Publications by authors named "Jeffrey R O'connell"
Integrating multi-omics data may help researchers understand the genetic underpinnings of complex traits and diseases. However, the best ways to integrate multi-omics data and use them to address pressing scientific questions remain a challenge. One important and topical problem is how to assess the aggregate effect of multiple genomic data types (e.
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- Antiplatelet therapy, particularly with P2Y receptor inhibitors alongside aspirin, is essential for treating coronary artery disease, and different medication options can help tailor patient care.
- A study investigated the effects of a specific genetic mutation (G143E in CES1) on the effectiveness of clopidogrel and ticagrelor in inhibiting platelet aggregation in patients.
- Results showed that the G143E mutation significantly affected platelet response to clopidogrel, but not to ticagrelor, indicating ticagrelor may provide more consistent treatment for patients with clopidogrel response-altering genetics.
Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk.
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- Genetic studies have highlighted the need for more diverse research on plasma fibrinogen levels, as previous studies largely focused on Europeans, leading to gaps in understanding and missing heritability.
- By analyzing data from whole-genome sequencing and genotype data from large cohorts, researchers identified 18 genetic loci related to fibrinogen levels, some of which are more common in African populations and include variants that may impact protein function.
- The study's findings indicate a connection between fibrinogen levels and various health conditions, emphasizing the importance of whole-genome sequencing in discovering genetic factors in diverse populations and enhancing knowledge about fibrinogen regulation.
Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels.
View Article and Find Full Text PDFAlthough both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways.
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- * Discovery of 7 new genetic loci associated with FVIII and 1 new locus for VWF, supporting their roles in thrombotic outcomes via Mendelian randomization.
- * Functional testing revealed that silencing genes like B3GNT2 and CD36 impacted FVIII and VWF release from endothelial cells, indicating their potential regulatory roles.
Article Synopsis
- The study focuses on apparent treatment-resistant hypertension (aTRH), defined by the need for four or more antihypertensive medications to control blood pressure in individuals.
- Researchers analyzed genetic data from 12 cohorts using whole-genome sequencing, comparing aTRH cases to normotensive controls and treatment-responsive patients.
- A significant genetic variant linked to hypertension was identified, and further validation of these results in larger and more diverse populations is necessary to understand its potential role in aTRH.
Article Synopsis
- Educational attainment is linked to cardiovascular health, and a large genomic study examined how it interacts with cholesterol and triglyceride levels in nearly 226,315 individuals across five population groups.
- The study identified 18 new genetic variations related to lipid levels—nine for low-density lipoprotein (LDL), seven for high-density lipoprotein (HDL), and two for triglycerides (TG)—some of which interact with educational attainment.
- Researchers also found five gene targets that potentially interact with FDA-approved drugs, suggesting a connection between genetics and drug responses related to lipid metabolism and overall health.
Article Synopsis
- Long non-coding RNAs (lncRNAs) play crucial roles in regulating lipid metabolism and have been studied in relation to genetic variants and complex traits.
- This research utilized high-coverage whole-genome sequencing of over 66,000 diverse participants to assess how rare variants in lncRNA genes affect blood lipid levels, using a statistical framework to analyze the associations.
- The study found 83 lncRNA variants significantly linked to lipid levels, with many being independent of common genetic variations, and replicated a majority of these findings with data from another large cohort.
Dysregulation of physiological processes may contribute to Alzheimer's disease (AD) development. We previously found that an increase in the level of physiological dysregulation (PD) in the aging body is associated with declining resilience and robustness to major diseases. Also, our genome-wide association study found that genes associated with the age-related increase in PD frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.
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- Nonalcoholic fatty liver disease (NAFLD) is widespread, partly genetic, and currently lacks effective treatment options.
- A genome-wide association study (GWAS) identified several genetic variants linked to NAFLD, focusing on genes related to metabolism and liver function.
- Genetic risk factors can help classify NAFLD into subtypes and significantly increase the risk of severe liver complications, potentially aiding in the development of targeted therapies.
Article Synopsis
- Long non-coding RNAs (lncRNAs) play key roles in regulating biological functions, and new genomic studies allow researchers to explore their connection to complex traits, like blood lipid levels.
- This research involved high-coverage whole genome sequencing from over 66,000 participants, focusing on the influence of rare variants in 165,375 lncRNA genes on lipid variability.
- The study found 83 rare lncRNA variant sets linked to blood lipid levels, with many of these associations being independent of common variants, suggesting potential new avenues for therapeutic interventions.
