Meta-Analysis

. 2025 Jun;18(3):e004626.

doi: 10.1161/CIRCGEN.123.004626. Epub 2025 Apr 21.

Dissecting the Genetic Architecture of Intracranial Aneurysms

Shaunak S Adkar^{1

2

3}, Julie Lynch^{4

5}, Ryan B Choi⁶, Tanmoy Roychowdhury⁷, Renae L Judy^{8

9}, Kaavya Paruchuri^{10

11

12}, Dong-Chuan Go¹³, Sharika Bamezai^{2

14}, John Cabot^{1

2

3}, Sabina Sorondo^{1

2

3}, Michael G Levin^{15

16}, Dianna M Milewicz¹³, Cristen J Willer^{17

18

19}, Pradeep Natarajan^{10

11

12

20}, Saiju Pyarajan^{21

22}, Kyong-Mi Chang^{23

24}, Scott Damrauer^{25

26

27

28}, Phil Tsao^{29

2

3}, Stephen Skirboll^{30

3}, Nicholas J Leeper^#^{1

29

2}, Derek Klarin^#^{1

3}

Affiliations

¹ Division of Vascular Surgery, Department of Surgery (S.S.A., J.C., S. Sorondo, N.J.L., D.K.), Stanford University School of Medicine, Palo Alto, CA.
² Stanford Cardiovascular Institute, Stanford University, CA (S.S.A., S.B., J.C., S. Sorondo. P.T., N.J.L.).
³ Veterans Affairs (VA) Palo Alto Healthcare System, CA (S.S.A., J.C., S. Sorondo, P.T., S. Skirboll, D.K.).
⁴ VA Salt Lake City Healthcare System, UT. (J.L.).
⁵ Epidemiology, School of Medicine, The University of Utah, Salt Lake City (J.L.).
⁶ Stanford University School of Medicine, Palo Alto, CA (R.B.C.).
⁷ Department of Biology and Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, Sonepat, India (T.R.).
⁸ Department of Surgery (R.L.J.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
⁹ Research (R.L.J.), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.
¹⁰ Department of Medicine (K.P., P.N.), Massachusetts General Hospital, Boston.
¹¹ Cardiovascular Research Center (K.P., P.N.), Massachusetts General Hospital, Boston.
¹² Program in Medical and Population Genetics (K.P., P.N.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.
¹³ Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (D.-C.G., D.M.M.).
¹⁴ University of Michigan School of Medicine, Ann Arbor (S.B.).
¹⁵ Division of Cardiovascular Medicine, Department of Medicine (M.G.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
¹⁶ Department of Medicine (M.G.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
¹⁷ Division of Cardiology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor (C.J.W.).
¹⁸ Department of Computational Medicine and Bioinformatics (C.J.W.), University of Michigan, Ann Arbor.
¹⁹ Department of Human Genetics (C.J.W.), University of Michigan, Ann Arbor.
²⁰ Cardiovascular Disease Initiative (P.N.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.
²¹ Center for Data and Computational Sciences, VA Boston Health Care System, MA (S.P.).
²² Research, Harvard Medical School, Boston, MA (S.P.).
²³ Division of Gastroenterology and Hepatology, Department of Medicine (K.-M.C.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁴ Research and Medicine (K.-M.C.), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.
²⁵ Division of Vascular Surgery and Endovascular Therapy, Department of Surgery (S.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁶ Department of Genetics (S.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁷ Penn Cardiovascular Institute (S.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁸ Department of Surgery (S.D.), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.
²⁹ Department of Medicine (P.T., N.J.L.), Stanford University School of Medicine, Palo Alto, CA.
³⁰ Department of Neurosurgery (S. Skirboll), Stanford University School of Medicine, Palo Alto, CA.

^# Contributed equally.

PMID: 40255156
PMCID: PMC12173771 (available on 2026-06-01)
DOI: 10.1161/CIRCGEN.123.004626

Meta-Analysis

Dissecting the Genetic Architecture of Intracranial Aneurysms

Shaunak S Adkar et al. Circ Genom Precis Med. 2025 Jun.

. 2025 Jun;18(3):e004626.

doi: 10.1161/CIRCGEN.123.004626. Epub 2025 Apr 21.

