Molecular basis and genetic predisposition to intracranial aneurysm

Figures & data

Table I. DNA linkage studies on intracranial aneurysms.

Chromosomal region	Study design ^a	Study population	LOD score ^c	Genetic marker	OMIM locus and phenotype IDs	Comments	PMID (ref.)
1p34.3 – p36.13	Family, AD	North American	4.2		ANIB3; 609122	1 family: 10 IA cases	15540160 (34)
1p36.21 – p36.13	Non-parametric	Dutch	3.18	D1S2826 – D1S234	ANIB3; 609122	1 family: same family also linked to X	18309175 (37)
4q32.2	Non-parametric	Multiple	2.5	rs1458149		192 families; LOD = 3.5 in gene × smoking interaction	18323491 (44)
4q32.3	Parametric	Multiple	2.6			333 families	9144135 (45)
5p15.2 – p14.3	Family, AD	French Canadian	3.57	D5S1954	ANIB4; 610213	1 family: 12 IA cases; results confirmed in a second family	16740915 (36)
5q22 – q31	Affected sib pair	Japanese	2.24	D5S471 – D5S2010		85 families	11536080 (41)
7q11	Affected sib pair	Japanese	3.22	D7S2415 – D7S657	ANIB1; 105800	85 families	11536080 (41)
7q11	Affecteds, AR	North American	2.34	D7S2421	ANIB1; 105800	13 families: 39 IA cases	14605871 (97)
8p22	Family, AD	Korean	3.61	D8S552	ANIB11; 614252	5 families: 9 members with and 22 without IA	21451530 (98)
11q24 – q25	Family	Colombian	4.3	rs618176 – rs1940033	ANIB7; 612161	1 family: 7 IA cases	16497978 (35)
12p12.3	Parametric	Multiple	3.1			333 families	9144135 (45)
13q14.12 – q21.1	Family	French Canadian	4.56	rs7983420 – rs17054625		1 family: 10 IA cases	19064780 (38)
14q22	Affected sib pair	Japanese	2.31	D14S258 – D14S74		85 families	11536080 (41)
14q23 – q31	Family	North American	3.0	rs235991 - rs2373098	ANIB8; 612162	1 family: 9 IA cases	16497978 (35)
17cen	Non-parametric	Japanese	3.0	D17S921 – D17S1800		29 families	15569837 (42)
19q13	Affected sib pair with covariates ^b	Finnish	5.70	D19S178 – D19S545	ANIB2; 608542		12153705 (39), 14872410 (40)
19q13	Non-parametric	Japanese	2.15	D19S198 – D19S596	ANIB2; 608542	29 families	15569837 (42)
19q13.3	Affecteds only, parametric^d	Japanese	4.10	D19S198 – D19S902	ANIB2; 608542		17322081 (43)
Xp22	Affected sib pair	Finnish	2.08	DXS987	ANIB5; 300870	48 affected sib pairs	12153705 (39)
Xp22	Non-parametric	Japanese	2.16	DXS987 – DXS7593	ANIB5; 300870	29 families	15569837 (42)
Xp22.32 – p22.2	Non-parametric	Dutch	4.54	DXS6807 – DXS1224	ANIB5; 300870	1 family: 10 IA cases; same family linked to ANIB3	18309175 (37)

AD = autosomal dominant; AR = autosomal recessive.

^aFamily study design refers to parametric analysis.

^bSex and number of affected first-degree relatives were used as covariates.

^cOnly studies with a LOD score of ≥ 2.0 are listed in the table.

^dRe-analyzed 41 affecteds from Yamada et al. 2004 (42).

Table II. Most significant associations with IA in candidate gene studies.