Article Synopsis
- Genetic studies on plasma fibrinogen levels primarily focused on Europeans, revealing numerous associated regions, but there are gaps in understanding due to missing heritability and representation of non-Europeans.
- The researchers utilized whole genome sequencing (WGS) and array-based genotyping data from large cohorts to identify 18 new genetic loci linked to fibrinogen levels, with some variants more common in African populations.
- The study highlights the importance of WGS in discovering genetic variations across diverse populations, linking fibrinogen polygenic risk scores to increased risk for thrombotic and inflammatory diseases like gout.
Article Synopsis
- A study analyzed over 43,000 blood genomes and discovered 7,131 recurrent non-missense somatic mutations (RNMSMs) that frequently occur in at least 50 individuals, challenging the idea that such mutations are rare and insignificant.
- RNMSMs were found to increase with age, averaging 27 mutations in individuals around 50 years old, and were linked to inherited genetic variations affecting immune functions.
- The presence of specific RNMSMs was associated with blood cell traits similar to the effects of inherited genetic mutations, suggesting that these somatic mutations have significant implications for human health.
Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point.
View Article and Find Full Text PDFMotivation: The amount of genomic data is increasing exponentially. Using many genotyped and phenotyped individuals for genomic prediction is appealing yet challenging.
Results: We present SLEMM (short for Stochastic-Lanczos-Expedited Mixed Models), a new software tool, to address the computational challenge.
Article Synopsis
- MetaSTAAR is a new framework designed for analyzing rare genetic variants in large studies, specifically whole genome and whole exome sequencing (WGS/WES).
- It effectively manages relatedness and population differences while analyzing various traits, enhancing the ability to detect significant rare variant associations by utilizing functional annotations.
- In tests with over 30,000 diverse samples, MetaSTAAR yielded results similar to pooled data analysis and successfully identified significant rare variant associations related to lipid traits.
Article Synopsis
- Large-scale whole-genome sequencing studies allow researchers to examine associations between rare noncoding variants and complex diseases, although current methods struggle with the noncoding genome analysis.
- The STAARpipeline framework offers a comprehensive solution for detecting noncoding rare variant associations through various analytical approaches, including gene-centric and non-gene-centric analyses that utilize functional annotations.
- The effectiveness of STAARpipeline is demonstrated through its application in identifying significant noncoding RV sets linked to lipid traits in over 21,000 samples, with successful replication in an additional group, and further analysis of other traits.
Article Synopsis
- * A study involving 66,329 participants from diverse ancestries discovered 428 million variants linked to lipid levels, many of which had not been explored in previous genetic research.
- * The research identified significant associations between blood lipid levels and both common and rare genetic variants, including a clinically significant rare non-coding variant model, enhancing understanding of lipid genetics across different populations.
Article Synopsis
- The QT interval is a key measure in electrocardiograms that indicates the timing of heart muscle contractions and recoveries; abnormalities can lead to serious heart conditions.
- A study involving over 250,000 individuals identified many genetic loci linked to various heart rhythm measures, revealing important genetic factors associated with QT, JT, and QRS intervals.
- The findings suggest that certain gene variations could inform new treatments for arrhythmias and highlight genetic pathways involved in heart function and energy metabolism.
Article Synopsis
- - The study analyzed genetic factors affecting fasting glucose (FG) and fasting insulin (FI) using high-coverage whole genome sequencing from over 23,000 non-diabetic individuals across five different racial and ethnic groups.
- - Researchers identified eight significant genetic variants linked to FG or FI in known gene regions, while also suggesting associations with additional regions related to metabolic processes.
- - The project compiled functional annotation resources to help understand the implications of these genetic variations and laid the groundwork for future research on glycemic traits.
Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.
Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.
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- The study investigates genetic factors influencing lipid species linked to cardiovascular disease (CVD) using data from the Amish founder population, which may reveal insights beyond traditional lipid measures.
- Researchers conducted a genome-wide scan of 355 lipid species in 650 Amish individuals, discovering associations with rare lipid variants unique to this population for the first time.
- The findings highlight the potential of studying founder populations to uncover novel genetic variants associated with lipid traits, emphasizing the importance of both rare and common variants in understanding lipidomics in relation to CVD risk.
Article Synopsis
- Analyses show that common SNPs account for about one-third to two-thirds of the heritability of human traits and diseases, but much of the remaining heritability is still unexplained.
- A study of over 25,000 individuals found heritability estimations of 0.68 for height and 0.30 for body mass index (BMI), highlighting differences across traits.
- Rare genetic variants, especially those in low linkage disequilibrium, contribute significantly to heritability, suggesting they could be key players in understanding complex traits and diseases.