Research Program Complex Trait Genetics

The main focus of our Complex Trait Genetics program is to facilitate gene discovery via innovative statistical and bioinformatics tools; guide functional developments by prioritizing genes and genetic pathways; and provide high output genotyping facilities for genetic discovery studies. Projects within our program include the collaborative DARWIN (DNA Analysis of Residents Within an Isolate in the Netherlands) initiative, and a study on how genomic evolution has shaped and rewired gene regulatory networks involved in human brain development.

Rationale and common goals

This program explores the genetic, epigenetic and environmental causes of individual differences in brain function and dysfunction related to cognitive, mental and physical health. In the past decade major advances in technology (e.g. microarrays, next generation sequencing, brain imaging, induced pluripotent stem cells) in a number of fields have been made, which led to unprecedented leaps forward in our knowledge and understanding of the genetic architecture of brain disorders. Progress in genotyping technology have been paralleled by a reduction of costs and an increase of datasets and sample sizes available for research. Large-scale genetic studies provided novel insights and keys for functional and pharmaceutical follow-up.

Sample sizes for genetic association discovery analyses have increased tremendously in the past five years and this has yielded an increasing amount of reliable genetic in relation to wellbeing, insomnia, intelligence, cannabis use, refractive error, and neuroticism.The interpretation of this wealth of information has induced the development of new statistical, bioinformatics and methodological tools that are currently used wordwide in the field of genetics(e.g., MAGMA, FUMA).

Investigators of the CTG program has started the socalled collaborative initiative DARWIN (DNA Analysis of Residents Within an Isolate in the Netherlands) that collects data in a genetic isolate in the Netherlands. A total of 1248 individuals from the Dutch genetic isolate have now been genotyped and the first results indicate that this population is indeed genetically isolated. Goal of this study is to assess if individuals from this population have a higher genetic risk for complex diseases than outbred populations, such as the UK Biobank. Another project in this genetic isolate identified several new genetic mutations increasing the risk for heart disease, and a severe form of autism with intellectual disability.

In addition there is a strong fundamental research line within the CTG program that is focussed on how genomic evolution has shaped and rewired gene regulatory networks involved in human brain development; and the investigators of this research succesfully identified the NOTCH2NL genes as being key regulators of the human cortical neurogenesis.

Main goals

To develop and apply statistical tools for the analyses of genetic data.
To develop and apply bioinformatics tools integrating biological information with outcomes from genetic studies.
To develop and apply a pipeline for integrating knowledge from Mendelian forms of a disorder with polygenic forms of a disorder.
To develop and apply pipelines for genetically informed prioritization for follow-up functional.

Assets

The Genetics Cluster Computer at the Department of Complex Trait Genetics, location VUmc.
The genomics facility of Amsterdam UMC delivers services for large scale genome analyses (e.g. whole exome sequencing in collaboration with the foundation HMF whole genome sequencing), RNA sequencing and epigenic analyses.
The desk of Clinical Genetics provides a platform where clinicians and scientists meet on a monthly basis to discuss patient cases and possibilities for follow-up research.
The IPS Center provides induced pluripotent stem (IPS) cell lines for patients and controls, which can be differentiated into glial or neuronal cell types.
Cohorts of patients with Mendelian inherited diseases due to high-risk alleles will serve as a source to dissect complex traits. Cohorts of patients with mental retardation with unknown cause after whole exome sequencing.
A cohort of approximately three thousand patients annually with familial causes of brain related disorders.
Netherlands Study of Cognition (NESCOG) provides a population based control cohort with information on a wide range of phenotypes and genotypic information.

Clinical relevance

The work of the CTG program has direct clinical relevance, e.g., the Ophthalmology Amsterdam UMC department will, in 2019, participate in one of the first international gene therapy clinical trials for the retinal disease Retinitis Pigmentosa. Furthermore, the CTG project in Volendam (i.e., genetic isolate) as mentioned above, contributes importantly to a pilot for the introduction of new Dutch health policies regarding prenatal testing procedures (Non-Invasive Prenatal Diagnostics, i.e. NIPD).

Making the difference

The Complex Trait Genetics program:

Facilitates gene-discovery using innovative statistical and bioinformatics tools;
Guides functional follow-up by prioritizing genes, and genetic pathways;
Provides high throughput genotyping facilities and large scale computing power for genetic discovery studies.