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Approved research

Investigating incomplete penetrance and the genetic architectures of human traits and diseases

Principal Investigator: Dr Hilary Martin
Approved Research ID: 44165
Approval date: November 26th 2018

Lay summary

Human genetics research has typically been divided into research into common diseases, which are due to a combination of many common genetic variants of small effect and environmental factors, and rare diseases, which are thought to be due largely to rare genetic variants. These two fields are starting to converge, with multiple studies showing that rare variation contributes to common diseases and evidence emerging for a role of common variants in rare disorders. We will investigate the interplay between these different types of genetic variation and their contribution to various traits in the UK Biobank. Specifically, we will look at how common genetic variation modifies the 'penetrance' of rare variants (meaning the probability that a person has a particular disease, given they have the variant). Some genes have been shown to be very intolerant of variation (i.e. genetic variants in them damage normal functioning and are thus removed from the population by natural selection). Previous work focused on identifying genes in which loss of one of the two copies is very damaging. In contrast, other genes are recessive, meaning both copies have to be lost in order to affect normal functioning. We will use the Biobank data to infer which genes act recessively, which will inform the discovery of new genes for rare diseases and increase our understanding of fundamental biology (i.e. how many copies of each human gene are essential to have). To understand the impact of disrupting these variation-intolerant genes, we will test for associations between different classes of variants in these genes and various traits. Demographic processes such as population growth, migration and endogamy (marriage within groups or between family members) impact the distribution of genetic variants within the genome, and can contribute to differences in disease risk. In particular, it is well known that having parents who are related increases risk of rare, early-onset conditions because it increases the chance of inheriting the same damaging variant from each parent in a recessive gene. However, the effects of parental relatedness on later-onset diseases have not been quantified. We will investigate patterns of genetic variation in people of different ancestries from UK Biobank and other cohorts enriched for parental relatedness. Our research will increase fundamental understanding of how genetics contribute to human disease risk, which will lead to better risk prediction, as well as potential diagnoses and treatment. The project duration will be three years.