Gene symbol	Polymorphism	Region	Context	Genetic model	Sample size (n)		OR [95% CI]	P value^b	Multiple testing correction	Potential biological mechanism	PMID (ref.)
					Cases^a	Controls^a
ACE	rs4646994	17q23.3	intron	Recessive	854	1,280	1.27 [1.03–1.57]	0.03	Bonferroni	Vascular endothelium	23860151 (57)
COL1A2	rs42524	7q21	missense (p.549P> A)	Dominant	812	806	1.77 [1.14–2.75]	0.0009	Bonferroni	ECM	23733552 (46)
COL3A1	rs1800255	2q32	missense (p.698A> T)	Dominant	546	2,235	1.55 [1.21–2.00]	< 0.00001	Bonferroni	ECM	23733552 (46)
ELN	rs8326	7q11.2	3’-UTR	Allelic	404	458	3.11 [1.96–5.45]	0.000001	Permutation	Vascular endothelium	16611674 (59)
HSPG2	rs3767137	1p36.1	intron	Additive	1,316	1,742	1.22 [1.08–1.39]	0.002	Bonferroni	ECM	23733552 (46)
IL6	rs1800796	7p15	intergenic	Recessive	912	3,410	0.47 [0.34–0.65]	< 0.00001	Bonferroni	Inflammatory mediator	23733552 (46)
JDP2	rs175646	14q24	intron	Allelic	403	412	1.44 [1.15–1.81]	0.0042	Bonferroni	Apoptosis	20452405 (62)
KLK8	rs1722561	19q13.3	intron	Additive	524	578	1.35 [1.14–1.60]	0.008	Sidak	ECM	17761919 (58)
LIMK1	rs6460071	7q11.2	intergenic	Dominant	2,050	1,835	1.31 [1.12–1.53]	0.026	Bonferroni	Actin depolymerization	21228795 (60)
SERPINA3	rs4934	14q32	missense (p.9A> T)	Dominant	892	1,029	2.22 [1.68–2.94]	< 0.00001	Bonferroni	ECM	23733552 (46)
TCN2	rs1801198	22q12	missense (p.259R> P)	Genotypic	255	348	0.48 [0.30–0.77]	0.002	Step-down Sidak–Holm	Methionine metabolism	18799873 (63)
TNFRSF13B	rs4985754	17p11.2	promoter	Haplotype	304	332	0.69 [0.52–0.92]	0.048	Bonferroni	Immunity	16618819 (61)
	rs2274892	17p11.2	intron
	rs34562254	17p11.2	missense (p.251P> L)
	rs11078355	17p11.2	synonymous
VCAN	rs173686	5q14	intron	Additive	857	879	1.23 [1.05–1.43]	0.008	Bonferroni	ECM	23733552 (46)
VCAN	rs251124	5q14	intron	Additive	1,489	1,687	1.25 [1.1–1.41]	0.0007	Bonferroni	ECM	23733552 (46)

^a Only studies with a minimum of 250 cases and 250 controls, and a replication sample and correction for multiple testing were included in the table.

^bP values are taken from either a meta-analysis or the report with largest sample size demonstrating association with IA.

Table III. Most significant associations from genome-wide association studies.

Gene symbol	Polymorphism	Region	Context	OR	95% CI	P value^a	Sample size (n)
							Cases	Controls	PMID (ref.)
CDKN2B-AS1 (ANRIL)	rs1333040	9p21	intron	1.24	[1.2–1.29]	9.83 × 10^−08	11,949	29,014	23733552 (46)
CDKN2B-AS1 (ANRIL)	rs10757278	9p21	intergenic	1.29	[1.21–1.38]	1.59 × 10^−13	3,394	17,075	23733552 (46)
CDKN2B-AS1 (ANRIL)	rs6475606	9p21	intron	1.35	NR	3.59 × 10^−08	1,483	1,683	22961961 (53)
CNNM2	rs12413409	10q24.3	intron	1.29	[1.19–1.40]	1.20 × 10^−09	2,780	12,515	20364137 (72)
EDNRA	rs6841581	4q31.23	intergenic	1.22	[1.14–1.31]	1.95 × 10^−08	4,370	14,181	23733552 (46)
FGD6	rs6538595	12q22	intron	1.16	[1.10–1.23]	1.12 × 10^−07	4,370	14,181	23733552 (46)
RRBP1	rs1132274	20p12.1	missense (p.891R> L)	1.19	[1.11–1.28]	8.29 × 10^−07	4,370	14,181	23733552 (46)
SOX17	rs10958409	8q11.23	intergenic (5’)	1.20	[1.15–1.26]	1.78 × 10^−15	9,873	27,029	23733552 (46)
SOX17	rs9298506	8q11.23	intergenic (3’)	1.21	[1.15–1.27]	1.55 × 10^−13	9,246	26,331	23733552 (46)
STARD13	rs9315204	13q13	intron	1.20	[1.13–1.28]	2.50 × 10^−09	2,780	12,515	20364137 (72)

NR = not reported.

