Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure.

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dc.contributor.author Gaál, Emilia I -
dc.contributor.author Salo, Perttu -
dc.contributor.author Kristiansson, Kati -
dc.contributor.author Rehnström, Karola -
dc.contributor.author Kettunen, Johannes -
dc.contributor.author Sarin, Antti-Pekka -
dc.contributor.author Niemelä, Mika -
dc.contributor.author Jula, Antti -
dc.contributor.author Raitakari, Olli T -
dc.contributor.author Lehtimäki, Terho -
dc.contributor.author et al. -
dc.date.accessioned 2012-06-17T20:15:43Z
dc.date.available 2012-06-16 08:49:23 -
dc.date.available 2012-06-17T20:15:43Z
dc.date.issued 2012 -
dc.identifier.issn 1553-7404 -
dc.identifier.uri http://tampub.uta.fi/handle/10024/66119
dc.description Public Library of Science open access -
dc.description.abstract Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN)  =  11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n  =  19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN)  =  3.01E-05, p(ICBP-GWAS)  =  0.0007, p(ALL)  =  8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance. -
dc.language.iso en -
dc.title Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure. -
dc.type fi=Artikkeli aikakauslehdessä | en=Journal article| -
dc.identifier.urn urn:nbn:uta-3-991 -
dc.identifier.doi 10.1371/journal.pgen.1002563 -
dc.type.version fi=Kustantajan versio | en=Publisher's version| -
dc.subject.okm fi=Biolääketieteet | en=Biomedicine| -
dc.administrativeunit fi=Lääketieteen yksikkö | en=School of Medicine| -
dc.journal.title Plos Genetics -
dc.journal.volume 8 -
dc.journal.number 3 -
dc.journal.volumepagerange 1-8 -
dc.oldstats 21 -

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