The goal of this R01 proposal is to use high-throughput DNA sequencing and genotyping technologies to identify genes and pathways that contribute to the risk for myocardial infarction (MI). Our research team combines strengths in cardiovascular disease, high-throughput genetics and genomics and development and application of innovative computational and statistical methods to maximize the benefits of next-generation sequencing technologies.
In Aim 1, we will sequence DNA from 1,000 individuals, 700 with MI and 300 controls, at ~5X coverage for the genome, and at ~100X average coverage for the exome. We will select MI cases with known family history of MI and additional cases with the earliest-onset from 3,100 MI cases collected by the HUNT Biobank.
In Aim 2, we will carry out MI association analyses based on sequence data from these 1,000 samples and an additional 1,000 samples (500 with early-onset MI) with publically-available exome data from the NHLBI Exome Sequencing Project (ESP). We will analyze variants with MAF>0.5% individually. For variants with MAF<1%, we will use "burden" tests designed to identify regions where clusters of rare variants are more common in cases than controls (or vice versa).
In Aim 3, we will use the Metabochip custom SNP array to genotype dense marker sets from 94 MI-related loci in 1,044 additional MI cases and 4,919 MI controls from the Finnish FUSION and METSIM studies. Using reference haplotypes from this project (Aim 1) together with haplotypes from the 1000 Genomes Project, T2DGO and Sardinia whole genome sequencing studies, we will impute variants into samples with Metabochip genotypes and perform association testing in 2,244 MI cases and 5,719 controls.
In Aim 4, we will select for follow-up ~200 genes that show the strongest evidence for association with MI from Aims 2 and 3. These 200 genes will be sequenced in an additional 2,100 MI cases and 2,100 MI controls from the HUNT Biobank.
In Aim 5, we will share data and methods to support similar studies for MI and other cardiovascular phenotypes, for imputation into larger samples with GWAS data, and more broadly across the scientific community. Completion of these aims will provide new insights into disease mechanism that have the potential to catalyze breakthroughs in MI prevention, treatment, and diagnosis.

Public Health Relevance

Myocardial infarction (MI) is the leading cause of death in the United States. Despite nearly 2400 Americans dying of cardiovascular disease every day, little is known about the etiology of MI. Preventive therapies currently include antiplatelet agents such as aspirin, and therapies aimed at reducing LDL cholesterol, a risk factor for atherosclerosis and CVD. Improved understanding of the genetic basis of MI may improve our understanding of disease etiology, support identification of novel drugs and therapies, and enable better targeting of preventive and therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL109946-02
Application #
8322631
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2011-08-18
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$735,403
Indirect Cost
$241,537
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Feng, Shuang; Pistis, Giorgio; Zhang, He et al. (2015) Methods for association analysis and meta-analysis of rare variants in families. Genet Epidemiol 39:227-38
Schmidt, Ellen M; Willer, Cristen J (2015) Insights into blood lipids from rare variant discovery. Curr Opin Genet Dev 33:25-31
Tang, Clara S; Zhang, He; Cheung, Chloe Y Y et al. (2015) Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. Nat Commun 6:10206
Schmidt, Ellen M; Zhang, Ji; Zhou, Wei et al. (2015) GREGOR: evaluating global enrichment of trait-associated variants in epigenomic features using a systematic, data-driven approach. Bioinformatics 31:2601-6
Lange, Leslie A; Willer, Cristen J; Rich, Stephen S (2015) Recent developments in genome and exome-wide analyses of plasma lipids. Curr Opin Lipidol 26:96-102
(2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518:197-206
(2015) New genetic loci link adipose and insulin biology to body fat distribution. Nature 518:187-96
(2014) Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 46:1173-86
TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute; Crosby, Jacy; Peloso, Gina M et al. (2014) Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 371:22-31
Lange, Leslie A; Hu, Youna; Zhang, He et al. (2014) Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. Am J Hum Genet 94:233-45

Showing the most recent 10 out of 16 publications