The Biobank Rare Variant consortium powers the discovery of rare genetic associations through global collaboration

Tuesday, 26 May 2026, 9.30am to 10.30am

For our next talk, in the BDI/CHG (gen)omics Seminar series, we will be hearing from Duncan Palmer, SMARTbiomed Senior Research Fellow; co-lead, the Biobank Rare-Variant Consortium (BRaVa), BDI and Department of Statistics, University of Oxford. We’re delighted to host Duncan in what promises to be a great talk!

Date: Tuesday 26 May
Time: 9:30 am – 10:30 am
Talk title: The Biobank Rare Variant consortium powers the discovery of rare genetic associations through global collaboration
Location: Big Data Institute, Seminar Room 0

Abstract
Rare coding variants can have large effects on disease risk, but their discovery is fundamentally constrained by sample size. The low frequency of these variants limits power even in the largest individual biobanks, particularly for disease endpoints. Here we introduce the Biobank Rare Variant Analysis (BRaVa) consortium, which unites 10 biobanks and cohorts, comprising over 1.25 million individuals with matched genetic and healthcare record data, to advance our understanding of the genetic basis of human disease.

We performed gene-based meta-analyses of rare coding variation across 32 disease endpoints and 12 quantitative traits in diverse populations. Aggregating evidence across biobanks and ancestries substantially increased power, identifying 579 gene-trait associations, including 36 not previously reported in prior studies or curated genetic association resources following systematic literature curation. Notably, 42.5% of associations were not detected in any individual biobank, and 111 were identified only through cross-ancestry meta-analysis, demonstrating that large-scale integration enables discovery beyond the reach of single cohorts; improvements in discovery were also observed at the variant level, where 15.8% of associations were detectable only through meta-analysis.

Effect size estimates were consistent across genetic ancestries with concordant directions of effect, supporting the generalizability of rare variant associations. The identified signals implicate biological pathways spanning transcriptional and epigenetic regulation, metabolic homeostasis, vascular and epithelial biology, and immune function. These findings highlight the ability of rare coding variation to directly implicate causal genes and disease mechanisms. For example, damaging variation in ANKRD12 implicates dysregulated transcriptional control of inflammatory pathways in asthma and chronic obstructive pulmonary disease, while ultra-rare predicted loss-of-function variants in NAA15 link protein acetylation processes to type 2 diabetes risk.

Together, BRaVa establishes a scalable framework for rare variant meta-analysis across global biobanks and enables systematic discovery of gene-level mechanisms underlying complex human disease, accelerating the identification of biologically grounded therapeutic targets as sequencing resources continue to expand.

Speaker(s): Duncan Palmer (BDI, University of Oxford)

Series: BDI/CHG Genomics seminar

Venue: Big Data Institute - Lower Ground Seminar Room 0 - Lower Ground Seminar Room 0 Big Data Institute Old Road Campus Oxford Oxfordshire OX3 7LF United Kingdom

Department: Big Data Institute - NDPH (Unit)

Organiser: Sumeeta Maheshwari

Host: Prof Thomas Nichols

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