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 #
3R01HL117626-02S1
Application #
8930263
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
2014-09-30
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$1,600,000
Indirect Cost
Name
University of Michigan Ann Arbor
Department
None
Type
Schools of Public Health
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Pistis, Giorgio; Porcu, Eleonora; Vrieze, Scott I et al. (2015) Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs. Eur J Hum Genet 23:975-83
Fuchsberger, Christian; Abecasis, Gonçalo R; Hinds, David A (2015) minimac2: faster genotype imputation. Bioinformatics 31:782-4
Liu, Dajiang J; Peloso, Gina M; Zhan, Xiaowei et al. (2014) Meta-analysis of gene-level tests for rare variant association. Nat Genet 46:200-4
Iacono, William G; Vaidyanathan, Uma; Vrieze, Scott I et al. (2014) Knowns and unknowns for psychophysiological endophenotypes: integration and response to commentaries. Psychophysiology 51:1339-47
Vrieze, Scott I; Malone, Stephen M; Pankratz, Nathan et al. (2014) Genetic associations of nonsynonymous exonic variants with psychophysiological endophenotypes. Psychophysiology 51:1300-8
Vrieze, Scott I; Malone, Stephen M; Vaidyanathan, Uma et al. (2014) In search of rare variants: preliminary results from whole genome sequencing of 1,325 individuals with psychophysiological endophenotypes. Psychophysiology 51:1309-20
Chew, Emily Y; Klein, Michael L; Clemons, Traci E et al. (2014) No clinically significant association between CFH and ARMS2 genotypes and response to nutritional supplements: AREDS report number 38. Ophthalmology 121:2173-80
Iacono, William G; Malone, Stephen M; Vaidyanathan, Uma et al. (2014) Genome-wide scans of genetic variants for psychophysiological endophenotypes: a methodological overview. Psychophysiology 51:1207-24
Holmen, Oddgeir L; Zhang, He; Fan, Yanbo et al. (2014) Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nat Genet 46:345-51
Feng, Shuang; Liu, Dajiang; Zhan, Xiaowei et al. (2014) RAREMETAL: fast and powerful meta-analysis for rare variants. Bioinformatics 30:2828-9

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