS data from the QBB are protected and are not available for deposition into public databases due to data privacy laws. Access to QBB/QGP phenotype and whole-genome sequence data can be obtained through an ISO-certified protocol, which involves submitting a project request at https://www.qatarbiobank.org.qa/research/how-apply, subject to approval by the Institutional Review Board of the QBB. Requests to access these datasets should be directed to https://www.qatarbiobank.org.qa/research/how-apply.