HUNTing for genes that affect cardiovascular related traits

HUNTing for genes that affect cardio vascular related traits In this project, we look for novel genetic markers and disease mechanisms that may contribute to the risk of cardio vascular diseases (CVD). We will apply new technologies for extensive genetic analyses, i.e. whole genome sequencing and genome wide mapping with new chip array. Subsequently, these data sets will be enriched through additional methods such as phasing and imputation. We make use of one of the best biobanks in Europe, The HUNT Biobank, data from the extensive population based HUNT Study and from various health registries such as clinical patient registries and family registries. We will include at least 70 000 study participants from the HUNT study that have been screened either through HUNT 2(1995-97), HUNT 3 (2006-08) or through both. In addition to high-quality DNA, the HUNT biobank may also provide access to serum/plasma samples for additional analyses. The project was initially designed for genetic analyses of 10 000 HUNT-participants, with an additional deep sequencing of approx. 100 of the most relevant genes (Aim 4). In May 2014, we filed an application to the biobank program board for the acceptance of a revised protocol, where aim 4 was substituted with the project design described above, namely genotyping all HUNT participants with available DNA. Professor Goncalo Abecasis, University of Michigan, and already involved in the project from the start, has also contributed with $ 2 mill for this purpose. The revised protocol, opens up for the possibility of studying new and rare genetic variants involved in the risk for developing CVD. On Dec 12th, 2014, a new collaboration agreement was signed by the Dean of the Faculty of Medicine, NTNU and the Dean of the Dept. of Biostatistics, University of Michigan, also approved by the biobank program board, RCN.

The goal of this RCN proposal is to use high-throughput cost-effective DNA genotyping arrays and targeted sequencing to identify genes and pathways that contribute to the risk for cardiovascular disease (CVD). Our research team combined strengths in cardi ovascular disease, high-throughput genetics, statistical analysis and development of related methods and software, epidemiology and ethics to maximize the benefits of the innovative exome array genotyping technologies. In Aim 1, we will genotype ~10,000 u nrelated individuals registered with cardiovascular related traits in both HUNT 1, HUNT 2 and HUNT 3 using an innovative exome array enriched for variants especially relevant for the Norwegian population. We expect our enriched exome array to capture >85% of protein coding variants with frequency >0.1%. In Aim 2, we will carry out association analyses between our selected cardiovascular related traits and genetic variants in combined sample set of ~17,000 including already genotyped HUNT samples. 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 common. In Aim 3, we will perform direct assessment of association with clinically-verified myocardial infarction for the top-ranking genes and genetic variants in Aim 2 in a combined 3,469 MI cases and 3,760 healthy controls. In Aim 4, we will perform targeted sequencing to both follow-up in ~10,000 additional samples and simultaneously evaluat e their potential as future drug targets. In Aim 5, we will share data and methods. In Aim 6, we will address important ethical aspects regarding incidental findings and return of information to the participants. Completion of these aims will provide new insights into disease mechanism that have the potential to catalyze breakthroughs in CVD prevention, treatment, and diagnosis.