Elucidating the etiology of cryptogenic stroke with human genetics

• Applicant: Marios Georgakis, Ph.D.
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Epidemiology and Medical Biometry/Statistics ; Human Genetics
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466957018

• Final Report Year: 2022

Final Report Abstract

The etiology of ischemic stroke remains undetermined in almost one third of the cases, thus hindering our efforts for precise secondary prevention in the growing population of stroke survivors. While observational studies have proposed several mechanisms as potential explanations for stroke of undetermined source, such as paroxysmal atrial fibrillation, trials informed by these studies have failed to deliver specific treatments. In the context of this project, we explored the genetic architecture of ischemic stroke classified as undetermined to test if mechanisms and risk factors underlying large-artery atherosclerotic (LAAS), cardioembolic (CES), and small-vessel stroke (SVS) contribute to its pathogenesis and to detect novel paradigms for prevention. We analyzed genome-wide data from 16,851 ischemic stroke cases and 32,473 controls from the Stroke Genetics Network (SiGN). We found that genetic risk for LAAS, CES, and SVS, as captured by polygenic risk scores, was associated with stroke of undetermined source pointing to overlap in their genetic architecture. Pairwise genome-wide analyses revealed 19 shared colocalized loci with LAAS, 2 with CES, and 5 with SVS that have been primarily implicated in atherosclerosis-related phenotypes. Importantly, genetic liability to both carotid atherosclerosis and atrial fibrillation was associated with stroke of undetermined source, but the association with atrial fibrillation was attenuated after excluding cases with incomplete diagnostic workup. Using Mendelian randomization, we found significant effects of genetic predisposition to elevated blood pressure, diabetes, and abdominal obesity on stroke of undetermined source, pointing to potential causal associations. Furthermore, using variants proxying the effects of under development anti-inflammatory and anticoagulation approaches, we provided genetic evidence that approaches targeting IL-6 signaling, the CCL2/CCR2 axis, or factor XI might hold promise for lowering risk of stroke of undetermined source. Collectively, this project provided evidence that stroke of undetermined source shares genetic and vascular risk factors with other stroke subtypes, especially LAAS, thus highlighting the diagnostic limitations of current subtyping approaches. The results from this project for potentially causal associations of carotid atherosclerosis and atherosclerotic risk factors with stroke of undetermined sourcecould inform the design of secondary prevention trials for this group of patients.

Publications

• Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups. BMC Medicine, 20(1).
  Georgakis, Marios K.; Malik, Rainer; Richardson, Tom G.; Howson, Joanna M. M.; Anderson, Christopher D.; Burgess, Stephen; Hovingh, G. Kees; Dichgans, Martin & Gill, Dipender
  
• Circulating Interleukin-6 Levels and Incident Ischemic Stroke. Neurology, 98(10).
  Papadopoulos, Andreas; Palaiopanos, Konstantinos; Björkbacka, Harry; Peters, Annette; de Lemos James, A.; Seshadri, Sudha; Dichgans, Martin & Georgakis, Marios K.
  
• Genetic Architecture of Stroke of Undetermined Source: Overlap with Known Stroke Etiologies and Associations with Modifiable Risk Factors. Annals of Neurology, 91(5), 640-651.
  Georgakis, Marios K.; Parodi, Livia; Frerich, Simon; Mayerhofer, Ernst; Tsivgoulis, Georgios; Pirruccello, James P.; Slowik, Agnieszka; Rundek, Tatjana; Malik, Rainer; Dichgans, Martin; Rosand, Jonathan & Anderson, Christopher D.
  
• Genetically predicted on-statin LDL response is associated with higher intracerebral haemorrhage risk. Brain, 145(8), 2677-2686.
  Mayerhofer, Ernst; Malik, Rainer; Parodi, Livia; Burgess, Stephen; Harloff, Andreas; Dichgans, Martin; Rosand, Jonathan; Anderson, Christopher D. & Georgakis, Marios K.
  
• Targeting the CCL2–CCR2 axis for atheroprotection. European Heart Journal, 43(19), 1799-1808.
  Georgakis, Marios K.; Bernhagen, Jürgen; Heitman, Laura H.; Weber, Christian & Dichgans, Martin