If you’re from Trøndelag county you probably know someone who has participated in the Nord-Trøndelag Health study (HUNT). Maybe you even participated! But did you know that researchers at the K.G. Jebsen Center for Genetic Epidemiology collaborate with international scientists to study the genetics of diseases like heart disease and diabetes using HUNT?

Genotyping allows researchers to read the DNA nucleotide (e.g. A, T, C, or G) at millions of places in the human genome, and from 2014-2015, DNA from a subset of blood samples donated by HUNT participants was genotyped in an international effort between NTNU’s Dr. Kristian Hveem and Dr. Cristen Willer of the University of Michigan.

Variation in the human genome

The human genome is 3.1 billion nucleotides in size, and these nucleotides ultimately create the proteins that run the human body. Variation in the human genome is normal — I may have a T in a place that you have a C. But sometimes that variation puts a person at increased risk for developing a given disease. Usually this is because a person has inherited a unique combination of risk increasing alleles that in aggregate contribute to disease predisposition.

Genome Wide Association Study (GWAS)

To identify the genetic variants which increase disease risk, scientists use a statistical method called Genome Wide Association Study (GWAS) to identify which nucleotides at which genomic locations are associated with a given disease. Ultimately, identifying and understanding these associations may lead to treatments and pharmaceutical therapies. It also helps clinicians identify people with a high genetic risk score, which means they have a greater genetic burden of risk increasing variants than the average person. It is a current topic of research if people with higher genetic risk scores might benefit from lifestyle interventions and preventative care.

Phenome Wide Association Study (PheWAS)

Scientists from NTNU and the University of Michigan’s Center for Statistical Genetics use HUNT to develop statistical methods and discover novel disease-causing genetic variants. One example of their work is performing GWAS on hundreds of diseases, or phenotypes, in a phenome wide association study (PheWAS). A phenotype is the expressed characteristic in an organism that results from the genotype and the environment. When we consider many or all the phenotypes of an organism, we call this the phenome. PheWAS can identify genomic locations where a nucleotide leads to increased risk for multiple diseases.

PheWAS was performed on hundreds of diseases like coronary artery disease and laboratory measurements like blood lipid levels across multiple instances of HUNT enrollment. The LPA variant on chromosome 6, rs10455872, is associated with many of these phenotypes—coronary artery disease (CAD), myocardial infarction or heart attack (MI), coronary artery bypass graft which is a type of heart surgery (CABG.PCA), angina or chest pain (AnginaPecICD), and increased blood levels of serum cholesterol (SeChol.NT2BLM, SeChol.NT23BLM, SeChol.NT3BLM), and total cholesterol (TC, TC.NT2, TC.NT3).

For example, a variant in the LPA gene, which codes for the Lp(a) lipoprotein responsible for transporting fats in the body, is known to be associated with heart disease. By performing PheWAS for this LPA variant in HUNT (Figure 1), researchers find the G nucleotide is associated with an increased risk of coronary artery disease, myocardial infarction or heart attack, coronary artery bypass graft which is a type of heart surgery, angina or chest pain, and increased blood levels of serum cholesterol and total cholesterol.

HUNT Data can help us understand diseases

While these associations have been previously noted by clinicians and researchers, PheWAS enables many cross-phenotype comparisons in HUNT. This is important information for understanding disease mechanism and creating potential therapies. PheWAS may also identify a nucleotide that is protective for one disease but increases the risk for another. Because of Norway’s national registries and HUNT’s detailed questionnaires which span decades, HUNT is a valuable resource for international researchers who work to understand how variation in the human genome affects the entire phenome.

A collaboration between several institutions, including the Norwegian University of Science and Technology (NTNU), the University of Michigan Medical School, Geisinger and Regeneron, and deCODE Genetics/Amgen in Iceland, has resulted in surprising results linking atrial fibrillation in adults to fetal heart development. 

The group studied an unprecedented sample size of over one million people, including over 60,000 individuals with atrial fibrillation, to discover over 140 genetic changes associated with this common, adult-onset cardiac arrhythmia. The results were surprising in that they identified a number of genes that control heart development in the fetus.

This could have important implications for future treatment and possibly prevention of atrial fibrillation.

Experiments in rabbits with induced heart failure showed that at least one of the fetal genes becomes active again in the damaged heart. Because the fetal genes have different rates of conduction of the cardiac electrical impulses relative to the adult form of the gene, atrial fibrillation is induced. This could have important implications for future treatment and possibly prevention of atrial fibrillation.

The group are hopeful that additional molecular biology experiments will determine how to create sustained regular heart rhythms by studying the genes they, and others, have identified.

Significance of the expression enrichment for the atrial fibrillation candidate genes.

They also found that for each individual, they could count the number of genetic changes that each person carries to predict which people are most at risk for developing atrial fibrillation in the future. This may have important implications for precision health and prevention of cardiovascular disease.

Another paper on atrial fibrillation was also published recently in Nature Genetics and we look forward to bringing these two collaborative groups together to generate an even larger study for the benefit of those afflicted by atrial fibrillation.

Read the full article in Nature Genetics. 

 Researchers at the Department of Laboratory Medicine, Children’s and Women’s Health (LBK), NTNU, has developed a better, quicker and cheaper method for typing group B streptococcus (GBS) based on repeated areas in the genome.

Publikasjoner

• Multiple-locus variant-repeat assay (MLVA) is a useful tool for molecular epidemiologic analysis of Streptococcus agalactiae strains causing bovine mastitis. Radtke etl.al. Vet Microbiol. 2012 Jun 15;157(3-4):398-404. Epub 2012 Jan 8.
• Rapid multiple-locus variant-repeat assay (MLVA) for genotyping of Streptococcus agalactiae. Radtke et.al. J Clin Microbiol. 2010 Jul;48(7):2502-8. Epub 2010 May 26.
• Identification of surface proteins of group B streptococci: serotyping versus genotyping. Radtke et.al. J Microbiol Methods. 2009 Sep;78(3):363-5. Epub 2009 Jun 30.