beschrijf ik een methode die ik heb ontwikkeld die deze interactie-effecten

kan bestuderen. Door deze methode toe te passen op een grootschalige eQTL-dataset van verschillende bio-banken, zoals Lifelines, verenigd in BBMRI-NL, werd het duidelijk dat cel- type-samenstellingsverschillen en virale stimuli de moleculaire gevolgen van ziekte gerela- teerde varianten sterk veranderen. Door statistisch te corrigeren voor deze sterke effecten, konden we ook meer subtiele effecten detecteren die onthulden hoe de regulerende effect- en van transcriptiefactoren worden beïnvloed door genetische varianten.

Hoewel GWAS-onderzoeken zeer succesvol zijn geweest in de identificatie van varianten die bijdragen aan veel voorkomende ziekten, hebben ze te weinig kracht om zeldzame variant- en te identificeren die ten grondslag liggen aan zeldzame ziekten. In hoofdstuk 8 beschrijf

ik een nieuwe methode die openbare RNA-seq data gebruikt om kandidaat-genen te voor- spellen die de symptomen zouden kunnen verklaren van een patiënt met vermoedelijke varianten die zeldzame ziekten veroorzaken. Ik laat zien dat het met deze methode mogelijk is om meer patiënten een diagnose te geven. Bovendien kan ik ook genen markeren die mogelijk vals zijn geassocieerd met een ziekte.

Het hier gepresenteerde werk maakt deel uit van een snelgroeiend veld en is in hoofd- stuk 9 in de juiste context geplaatst. Hier bespreek ik hoe de vorderingen die hier worden

gemaakt bijdragen aan het gebied van de menselijke genetica en welke toekomstige uit- dagingen wachten. Ik bespreek ook hoe de zorg kan profiteren van verdere implementatie van genetica en speculeren over hoe dit kan worden geïmplementeerd. Ten slotte leg ik uit waarom het nodig is om moleculaire fenotypen te meten bij complexe patiënten om hun ziekte volledig te verklaren.

Acknowledgements

Dear family, friends and colleagues, while it is nearly impossible to acknowledge everyone by name, I would like to thank everyone for their support and collaboration.

First of all, I would like to thank my parents Bert & Ingrid for all their support and enabling me to develop.

I would like to thank my loving wife Marieke for being there for me. I could not have done it without your patience and support.

John, you are only 3-years-old now, but I would like to thank you for the joy you bring and for once in a while allowing me to type on my laptop without joining in.

Eline, thank you for designing the cover of this thesis and for being my sister. Morris, I want to thank you for your guidance and mentoring me during my PhD. Lude, I really enjoyed your input and our brainstorming sessions.

Cisca, I’m very grateful for your critical input and the opportunities you have given me. Marc Jan, we have known each other since our bachelors, and I have benefited a lot from our shared time during our studies and PhD projects. I’m honored you are coming back to the Netherlands to be a paranymf during my defense.

Pieter, you have been a great college and I’m happy you will support me during my defense as a paranymf.

Dasha, we co-authored several papers and it was always a pleasure working with you. Jingyuan, you where the supervisor of my first internship in human genetics, thank you for introducing me to the field and for your patience.

Jan Jakob Schuringa, I want to thank you and your colleagues for a very interesting intern- ship at the UMCG hematology department.

I would like to thank Ramnik Xavier and Daniel MacArthur for hosting me at the Broad insti- tute and all the members of their labs for all the interesting discussions.

Jackie & Kate, you both have been invaluable in making my writing readable and profession- al, thank you.

I enjoyed working with everyone in the FrankeSwertzLab, where there is room for feedback and room for encouragement. I feel we really conduct science as group instead of as com- petitive individuals.

I want to thank all the members of the GCC for their support with Molgenis and program- ming, for finding all the samples on the cluster, and for the research projects we worked on together.

It was also a pleasure collaborating with all the other researchers in the genetics depart- ment. It was really nice to get together with people from different disciplines and jointly work on projects.

I’m also grateful for the collaboration with the clinical geneticists and everyone from diag- nostics, for collecting patient material and collaborating on rare disease projects.

I want to thank all the members of the GoNL consortium, the BIOS consortium and the eQTL consortium for their contributions in doing the big things we could have never have done on our own.

I have supervised several interns, and I would like to thank Matthieu Beukers, Harmen Boers, Marije van der Geest, Adriaan van der Graaf, Rahul Gannamani and Sophie Mulcahy Symmons for their efforts.

Without our computer clusters my work would not have been possible, at least not within a normal human lifespan, so I want to thank the CIT and everyone involved in keeping our computer infrastructure running.

I am also grateful to everyone working in the wet lab who generated the data I worked on. I also want to thank the support staff, including the secretaries, facility management and financial managers for keeping the genetics department running smoothly.

I would like to thank my teachers from both the Hanze University and the VU for teaching me the skills needed for my PhD project.

Finally, I would like to thank all the biobank participants and patients that have allowed us to work with their data.