PLoS Genetics (Jan 2014)

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

  • Mitja I Kurki,
  • Emília Ilona Gaál,
  • Johannes Kettunen,
  • Tuuli Lappalainen,
  • Androniki Menelaou,
  • Verneri Anttila,
  • Femke N G van 't Hof,
  • Mikael von Und Zu Fraunberg,
  • Seppo Helisalmi,
  • Mikko Hiltunen,
  • Hanna Lehto,
  • Aki Laakso,
  • Riku Kivisaari,
  • Timo Koivisto,
  • Antti Ronkainen,
  • Jaakko Rinne,
  • Lambertus A L Kiemeney,
  • Sita H Vermeulen,
  • Mari A Kaunisto,
  • Johan G Eriksson,
  • Arpo Aromaa,
  • Markus Perola,
  • Terho Lehtimäki,
  • Olli T Raitakari,
  • Veikko Salomaa,
  • Murat Gunel,
  • Emmanouil T Dermitzakis,
  • Ynte M Ruigrok,
  • Gabriel J E Rinkel,
  • Mika Niemelä,
  • Juha Hernesniemi,
  • Samuli Ripatti,
  • Paul I W de Bakker,
  • Aarno Palotie,
  • Juha E Jääskeläinen

DOI
https://doi.org/10.1371/journal.pgen.1004134
Journal volume & issue
Vol. 10, no. 1
p. e1004134

Abstract

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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.