Dataset Information

Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.

ABSTRACT: Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-body MRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality.

SUBMITTER: Perkins BA

PROVIDER: S-EPMC5889622 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Publications

Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.

Perkins Bradley A BA Caskey C Thomas CT Brar Pamila P Dec Eric E Karow David S DS Kahn Andrew M AM Hou Ying-Chen Claire YC Shah Naisha N Boeldt Debbie D Coughlin Erin E Hands Gabby G Lavrenko Victor V Yu James J Procko Andrea A Appis Julia J Dale Anders M AM Guo Lining L Jönsson Thomas J TJ Wittmann Bryan M BM Bartha Istvan I Ramakrishnan Smriti S Bernal Axel A Brewer James B JB Brewerton Suzanne S Biggs William H WH Turpaz Yaron Y Venter J Craig JC

Proceedings of the National Academy of Sciences of the United States of America 20180319 14

Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical histor ...[more]

PMID: 29555771

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Project description:BackgroundRisk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies.MethodsThe 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants).ResultsSingle variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only PROC (odds ratio, 6.2 for carriers of rare variants; P=7.4×10-14) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at PROC (odds ratio, 3.8; P=1.6×10-14), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: PROS1 became significant (minimum P=1.8×10-6 with the secondary filter), while SERPINC1 did not (minimum P=4.4×10-5 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, MS4A1, became significant (P=4.4×10-7 using all missense variants with minor allele frequency <0.0005).ConclusionsHere, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel MS4A1 locus and to identify additional rare variation associated with venous thromboembolism.

Dataset Information

Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.

Publications

Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.

Similar Datasets

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