Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.
Mark K BakkerRick A A van der SpekWouter Van RheenenSandrine MorelRomain BourcierIsabel Charlotte HostettlerVarinder S AlgKristel R van EijkMasaru KoidoMasato AkiyamaChikashi C TeraoKoichi MatsudaRobin G WaltersKuang LinLiming LiIona Y MillwoodZhengming ChenGuy A RouleauSirui ZhouKristiina RannikmäeCathie L M SudlowHenry HouldenLeonard H van den BergChristian DinaOlivier NaggaraJean-Christophe GentricEimad ShotarFrancisco MacianHubert DesalBendik Slagsvold WinsvoldSigrid BørteMarianne Bakke JohnsenBen Michael BrumptonMarie Søfteland SandveiCristen J WillerKristian HveemJohn-Anker ZwartW M Monique VerschurenChristoph M FriedrichSven HirschSabine SchillingJérôme DauvillierOlivier Martinnull nullnull nullnull nullnull nullnull nullnull nullnull nullGregory T JonesMatthew J BownNerissa U KoHelen KimJonathan R I ColemanGerome BreenJonathan G ZaroffCatharina J M KlijnRainer MalikMartin DichgansMuralidharan SargurupremrajTurgut TatlisumakPhillippe AmouyelStephanie DebetteGabriel J E RinkelBradford B WorrallJoanna PeraAgnieszka SlowikEmília I Gaál-PaavolaMika NiemeläJuha E JääskeläinenMikael von Und Zu FraunbergAntti E LindgrenJoseph P BroderickDavid John WerringDaniel WooRichard RedonPhilippe BijlengaYoichiro KamataniJan Herman VeldinkYnte M RuigrokPublished in: Nature genetics (2020)
Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
Keyphrases
- genome wide association study
- genome wide
- subarachnoid hemorrhage
- risk factors
- dna methylation
- copy number
- blood pressure
- coronary artery
- endothelial cells
- brain injury
- gene expression
- type diabetes
- risk assessment
- emergency department
- transcription factor
- mass spectrometry
- human health
- drug induced
- blood glucose
- middle cerebral artery
- adverse drug