High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms.
3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), 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 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 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland ; Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland ; Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Mitja I
MI
Kurki
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
Emília Ilona
EI
Gaál
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Johannes
J
Kettunen
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Tuuli
T
Lappalainen
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Androniki
A
Menelaou
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America ; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Verneri
V
Anttila
UMC Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.
Femke N G
FN
van 't Hof
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland ; Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Mikael
M
von Und Zu Fraunberg
Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Seppo
S
Helisalmi
Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Mikko
M
Hiltunen
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
Hanna
H
Lehto
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
Aki
A
Laakso
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
Riku
R
Kivisaari
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
Timo
T
Koivisto
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
Antti
A
Ronkainen
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
Jaakko
J
Rinne
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands ; Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Lambertus A L
LA
Kiemeney
Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Sita H
SH
Vermeulen
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Folkhälsan Research Centre, Helsinki, Finland.
Mari A
MA
Kaunisto
Folkhälsan Research Centre, Helsinki, Finland ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland ; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland ; Department of Internal Medicine, Vasa Central Hospital, Vasa, Finland ; Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.
Johan G
JG
Eriksson
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Arpo
A
Aromaa
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland ; Estonian Genome Center, University of Tartu, Tartu, Estonia.
Markus
M
Perola
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and University of Tampere, Tampere, Finland.
Terho
T
Lehtimäki
Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland ; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Central Hospital, Turku, Finland.
Olli T
OT
Raitakari
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
Veikko
V
Salomaa
Department of Neurosurgery, Department of Neurobiology and Department of Genetics, Program on Neurogenetics, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, United States of America.
Murat
M
Gunel
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Emmanouil T
ET
Dermitzakis
UMC Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.
Ynte M
YM
Ruigrok
UMC Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.
Gabriel J E
GJ
Rinkel
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
Mika
M
Niemelä
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
Juha
J
Hernesniemi
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland ; Hjelt Institute, University of Helsinki, Helsinki, Finland.
Samuli
S
Ripatti
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands ; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America ; Department of Epidemiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Paul I W
PI
de Bakker
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America ; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America ; Department of Human Genetics, The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
Aarno
A
Palotie
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland ; Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Juha E
JE
Jääskeläinen
D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D005060:Europe; D005387:Finland; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D020521:Stroke / Q000235:genetics* / Q000473:pathology; D013345:Subarachnoid Hemorrhage / Q000235:genetics* / Q000473:pathology