title: Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure.
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.
authors.affiliation: Public Health Genomics Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. emilia.gaal@helsinki.fi
authors.forename: Emília Ilona
authors.initials: EI
authors.lastname: Gaál
authors.forename: Perttu
authors.initials: P
authors.lastname: Salo
authors.forename: Kati
authors.initials: K
authors.lastname: Kristiansson
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnström
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Sarin
authors.forename: Mika
authors.initials: M
authors.lastname: Niemelä
authors.forename: Antti
authors.initials: A
authors.lastname: Jula
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Widen
authors.forename: Murat
authors.initials: M
authors.lastname: Günel
authors.forename: Mitja
authors.initials: M
authors.lastname: Kurki
authors.forename: Mikael
authors.initials: M
authors.lastname: von und Zu Fraunberg
authors.forename: Juha E
authors.initials: JE
authors.lastname: Jääskeläinen
authors.forename: Juha
authors.initials: J
authors.lastname: Hernesniemi
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D005387:Finland; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; C574688:PRDM6 protein, human; D014157:Transcription Factors