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PLoS Genet. 2014 Jan 30;10(1):e1004134. doi: 10.1371/journal.pgen.1004134. eCollection 2014 Jan.

High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms.

Author information

1
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.
2
Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
3
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
4
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
5
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
6
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.
7
UMC Utrecht Stroke Center, Department of Neurology and Neurosurgery, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.
8
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland ; Neurosurgery, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
9
Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
10
Neurosurgery, NeuroCenter, Kuopio University Hospital, Kuopio, Finland.
11
Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands ; Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
12
Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
13
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland ; Folkhälsan Research Centre, Helsinki, Finland.
14
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.
15
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
16
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.
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 ; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Central Hospital, Turku, Finland.
19
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.
20
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.
21
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.
22
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.

Abstract

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.

PMID:
24497844
PMCID:
PMC3907358
DOI:
10.1371/journal.pgen.1004134
[Indexed for MEDLINE]
Free PMC Article
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