High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms. M. I. Kurki1,2, E. I. Gaál3, J. Kettunen4,5, T. Lappalainen6, V. Anttila4,7,8, F. N. G. van 't Hof9, M. von und zu Fraunberg1,2, H. Lehto3, A. Laakso3, R. Kivisaari3, T. Koivisto1, A. Ronkainen1, J. Rinne1, L. A. L. Kiemeney10,11, S. H. Vermeulen12, M. Kaunisto4,13, J. G. Eriksson5,14,15,16, T. Lehtimäki17, O. T. Raitakari18,19, V. Salomaa5, M. Gunel20, E. T. Dermitzakis6, Y. M. Ruigrok9, G. J. E. Rinkel9, M. Niemelä3, J. Hernesniemi3, S. Ripatti4,5,21, P. I. W. de Bakker8, 22,23,24, A. Palotie4,7,8,25, J. E. Jääskeläinen1,2 1) Kuopio University Hospital, Kuopio, Finland; 2) Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 3) Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland; 4) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; 5) Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; 6) Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland; 7) Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 8) Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; 9) UMC Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands; 10) Department of Urology, Radboud University Nijmegen Medical Centre, The Netherlands; 11) Department for Health Evidence, Radboud University Nijmegen Medical Centre, The Netherlands; 12) Department of Epidemiology, Biostatistics and HTA, Radboud University, Nijmegen Medical Centre, The Netherlands; 13) Folkhälsan Research Centre, Helsinki, Finland; 14) Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; 15) Department of Internal Medicine, Vasa Central Hospital, Vasa, Finland; 16) Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland; 17) Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and University of Tampere, Tampere, Finland; 18) Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland; 19) Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Central Hospital, Turku, Finland; 20) Department of Neurosurgery, Department of Neurobiology and Department of Genetics, Program on Neurogenetics, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT, USA; 21) Hjelt Institute, University of Helsinki, Finland; 22) Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; 23) Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; 24) Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands; 25) Department of Human Genetics, The Wellcome Trust Sanger Institute, Cambridge, UK.

   Population isolates have the potential to provide a shortcut for identification of low frequency and rare variants associated with common diseases. Here we use the benefits of the isolated population of Finland, a sample enriched for familial cases and dense 1000 Genomes based imputation of GWAs data, to identify low frequency variants associated to intracranial aneurysm disease. About 3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form in 10% of the cases. The familial sIA patients more often have multiple aneurysms, suggesting genetic factors contributing to the aneurysm formation process. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain genetic variants are rare throughout Europe but are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2x higher than worldwide, such variants may associate with sIA in the Finnish population. We tested genotyped and 1000 Genomes imputed variants for association in 760 Finnish sIA patients (40% familial cases), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p < 5E-6) were replicated in an additional 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42 x 10-8); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17 x 10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87 x 10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08 x -9). Two of the loci (5q31.3, 6q24.2) were also replicated in the Dutch sample . The 7p22.1 locus was strongly differentiated, as the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusively locus on 2q33.1 in all samples tested (OR 1.27, p 1.87 x 10-12). This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.

You may contact the first author (during and after the meeting) at