HCR.20.051 – SENDER

Route: Health care research, sickness prevention and treatment

Cluster question: 081 How will our knowledge of genetics play a role in analysing, screening for, and treating diseases?

Genome wide association studies (GWAS) are successful in identifying genetic variation as risk factors for complex traits and most traits are influenced by many variants across the genome. The risk of spurious associations in GWAS is often controlled by selecting homogeneous study populations with correction for residual admixture, a method that comes with various limitations. Firstly, by excluding sizeable subgroups in the population, the generalizability of findings is limited. Secondly, the variation of traits is often smaller by homogenizing which limits statistical power and confounds estimates of heritability. Thirdly, when certain genes increase the exposure to a certain environment that influences a range of traits then this environmental effect may inflate GWAS signals and intertwine GWAS signals for traits. Finally, imputation depends on genetic reference panels in mainly non-admixture selected population; resulting in imputations that vary substantially depending on the reference panel and imputation-server.
We have formed a consortium of pivotal cohort studies of healthy subjects in the Netherlands (a.o. GenerationR, LifeLines and Helius) that all generated GWAS data, and have collaborated in numerous GWAS studies. Given the different populations involved in these studies, diversity is maximized in many aspects such as social economic status, urban/rural environment, ethnic background and exposomes such as pollution. This unique feature will enable us to identify new genetic signals for complex traits. We will focus on blood pressure and serum lipid levels to illustrate and quantify the value of sampling from the entire population instead of homogeneous subgroups. To assist imputation of genetic variants the consortium will create high quality genetic reference panels by whole genome sequencing of subgroups based on ethnicity and environmental exposures. These reference panels will be crucial for all genetic research in the Netherlands.

Keywords

Cardiovascular diseases, Diversity, environments, genetics, whole genome sequencing

Other organisations

Erasmus Medical Center (EMC), Hartwig Medical Foundation, Lifelines, UMCG

Submitter

Organisation Amsterdam UMC
Name Prof. dr. A.H. (Koos) Zwinderman
E-mail a.h.zwinderman@AmsterdamUMC.nl