Rationale
ROAR-DNA is a landmark genetic study of intracranial aneurysms using whole-genome sequencing (WGS) to identify who to screen, who to treat, and which biological pathways to target for further research.
While most intracranial aneurysms are sporadic, they often run in families with 16.4% of patients having an affected parent or sibling. Currently, in the UK screening is limited to individuals with two affected first-degree relatives. However, even with highly penetrant mutations, we estimate <10% of individuals with a genetic risk factor are eligible for screening. There's no genetic test to guide screening, which involves costly, lifelong MRI scans. Previous studies have lacked power and only examined common variants. ROAR-DNA will be the first large-scale study to assess both rare and common genetic risk, enabling personalised screening based on a comprehensive genetic risk model.
"What is my personal risk of aneurysm rupture?"
This is the key question patients face and a core aim of the ROAR study. Using whole-genome sequencing and long-term follow-up from national healthcare databases, ROAR-DNA will compare ruptured and unruptured aneurysms to identify genetic differences and predict future risk providing patients with the data they need to make informed treatment decisions.
Currently, other than blood pressure control and smoking cessation, there are no medical options which can reduce the risk of rupture. Using genetic data, we will explore underlying mechanisms to identify new targets for novel medical treatments or risk modification.
Aims
1. Predict aneurysm formation – enabling screening in high-risk individuals.
2. Predict rupture risk – improving decisions on who should receive treatment.
3. Reveal molecular pathways – unlocking new opportunities for targeted therapies.
Study design
DNA from 6,000 ROAR patients will be collected. 1,000 with extreme phenotypes will undergo WGS. These will be combined with WGS data from 1,500 publicly available cases and 300,000 healthy controls. Rare and common variants associated with aneurysm formation and rupture will be identified using burden and single variant tests. Rare variants identified will be added to a customised genotyping array, which will be used to type the remaining 5,000 ROAR-DNA patients and over 3,000 patients from our ongoing GO-SAH study of ruptured aneurysms. The significance and effect-size of both rare and common variants will be determined by a final meta-analysis involving over 10,000 patients with rare variant data.
