Gene-Based Rare Variant Burden Analyses Across Biobanks Identify Novel High-Risk Genes for Thoracic Aortic Disease
- 1UTHealth Houston
Abstract
BackgroundThoracic aortic aneurysms enlarge silently and can cause fatal aortic dissection without timely surgical repair, underscoring the need for improved approaches to identify individuals at high risk. Rare pathogenic variants in established heritable thoracic aortic disease (HTAD) genes explain only a subset of familial and fewer nonfamilial thoracic aortic disease (TAD) cases.
MethodsWe performed phenotype-stratified, genome-wide, gene-based rare-variant burden analyses of ultrarare damaging missense and predicted loss-of-function variants. Primary analyses focused on aortic dissection, thoracic aortic aneurysm requiring surgical repair, and their combined phenotype. Broader thoracic aortic aneurysm (TAA) was evaluated as a secondary phenotype. Discovery analyses were conducted in the UK Biobank and All of Us, followed by independent replication in the Penn Medicine BioBank, Mass General Brigham Biobank, and Million Veteran Program. Discovery and replication results were subsequently combined in an overall fixed-effect, inverse-variance-weighted meta-analysis across up to five biobanks. Implicated genes were further evaluated in additional clinically ascertained TAD cohorts and using single-cell transcriptomic data from human thoracic aortic tissue.
ResultsDiscovery analyses identified 80 genes reaching study-wide significance across the prespecified TAD phenotypes. These included six established and two putative HTAD genes. Fourteen genes demonstrated independent replication support and reached study-wide significance in the overall meta-analysis across up to five biobanks, which included more than 10,000 cases and 880,000 controls. The eight novel candidate genes among these were FNDC3B, ROCK1, URM1, SLFN11, ENPP1, CLEC16A, CREM, and VCAN. Associations were strongest for dissection and TAA requiring surgical repair. Four novel associations were driven exclusively by missense variants. FNDC3B was observed in a family with HTAD, while additional variants were identified primarily in sporadic dissection or aortic surgery cohorts, suggesting that other genetic or physiologic factors may influence penetrance. The implicated genes showed cell-type-specific expression patterns in human thoracic aortic tissue.
ConclusionsThese findings expand the genetic architecture of TAD by identifying eight novel candidate genes and demonstrate the utility of phenotype-stratified rare variant burden analyses across large biobanks for gene discovery.
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BibTeX
@misc{murdock2026genebased,
title = {{Gene-Based Rare Variant Burden Analyses Across Biobanks Identify Novel High-Risk Genes for Thoracic Aortic Disease}},
author = {D. R. Murdock and P. Guan and D. Guo and F. Bermudez and J. DePaolo and J. Cabot and S. Nazeen and H. Nasir and R. Gupta and A. Jha and J. Elefteriades and B. McGivern and K. McWalter and S. Anderson and C. Jones and J. Lynch and K.-M. Chang and P. Tsao and VA Million Veteran Program and Penn Medicine BioBank and S. Damrauer and H. Chen and D. Milewicz},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.26363254},
url = {https://www.medrxiv.org/content/10.64898/2026.09.16.26363254v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Gene-Based Rare Variant Burden Analyses Across Biobanks Identify Novel High-Risk Genes for Thoracic Aortic Disease
AU - D. R. Murdock
AU - P. Guan
AU - D. Guo
AU - F. Bermudez
AU - J. DePaolo
AU - J. Cabot
AU - S. Nazeen
AU - H. Nasir
AU - R. Gupta
AU - A. Jha
AU - J. Elefteriades
AU - B. McGivern
AU - K. McWalter
AU - S. Anderson
AU - C. Jones
AU - J. Lynch
AU - K.-M. Chang
AU - P. Tsao
AU - VA Million Veteran Program
AU - Penn Medicine BioBank
AU - S. Damrauer
AU - H. Chen
AU - D. Milewicz
PY - 2026
DA - 2026/09/16
PB - medRxiv
DO - 10.64898/2026.09.16.26363254
UR - https://www.medrxiv.org/content/10.64898/2026.09.16.26363254v1
AB - BackgroundThoracic aortic aneurysms enlarge silently and can cause fatal aortic dissection without timely surgical repair, underscoring the need for improved approaches to identify individuals at high risk. Rare pathogenic variants in established heritable thoracic aortic disease (HTAD) genes explain only a subset of familial and fewer nonfamilial thoracic aortic disease (TAD) cases. MethodsWe performed phenotype-stratified, genome-wide, gene-based rare-variant burden analyses of ultrarare damaging missense and predicted loss-of-function variants. Primary analyses focused on aortic dissection, thoracic aortic aneurysm requiring surgical repair, and their combined phenotype. Broader thoracic aortic aneurysm (TAA) was evaluated as a secondary phenotype. Discovery analyses were conducted in the UK Biobank and All of Us, followed by independent replication in the Penn Medicine BioBank, Mass General Brigham Biobank, and Million Veteran Program. Discovery and replication results were subsequently combined in an overall fixed-effect, inverse-variance-weighted meta-analysis across up to five biobanks. Implicated genes were further evaluated in additional clinically ascertained TAD cohorts and using single-cell transcriptomic data from human thoracic aortic tissue. ResultsDiscovery analyses identified 80 genes reaching study-wide significance across the prespecified TAD phenotypes. These included six established and two putative HTAD genes. Fourteen genes demonstrated independent replication support and reached study-wide significance in the overall meta-analysis across up to five biobanks, which included more than 10,000 cases and 880,000 controls. The eight novel candidate genes among these were FNDC3B, ROCK1, URM1, SLFN11, ENPP1, CLEC16A, CREM, and VCAN. Associations were strongest for dissection and TAA requiring surgical repair. Four novel associations were driven exclusively by missense variants. FNDC3B was observed in a family with HTAD, while additional variants were identified primarily in sporadic dissection or aortic surgery cohorts, suggesting that other genetic or physiologic factors may influence penetrance. The implicated genes showed cell-type-specific expression patterns in human thoracic aortic tissue. ConclusionsThese findings expand the genetic architecture of TAD by identifying eight novel candidate genes and demonstrate the utility of phenotype-stratified rare variant burden analyses across large biobanks for gene discovery.
ER -