^aOnly results reaching genome-wide significance (× 10⁻⁷) are listed in the table.

Table IV. Microarray-based mRNA and microRNA expression studies on intracranial aneurysms.

PMID of study	Samples for microarray study^a		Study design	Microarray platform (Vendor)	Analysis methods	Public data ID^b
	IA	Controls
17878320 (76)	Pool of 5 RIA (F) Pool of 3 RIA (M) Pool of 4 UIA (M)	Pool of 5 (F)^c Pool of 3 (M)^c 4 non-IA M	Establish expression profile of intracranial arteries to aid in selecting candidate genes for IA	HG-U133 Plus 2.0 (Affymetrix); Sentrix Human WG-6 (Illumina)	Genespring (Silicon Genetics); R and Bioconductor; Beadstudio (Illumina); GO; KEGG	GSE6551
18538937 (77)	6 RIA 4 UIA	4 AVMf	Compare mRNA expression levels between a) ruptured and unruptured IAs b) IA and control artery	Human 1A.v2 Oligo Microarray (Agilent)	GeneSpring GX 7.3 (Agilent); FDR; GO; Network analysis (IPA)
19228845 (79)	3 RIA 3 UIA	6 STA	Compare mRNA expression levels between ruptured and unruptured IAs	Sentrix Human WG-6 v2 (Illumina)	Bioconductor; FDR; GO; KEGG; Network analysis (IPA)
19752560 (78)^d	3 UIA	3 STA	Compare mRNA expression levels between unruptured IA and control arteries	HG-U133 Plus 2.0 (Affymetrix)	GeneSpring 9.05 (Agilent); GO; KEGG; DAVID	GSE26969
20487632 (80)	12 RIA 10 UIA	4 control STA^e 4 control MMA 9 SAH-STA 9 SAH-MMA 12 UIA-STA 12 UIA-MMA	Compare mRNA expression levels between: a) ruptured and unruptured IAs b) IA and control artery	HG-U133A (Affymetrix)	GeneSpring GX 7.3 (Agilent); FDR
20044533 (81)	8 RIA 6 UIA	5 control MMA	Compare mRNA expression levels between: a) ruptured and unruptured IAs b) IA and control artery	Human Gene ST 1.0 (Affymetrix)	dChip; FDR; GO	GSE15629
21336216 (82)^f	11 RIA 8 UIA		Compare mRNA expression levels between ruptured and unruptured IAs	HG-U133 Plus 2.0 (Affymetrix)	Bioconductor; R; FDR; GO; KEGG; DAVID; Whole Genome rVISTA	GSE13353
24079748 (83)	3 RIA^g	3 control MMA	Compare mRNA and miRNA expression levels between IA and control arteries. Investigate role of miRNAs in the control of gene regulation in IA	microRNA array 16.0 (Agilent); Whole Human Genome Oligo Microarray (Agilent)	Network analysis (IPA); miRNA target analysis (IPA)	GSE46338
23512133 (84)	43 RIA	18	Compare mRNA expression levels in blood between ruptured IA and controls	HumanHT-12 BeadChip (Illumina)	R; FDR; GO; KEGG	GSE36791

^aWeinsheimer et al. (76) study used autopsy samples, Pera et al. 2013 (84) used blood samples, and all other studies used aortic tissue samples obtained in operations.

^bData are available at http://www.ncbi.nlm.nih.gov/geo.

^cThese controls were from the non-aneurysmal contralateral artery.

^dThese data have been re-analyzed in another study (99).

^eControl artery samples were collected from the STA and MMA of SAH and UIA patients as well as from patients without IA.

^fThese data have been re-analyzed in another study (100).

^gOnly 2 IA and 2 control samples were used for miRNA microarray study, whereas 3 IA samples and 3 controls were used for mRNA expression study.

AVMf = arteriovenous malformation feeder; F = female; FDR = false discovery rate; GO = Gene Ontology; KEGG = Kyoto Encyclopedia of Genes and Genomes; M = male; MMA = middle meningeal artery; RIA = ruptured intracranial aneurysm; SAH = subarachnoid hemorrhage; STA = superficial temporal artery; UIA = unruptured intracranial aneurysm.

