OBJECTIVE: There is an urgent need to identify risk factors for sporadic intracranial aneurysm (IA) development and rupture. A genetic component has long been recognized, but firm conclusions have been elusive given the generally small sample sizes and lack of replication. Genome-wide association studies have overcome some limitations, but the number of robust genetic risk factors for IA remains uncertain. METHODS: We conducted a comprehensive systematic review and meta-analysis of all genetic association studies (including genome-wide association studies) of sporadic IA, conducted according to Strengthening the Reporting of Genetic Association Studies and Human Genome Epidemiology Network guidelines. We tested the robustness of associations using random-effects and sensitivity analyses. RESULTS: Sixty-one studies including 32,887 IA cases and 83,683 controls were included. We identified 19 single nucleotide polymorphisms associated with IA. The strongest associations, robust to sensitivity analyses for statistical heterogeneity and ethnicity, were found for the following single nucleotide polymorphisms: on chromosome 9 within the cyclin-dependent kinase inhibitor 2B antisense inhibitor gene (rs10757278: odds ratio [OR] 1.29; 95% confidence interval [CI] 1.21-1.38; and rs1333040: OR 1.24; 95% CI 1.20-1.29), on chromosome 8 near the SOX17 transcription regulator gene (rs9298506: OR 1.21; 95% CI 1.15-1.27; and rs10958409: OR 1.19; 95% CI 1.13-1.26), and on chromosome 4 near the endothelin receptor A gene (rs6841581: OR 1.22; 95% CI 1.14-1.31). CONCLUSIONS: Our comprehensive meta-analysis confirms a substantial genetic contribution to sporadic IA, implicating multiple pathophysiologic pathways, mainly relating to vascular endothelial maintenance. However, the limited data for IA compared with other complex diseases necessitates large-scale replication studies in a full spectrum of populations, with investigation of how genetic variants relate to phenotype (e.g., IA size, location, and rupture status).
OBJECTIVE: There is an urgent need to identify risk factors for sporadic intracranial aneurysm (IA) development and rupture. A genetic component has long been recognized, but firm conclusions have been elusive given the generally small sample sizes and lack of replication. Genome-wide association studies have overcome some limitations, but the number of robust genetic risk factors for IA remains uncertain. METHODS: We conducted a comprehensive systematic review and meta-analysis of all genetic association studies (including genome-wide association studies) of sporadic IA, conducted according to Strengthening the Reporting of Genetic Association Studies and Human Genome Epidemiology Network guidelines. We tested the robustness of associations using random-effects and sensitivity analyses. RESULTS: Sixty-one studies including 32,887 IA cases and 83,683 controls were included. We identified 19 single nucleotide polymorphisms associated with IA. The strongest associations, robust to sensitivity analyses for statistical heterogeneity and ethnicity, were found for the following single nucleotide polymorphisms: on chromosome 9 within the cyclin-dependent kinase inhibitor 2B antisense inhibitor gene (rs10757278: odds ratio [OR] 1.29; 95% confidence interval [CI] 1.21-1.38; and rs1333040: OR 1.24; 95% CI 1.20-1.29), on chromosome 8 near the SOX17 transcription regulator gene (rs9298506: OR 1.21; 95% CI 1.15-1.27; and rs10958409: OR 1.19; 95% CI 1.13-1.26), and on chromosome 4 near the endothelin receptor A gene (rs6841581: OR 1.22; 95% CI 1.14-1.31). CONCLUSIONS: Our comprehensive meta-analysis confirms a substantial genetic contribution to sporadic IA, implicating multiple pathophysiologic pathways, mainly relating to vascular endothelial maintenance. However, the limited data for IA compared with other complex diseases necessitates large-scale replication studies in a full spectrum of populations, with investigation of how genetic variants relate to phenotype (e.g., IA size, location, and rupture status).
Authors: K Osuka; Y Suzuki; T Tanazawa; K Hattori; N Yamamoto; M Takayasu; M Shibuya; J Yoshida Journal: Acta Neurochir (Wien) Date: 1998 Impact factor: 2.216
Authors: Tatiana Foroud; Daniel L Koller; Dongbing Lai; Laura Sauerbeck; Craig Anderson; Nerissa Ko; Ranjan Deka; Thomas H Mosley; Myriam Fornage; Daniel Woo; Charles J Moomaw; Richard Hornung; John Huston; Irene Meissner; Joan E Bailey-Wilson; Carl Langefeld; Guy Rouleau; E Sander Connolly; Bradford B Worrall; Dawn Kleindorfer; Matthew L Flaherty; Sharyl Martini; Jason Mackey; Felipe De Los Rios La Rosa; Robert D Brown; Joseph P Broderick Journal: Stroke Date: 2012-09-06 Impact factor: 7.914
Authors: Tatiana Foroud; Dongbing Lai; Daniel Koller; Femke Van't Hof; Mitja I Kurki; Craig S Anderson; Robert D Brown; Edward Sander Connolly; Johan G Eriksson; Matthew Flaherty; Myriam Fornage; Mikael von Und Zu Fraunberg; Emília I Gaál; Aki Laakso; Juha Hernesniemi; John Huston; Juha E Jääskeläinen; Lambertus A Kiemeney; Riku Kivisaari; Dawn Kleindorfer; Nerissa Ko; Hanna Lehto; Jason Mackey; Irene Meissner; Charles J Moomaw; Thomas H Mosley; Marek Moskala; Mika Niemelä; Aarno Palotie; Joanna Pera; Gabriel Rinkel; Stephan Ripke; Guy Rouleau; Ynte Ruigrok; Laura Sauerbeck; Agnieszka Słowik; Sita H Vermeulen; Daniel Woo; Bradford B Worrall; Joseph Broderick Journal: Stroke Date: 2014-09-25 Impact factor: 7.914
Authors: Teresa Santiago-Sim; Xiaoqian Fang; Morgan L Hennessy; Stephen V Nalbach; Steven R DePalma; Ming Sum Lee; Steven C Greenway; Barbara McDonough; Georgene W Hergenroeder; Kyla J Patek; Sarah M Colosimo; Krista J Qualmann; John P Hagan; Dianna M Milewicz; Calum A MacRae; Susan M Dymecki; Christine E Seidman; J G Seidman; Dong H Kim Journal: Stroke Date: 2016-11-15 Impact factor: 7.914