Biology subjects

Becker, L. C.

Publications and source records attributed to Becker, L. C..

7 recordsLinked to original sources

bioRxiv2023

Validation of human telomere length trans-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as novel human telomere length regulation genes

Telomere length genome-wide association studies (GWAS) have become well-powered to detect novel genes in telomere length regulation. However, no prior work has validated these putative novel genes to confirm the contribution of GWAS loci to telomere length regulation. We conducted a trans-ancestry meta-analysis of 211,369 individuals. Through enrichment analyses of chromatin state and cell-type heritability we identified blood and immune cells as the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6, a component of an E3 ubiquitin ligase complex, and POP5, a component of the Ribonuclease P/MRP complex, and demonstrating that both lengthened telomeres as predicted by our statistical analyses. CRISPR/Cas9 deletion of the predicted causal regions of these association peaks in K562 immortalized blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5, respectively. Together our results demonstrate the utility of telomere length GWAS in the identification of novel telomere length regulation mechanisms and highlight the importance of the proteasome-ubiquitin pathway in telomere length regulation.

genetics↗

bioRxiv2020

Rare coding variants in 35 genes associate with circulating lipid levels: a multi-ancestry analysis of 170,000 exomes

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency<1%) predicted damaging coding variation using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels. Ten of these: ALB, SRSF2, JAK2, CREB3L3, TMEM136, VARS, NR1H3, PLA2G12A, PPARG and STAB1 have not been implicated for lipid levels using rare coding variation in population-based samples. We prioritize 32 genes identified in array-based genome-wide association study (GWAS) loci based on gene-based associations, of which three: EVI5, SH2B3, and PLIN1, had no prior evidence of rare coding variant associations. Most of the associated genes showed evidence of association in multiple ancestries. Also, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes, and for genes closest to GWAS index single nucleotide polymorphisms (SNP). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

genetics↗

bioRxiv2020

Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

BackgroundGenome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To better understand etiological pathways that might lead to discovery of new treatments or prevention strategies, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome while also exploring associations with common variants. Methods and ResultsUsing samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR=1.80, 95% confidence interval: 1.43, 2.27; P=7.12 x 10-7). Three common variants, rs9349379 in PHACTR1, and rs1333048 and rs4977574 in the 9p21 region, were significantly associated with prevalent CHD. Four common variants (rs4977574, rs10757278, rs1333049, and rs1333048) within the 9p21 locus were significantly associated with incident MI. We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) [≥] 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. ConclusionThis study confirmed previously reported loci influencing heart disease risk, and one single variant and three genes associated with MI and CHD were newly identified and warrant future investigation.

genetics↗

bioRxiv2019

Genome Sequencing Unveils a New Regulatory Landscape of Platelet Reactivity

Exaggerated platelet aggregation at the site of vascular injury is the underlying pathophysiology of thrombotic diseases. Here, we conduct the largest whole genome sequencing (WGS) effort to uncover the genetic determinants of platelet aggregation. Leveraging 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) individuals deeply phenotyped for platelet aggregation, we identify 18 loci using single-variant approaches. This includes the novel RGS18 locus encoding a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with eQTL signatures for RGS18 expression in platelets. A gene-based approach focusing on deleterious coding variants identifies the SVEP1 gene, previously shown to be associated with coronary artery disease, as a novel determinant of platelet aggregation. Finally, in an integrative approach leveraging epigenetic data on megakaryocytes, we find strong association between rare variants mapping to a super enhancer region for PEAR1. This is a novel finding implicating the importance of rare variants with regulatory potential in a previously documented GWAS-identified locus.

genomics↗

bioRxiv2019

Loss-of-function genomic variants with impact on liver-related blood traits highlight potential therapeutic targets for cardiovascular disease

Cardiovascular diseases (CVD), and in particular cerebrovascular and ischemic heart diseases, are leading causes of death globally.1 Lowering circulating lipids is an important treatment strategy to reduce risk.2,3 However, some pharmaceutical mechanisms of reducing CVD may increase risk of fatty liver disease or other metabolic disorders.4,5,6 To identify potential novel therapeutic targets, which may reduce risk of CVD without increasing risk of metabolic disease, we focused on the simultaneous evaluation of quantitative traits related to liver function and CVD. Using a combination of low-coverage (5x) whole-genome sequencing and targeted genotyping, deep genotype imputation based on the TOPMed reference panel7, and genome-wide association study (GWAS) meta-analysis, we analyzed 12 liver-related blood traits (including liver enzymes, blood lipids, and markers of iron metabolism) in up to 203,476 people from three population-based cohorts of different ancestries. We identified 88 likely causal protein-altering variants that were associated with one or more liver-related blood traits. We identified several loss-of-function (LoF) variants reducing low-density lipoprotein cholesterol (LDL-C) or risk of CVD without increased risk of liver disease or diabetes, including variants in known lipid genes (e.g. APOB, LPL). A novel LoF variant, ZNF529:p.K405X, was associated with decreased levels of LDL-C (P=1.3x10-8) but demonstrated no association with liver enzymes or non-fasting blood glucose levels. Silencing of ZNF529 in human hepatocytes resulted in upregulation of LDL receptor (LDLR) and increased LDL-C uptake in the cells, suggesting that inhibition of ZNF529 or its gene product could be used for treating hypercholesterolemia and hence reduce the risk of CVD. Taken together, we demonstrate that simultaneous consideration of multiple phenotypes and a focus on rare protein-altering variants may identify promising therapeutic targets.

genomics↗

bioRxiv2019

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

genomics↗

bioRxiv2017

Evolution of Hominin Polyunsaturated Fatty Acid Metabolism: From Africa to the New World

BackgroundThe metabolic conversion of dietary omega-3 and omega-6 18 carbon (18C) to long chain (> 20 carbon) polyunsaturated fatty acids (LC-PUFAs) is vital for human life. Fatty acid desaturase (FADS) 1 and 2 catalyze the rate-limiting steps in the biosynthesis of LC-PUFAs. The FADS region contains two haplotypes; ancestral and derived, where the derived haplotypes are associated with more efficient LC-PUFA biosynthesis and is nearly fixed in Africa. In addition, Native American populations appear to be nearly fixed for the lesser efficient ancestral haplotype, which could be a public health problem due to associated low LC-PUFA levels, while Eurasia is polymorphic. This haplotype frequency distribution is suggestive of archaic re-introduction of the ancestral haplotype to non-African populations or ancient polymorphism with differential selection patterns across the globe. Therefore, we tested the FADS region for archaic introgression or ancient polymorphism. We specifically addressed the genetic architecture of the FADS region in Native American populations to better understand this potential public health impact.\n\nResultsWe confirmed Native American ancestry is nearly fixed for the ancestral haplotype and is under positive selection. The ancestral haplotype frequency is also correlated to Siberian populations geographic location further suggesting the ancestral haplotype s role in cold weather adaptation and leading to the high haplotype frequency within Native American populations. We also find that the Neanderthal is more closely related to the derived haplotypes while the Denisovan clusters closer to the ancestral haplotypes. In addition, the derived haplotypes have a time to the most recent common ancestor of 688,474 years ago which is within the range of the modern-archaic hominin divergence.\n\nConclusionsThese results support an ancient polymorphism forming in the FADS gene region with differential selection pressures acting on the derived and ancestral haplotypes due to the old age of the derived haplotypes and the ancestral haplotype being under positive selection in Native American ancestry populations. Further, the near fixation of the less efficient ancestral haplotype in Native American ancestry suggests the need for future studies to explore the potential health risk of associated low LC-PUFA levels in Native American ancestry populations.

evolutionary biology↗