Figure 1. Genetic map of intracranial aneurysm loci. Red vertical lines adjacent to the chromosome ideograms indicate regions identified by DNA linkage studies (Table I), pale red vertical lines indicate support for a region that arises from a family linked to two loci, blue stars indicate locations of SNPs found in genome-wide association studies (Table III), and green round symbols indicate locations of SNPs found in candidate gene association studies (Table II). The ideograms can be obtained from ‘Idiogram Album: Human’ (copyright^© 1994 David Adler, University of Washington, Department of Pathology) at http://www.pathology.washington.edu/research/cytopages/idiograms/human/.

Nahed BV, Seker A, Guclu B, Ozturk AK, Finberg K, Hawkins AA, et al. Mapping a Mendelian form of intracranial aneurysm to 1p34.3-p36.13. Am J Hum Genet. 2005;76:172–9.

 PubMed Web of Science ®Google Scholar

Ruigrok YM, Wijmenga C, Rinkel GJ, van’t Slot R, Baas F, Wolfs M, et al. Genomewide linkage in a large Dutch family with intracranial aneurysms: replication of 2 loci for intracranial aneurysms to chromosome 1p36.11-p36.13 and Xp22.2-p22.32. Stroke. 2008;39:1096–102.

 PubMedGoogle Scholar

Foroud T, Sauerbeck L, Brown R, Anderson C, Woo D, Kleindorfer D, et al. Genome screen to detect linkage to intracranial aneurysm susceptibility genes: the Familial Intracranial Aneurysm (FIA) study. Stroke. 2008;39:1434–40.

 PubMedGoogle Scholar

Foroud T, Sauerbeck L, Brown R, Anderson C, Woo D, Kleindorfer D, et al. Genome screen in familial intracranial aneurysm. BMC Med Genet. 2009;10:3.

 PubMed Web of Science ®Google Scholar

Verlaan DJ, Dube MP, St-Onge J, Noreau A, Roussel J, Satge N, et al. A new locus for autosomal dominant intracranial aneurysm, ANIB4, maps to chromosome 5p15.2-14.3. J Med Genet. 2006;43:e31.

 PubMedGoogle Scholar

Onda H, Kasuya H, Yoneyama T, Takakura K, Hori T, Takeda J, et al. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet. 2001; 69:804–19.

 PubMed Web of Science ®Google Scholar

Farnham JM, Camp NJ, Neuhausen SL, Tsuruda J, Parker D, MacDonald J, et al. Confirmation of chromosome 7q11 locus for predisposition to intracranial aneurysm. Hum Genet. 2004;114:250–5.

 PubMed Web of Science ®Google Scholar

Kim CJ, Park SS, Lee HS, Chung HJ, Choi W, Chung JH, et al. Identification of an autosomal dominant locus for intracranial aneurysm through a model-based family collection in a geographically limited area. J Hum Genet. 2011;56:464–6.

 Google Scholar

Ozturk AK, Nahed BV, Bydon M, Bilguvar K, Goksu E, Bademci G, et al. Molecular genetic analysis of two large kindreds with intracranial aneurysms demonstrates linkage to 11q24-25 and 14q23-31. Stroke. 2006;37:1021–7.

 PubMedGoogle Scholar

Santiago-Sim T, Depalma SR, Ju KL, McDonough B, Seidman CE, Seidman JG, et al. Genomewide linkage in a large Caucasian family maps a new locus for intracranial aneurysms to chromosome 13q. Stroke. 2009;40:S57–60.

 Google Scholar

Yamada S, Utsunomiya M, Inoue K, Nozaki K, Inoue S, Takenaka K, et al. Genome-wide scan for Japanese familial intracranial aneurysms: linkage to several chromosomal regions. Circulation. 2004;110:3727–33.

 PubMedGoogle Scholar

Olson JM, Vongpunsawad S, Kuivaniemi H, Ronkainen A, Hernesniemi J, Ryynanen M, et al. Search for intracranial aneurysm susceptibility gene(s) using Finnish families. BMC Med Genet. 2002;3:7.

 PubMedGoogle Scholar

van der Voet M, Olson JM, Kuivaniemi H, Dudek DM, Skunca M, Ronkainen A, et al. Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3. Am J Hum Genet. 2004;74:564–71.

 PubMed Web of Science ®Google Scholar

Mineharu Y, Inoue K, Inoue S, Yamada S, Nozaki K, Hashimoto N, et al. Model-based linkage analyses confirm chromosome 19q13.3 as a susceptibility locus for intracranial aneurysm. Stroke. 2007;38:1174–8.