Authors

Affiliations

¹ Division of Vascular Surgery, Department of Surgery (S.S.A., J.C., S. Sorondo, N.J.L., D.K.), Stanford University School of Medicine, Palo Alto, CA.
² Stanford Cardiovascular Institute, Stanford University, CA (S.S.A., S.B., J.C., S. Sorondo. P.T., N.J.L.).
³ Veterans Affairs (VA) Palo Alto Healthcare System, CA (S.S.A., J.C., S. Sorondo, P.T., S. Skirboll, D.K.).
⁴ VA Salt Lake City Healthcare System, UT. (J.L.).
⁵ Epidemiology, School of Medicine, The University of Utah, Salt Lake City (J.L.).
⁶ Stanford University School of Medicine, Palo Alto, CA (R.B.C.).
⁷ Department of Biology and Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, Sonepat, India (T.R.).
⁸ Department of Surgery (R.L.J.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
⁹ Research (R.L.J.), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.
¹⁰ Department of Medicine (K.P., P.N.), Massachusetts General Hospital, Boston.
¹¹ Cardiovascular Research Center (K.P., P.N.), Massachusetts General Hospital, Boston.
¹² Program in Medical and Population Genetics (K.P., P.N.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.
¹³ Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (D.-C.G., D.M.M.).
¹⁴ University of Michigan School of Medicine, Ann Arbor (S.B.).
¹⁵ Division of Cardiovascular Medicine, Department of Medicine (M.G.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
¹⁶ Department of Medicine (M.G.L.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
¹⁷ Division of Cardiology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor (C.J.W.).
¹⁸ Department of Computational Medicine and Bioinformatics (C.J.W.), University of Michigan, Ann Arbor.
¹⁹ Department of Human Genetics (C.J.W.), University of Michigan, Ann Arbor.
²⁰ Cardiovascular Disease Initiative (P.N.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA.
²¹ Center for Data and Computational Sciences, VA Boston Health Care System, MA (S.P.).
²² Research, Harvard Medical School, Boston, MA (S.P.).
²³ Division of Gastroenterology and Hepatology, Department of Medicine (K.-M.C.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁴ Research and Medicine (K.-M.C.), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.
²⁵ Division of Vascular Surgery and Endovascular Therapy, Department of Surgery (S.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁶ Department of Genetics (S.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁷ Penn Cardiovascular Institute (S.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.
²⁸ Department of Surgery (S.D.), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA.
²⁹ Department of Medicine (P.T., N.J.L.), Stanford University School of Medicine, Palo Alto, CA.
³⁰ Department of Neurosurgery (S. Skirboll), Stanford University School of Medicine, Palo Alto, CA.

^# Contributed equally.

PMID: 40255156
PMCID: PMC12173771 (available on 2026-06-01)
DOI: 10.1161/CIRCGEN.123.004626

Abstract

Background: The genetic risk of intracranial aneurysm (IA) development has been ascribed to the genetic risk of smoking exposure and hypertension. The relationship of IA to other cardiovascular traits and the contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear.

Methods: We performed a genome-wide association study in the Million Veteran Program and Finnish cohort study testing association of roughly 25 million DNA variants with unruptured IA (4694 cases and 877 091 controls) in individuals of European, African, and Hispanic ancestries. Meta-analysis with publicly available summary statistics generated a final cohort of 15 438 cases and 1 183 973 controls. We constructed a cerebrovascular single-nuclear RNA sequencing data set and integrated IA summary statistics to prioritize candidate causal cell types. We constructed a polygenic risk score to identify patients at risk of developing IA.

Results: We identified 5 novel associations with IA, increasing the number of known susceptibility loci to 22. At these susceptibility loci, we prioritized 17 candidate causal genes. We found a significant positive genetic correlation of IA with coronary artery disease and abdominal aortic aneurysm. Integration of an IA gene set with cerebrovascular single-nuclear RNA sequencing data revealed a significant association with pericytes and smooth muscle cells. Finally, a polygenic risk score was significantly associated with IA across European (odds ratio, 1.87 [95% CI, 1.61-2.17]; P=8.8×10^-¹⁷), African (odds ratio, 1.62 [95% CI, 1.19-2.15]; P=1.2×10^-³), and Hispanic (odds ratio, 2.28 [95% CI, 1.47-3.38]; P=1.0×10^-⁴) ancestries.

Conclusions: Here, we identify 5 novel loci associated with IA. Integration of summary statistics with cerebrovascular single-nuclear RNA sequencing reveals an association of cell types involved in matrix production. We validated a polygenic risk score that predicts IA, controlling for demographic variables including smoking status and blood pressure. Our findings suggest that a deficit in matrix production may drive IA pathogenesis independent of hypertension and smoking.

Keywords: aortic aneurysm; genetic risk score; genome-wide association study; hypertension; intracranial aneurysm.

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Conflict of interest statement

Dr Natarajan reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio; is a scientific co-founder of TenSixteen Bio; equity in Preciseli and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. D. Klarin is an employee of Bitterroot Bio. The other authors report no conflicts.

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Dissecting the Genetic Architecture of Intracranial Aneurysms

Affiliations

Dissecting the Genetic Architecture of Intracranial Aneurysms

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Grants and funding

LinkOut - more resources

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Medical