HUNTing for genes that affect cardiovascular related traits

I dette prosjektet ønsker vi å påvise nye gener og sykdomsmekanismer som bidrar til økt risiko for hjerte-karsykdom. Vi vil anvende en helt ny teknologier for omfattende genetisk kartlegging, dvs. avlesning av hele genets informasjon ved hjelp av såkalt helgenomsekvensering eller et utvalg av genmarkører (HumanCoreExome). Vi vil benytte en av Europas beste forskningsbiobanker, HUNT Biobank, data fra HUNT (Helseundersøkeslen i Nord-Trøndelag) og fra ulike sykdomsregistre, blant annet fra Helse Nord-Trøndelag/Helse Midt-Norge og Familieregisteret fra Statistisk Sentralbyrå (SSB). Forskningsutvalget vil bestå av inntil 70 000 personer som har deltatt i minst 2 av de tre HUNT-undersøkelsene, fortrinnsvis HUNT 2(1995-1997) og HUNT 3(2006-2008) hvor vi både har tilgang til DNA og kan benytte andre deler av blodprøvene for utvidede analyser. Genanalysene fra de 10 000 første er allerede gjennomført og de resterende 60 000 vil bli analysert første kvartal 2015.

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.