Next generation sequencing is gradually changing the face of human genetic studies. Instead of being largely confined to the analysis of common SNPs shared across many populations and amenable to microarray genotyping, genome-wide studies can now examine a wider range of genetic variants - including more diverse types of variation (such as insertion-deletion polymorphisms), variants specific to particular samples or populations, and rare and low frequency variants. Here, we request continued support for our genetic analysis of aging related traits - with a focus on cardiovascular risk factors - in the isolated population from the island of Sardinia, Italy. Over the next several years, we will use next-generation sequencing technology and high-throughput genotyping to study the relationship between rare genetic variation and key cardiovascular risk factors in a family sample containing ~6,000 individuals (and >30,000 close relative pairs) recruited in the Lanusei valley. As part of our planned experiments, we will evaluate problems related to the selection of samples for sequencing, the design of sequencing experiments and protocols, the analysis and curation of the resulting sequence data, and - finally - association analyses that connect the resulting variants to relevant biomedical traits. Individuals being studies are part of a longitudial study of aging and have been characterized for cardiovascular traits and outcomes, including multiple measurements of key traits such as blood lipid levels and blood pressure. We have previously studied this sample to identify common genetic variants that are associated with these cardiovascular traits and that also contribute to the risk of heart disease and obesity. Our proposed experimental plan presents a unique opportunity to evaluate the role of rare variation in this unique sample. We expect that these studies will result in experimental strategies and analysis tools that will be readily deployable by many laboratories to study the genomes of many other individuals and further our understanding of the genetics and biology of many different traits and conditions.

Public Health Relevance

In the past several years, genome-wide association studies have furthered our understanding of the molecular basis of several traits related to human health and disease. The success of these studies resulted, in large part, from their ability to explore the genome in a comprehensive manner, systematically assessing the impact of common variation on the trait of interest. Here we propose to use a well characterized family sample together with high-throughput sequencing technologies to extend these systematic whole genome assessments to rare variation. Our planned effort complements detailed efforts to characterize common and intermediate frequency genetic variants in the same sample. Our results should expand the understanding of the genetics of cardiovascular traits and also result in strategies that can be widely deployed to study many human traits.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL117626-01
Application #
8460364
Study Section
Special Emphasis Panel (ZRG1-GGG-E (03))
Program Officer
Jaquish, Cashell E
Project Start
2013-01-15
Project End
2017-12-31
Budget Start
2013-01-15
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$736,517
Indirect Cost
$241,841
Name
University of Michigan Ann Arbor
Department
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chiang, Charleston W K; Marcus, Joseph H; Sidore, Carlo et al. (2018) Genomic history of the Sardinian population. Nat Genet 50:1426-1434
Hu, Yao; Raffield, Laura M; Polfus, Linda M et al. (2018) A common TCN1 loss-of-function variant is associated with lower vitamin B12 concentration in African Americans. Blood 131:2859-2863
Natarajan, Pradeep; Peloso, Gina M; Zekavat, Seyedeh Maryam et al. (2018) Deep-coverage whole genome sequences and blood lipids among 16,324 individuals. Nat Commun 9:3391
Montasser, May E; O'Hare, Elizabeth A; Wang, Xiaochun et al. (2018) An APOO Pseudogene on Chromosome 5q Is Associated With Low-Density Lipoprotein Cholesterol Levels. Circulation 138:1343-1355
Regier, Allison A; Farjoun, Yossi; Larson, David E et al. (2018) Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects. Nat Commun 9:4038
Sarnowski, ChloƩ; Satizabal, Claudia L; DeCarli, Charles et al. (2018) Whole genome sequence analyses of brain imaging measures in the Framingham Study. Neurology 90:e188-e196
Geng, Xin; Irvin, Marguerite R; Hidalgo, Bertha et al. (2018) An exome-wide sequencing study of lipid response to high-fat meal and fenofibrate in Caucasians from the GOLDN cohort. J Lipid Res 59:722-729
Mak, Angel C Y; White, Marquitta J; Eckalbar, Walter L et al. (2018) Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. Am J Respir Crit Care Med 197:1552-1564
Prokopenko, Dmitry; Sakornsakolpat, Phuwanat; Fier, Heide Loehlein et al. (2018) Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease. Am J Respir Cell Mol Biol 59:614-622
Brody, Jennifer A; Morrison, Alanna C; Bis, Joshua C et al. (2017) Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology. Nat Genet 49:1560-1563

Showing the most recent 10 out of 41 publications