Project Reference: TRG27-CHI-EO1

Project title: Rare variant burden scores across the medical spectrum: effects on disease liability and on common traits and phenotypes

Project outline

Most genetic research looks either at common DNA changes, each with a tiny effect - which are measured by GWAS, or at rare changes with largeeffects. Bringing the two together could greatly improve how well we predict who develops illness. In recent work, our team applied a ""rare variantburden score"" (IOGC) that counts the rare genetic changes a person carries which disturb how nearby genes are switched on and off. Added tostandard common-variant polygenic risk scores (calculated for each person from GWAS), it improved prediction of schizophrenia and a heartcondition. This PhD extends that idea along two strands. First, the student will test whether combining rare- and common-variant scores improvesprediction across ten mental health and treatment outcomes: depression, schizophrenia, bipolar disorder, PTSD, OCD, panic disorder, opioid usedisorder, treatment resistance in depression and in schizophrenia, and response to antidepressants. These were chosen for their prevalence, impacton quality of life, and the availability of suitable GWAS data. Second, the student will explore how rare variant burden relates to common traits andlife outcomes, such as having several conditions at once, height, BMI, intelligence, number of children, and level of education, to map the broaderbiological footprint of these scores. The work draws on two of the world's largest health resources, UK Biobank and Our Future Health, alongsidepublicly available genetic studies and biological measurements. The student will develop skills in genetics, statistics, and large-scale data analysis,supported by a team with established expertise in these methods and datasets. Together, the two strands aim to move genetic risk prediction closerto real clinical use and to deepen our understanding of how rare variation shapes health across the medical spectrum.

Principal Supervisor

Dr Emanuele Osimo

Email address: efo22@cam.ac.uk

Department / Partner Institute: Psychiatry

Website: https://www.cppds.org.uk/

BBSRC strategic theme

Bioscience for an integrated understanding of health