Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits

Abstract

Background Genetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai Bio Me Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene. Results We identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in Bio Me that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight. Conclusion In sum, by integrating genetic and electronic medical record data, and leveraging one of the world’s largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation. Electronic supplementary material The online version of this article (10.1186/s12920-019-0542-3) contains supplementary material, which is available to authorized users.

Historical population declines prompted significant genomic erosion in the northern and southern white rhinoceros (Ceratotherium simum)

“…Following Kuang et al ( 2020 ), we counted the total number of missense and loss‐of‐function (LoF) homozygous derived sites, and divided those numbers by the total count of synonymous sites. To define LoF sites, we chose the approach of Glicksberg et al ( 2019 ), and considered only sites of high impact under the effect categories “stop_gained,” “frameshift_variant,” “splice_acceptor_variant” and “splice_donor_variant.”…”

TRPM2, PDLIM5, BCL3, CD14, GBA Genes as Feasible Markers for Premature Coronary Heart Disease Risk

“…We expect that further studies in larger sample sizes and multi-center Thai male and female populations will help to confirm the feasibility of using the FH-CHD biomarker in Thai ethnicities. Moreover, further meta-analysis studies using publicly available transcriptomic data from different ethnic populations to compare and share appropriate CHD biomarker is expected to be more reliable and advantageous; (5) Several current studies into the genetic basis of coronary heart disease have intensively reported the discovery and aggregation of genetic variants from multiple genes from lipid and other pathologic pathways ( Yao et al, 2015 ; Glicksberg et al, 2019 ; Cohain et al, 2021 ). Based on our current NGS data, we are continuing to investigate the variant genes observed only in FH and FH-CHD patient groups, to identify potential predictive markers.…”

Whole-genome sequencing reveals KRTAP1-1 as a novel genetic variant associated with antidepressant treatment outcomes

“…With approximately 10 million independent variants generated using WGS, reaching a genome-wide threshold is very unlikely to identify variants associated with a rare allele frequency, low relative risk, and low fraction of variance explained, even if they are the causal variants 38 . Therefore, using lenient p-value thresholds (p < 0.1 for discovery) 39 , we focused on LOF variants with a high-penetrance conferring moderate or high risk, even if those were common allelic frequency, showing evidence for pathway-related co-expression in human cerebral tissue. Second, there might have been a potential bias related to the physician's independent choice of antidepressant drug because of the study's naturalistic design of the study.…”