 PubMedGoogle Scholar

Chen Z, Ma J, Cen Y, Liu Y, You C. The angiotensin converting enzyme insertion/deletion polymorphism and intracranial aneurysm: a meta-analysis of case-control studies. Neurol India. 2013;61:293–9.

 Google Scholar

Alg VS, Sofat R, Houlden H, Werring DJ. Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals. Neurology. 2013;80:2154–65.

 PubMed Web of Science ®Google Scholar

Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, et al. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Hum Mol Genet. 2006;15:1722–34.

 PubMed Web of Science ®Google Scholar

Krischek B, Tajima A, Akagawa H, Narita A, Ruigrok Y, Rinkel G, et al. Association of the Jun dimerization protein 2 gene with intracranial aneurysms in Japanese and Korean cohorts as compared to a Dutch cohort. Neuroscience. 2010;169:339–43.

 Google Scholar

Weinsheimer S, Goddard KA, Parrado AR, Lu Q, Sinha M, Lebedeva ER, et al. Association of kallikrein gene polymorphisms with intracranial aneurysms. Stroke. 2007;38:2670–6.

 Google Scholar

Low SK, Zembutsu H, Takahashi A, Kamatani N, Cha PC, Hosono N, et al. Impact of LIMK1, MMP2 and TNF-alpha variations for intracranial aneurysm in Japanese population. J Hum Genet. 2011;56:211–16.

 PubMed Web of Science ®Google Scholar

Semmler A, Linnebank M, Krex D, Gotz A, Moskau S, Ziegler A, et al. Polymorphisms of homocysteine metabolism are associated with intracranial aneurysms. Cerebrovasc Dis. 2008;26:425–9.

 PubMed Web of Science ®Google Scholar

Inoue K, Mineharu Y, Inoue S, Yamada S, Matsuda F, Nozaki K, et al. Search on chromosome 17 centromere reveals TNFRSF13B as a susceptibility gene for intracranial aneurysm: a preliminary study. Circulation. 2006;113:2002–10.

 PubMedGoogle Scholar

Foroud T, Koller DL, Lai D, Sauerbeck L, Anderson C, Ko N, et al. Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk. Stroke. 2012;43:2846–52.

 PubMed Web of Science ®Google Scholar

Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet. 2010;42:420–5.

 PubMed Web of Science ®Google Scholar

Weinsheimer S, Lenk GM, van der Voet M, Land S, Ronkainen A, Alafuzoff I, et al. Integration of expression profiles and genetic mapping data to identify candidate genes in intracranial aneurysm. Physiol Genomics. 2007;32:45–57.

 Google Scholar

Krischek B, Kasuya H, Tajima A, Akagawa H, Sasaki T, Yoneyama T, et al. Network-based gene expression analysis of intracranial aneurysm tissue reveals role of antigen presenting cells. Neuroscience. 2008;154:1398–407.

 PubMedGoogle Scholar

Shi C, Awad IA, Jafari N, Lin S, Du P, Hage ZA, et al. Genomics of human intracranial aneurysm wall. Stroke. 2009;40:1252–61.

 PubMedGoogle Scholar

Li L, Yang X, Jiang F, Dusting GJ, Wu Z. Transcriptome-wide characterization of gene expression associated with unruptured intracranial aneurysms. Eur Neurol. 2009;62:330–7.

 Google Scholar

Marchese E, Vignati A, Albanese A, Nucci CG, Sabatino G, Tirpakova B, et al. Comparative evaluation of genome-wide gene expression profiles in ruptured and unruptured human intracranial aneurysms. J Biol Regul Homeost Agents. 2010;24:185–95.

 Google Scholar

Pera J, Korostynski M, Krzyszkowski T, Czopek J, Slowik A, Dziedzic T, et al. Gene expression profiles in human ruptured and unruptured intracranial aneurysms: what is the role of inflammation? Stroke. 2010;41:224–31.

 PubMed Web of Science ®Google Scholar

Kurki MI, Hakkinen SK, Frosen J, Tulamo R, von und zu Fraunberg M, Wong G, et al. Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: an emerging regulative role of Toll-like receptor signaling and nuclear factor-kappaB, hypoxia-inducible factor-1A, and ETS transcription factors. Neurosurgery. 2011;68: 1667–75; discussion 1675–6.

 PubMed Web of Science ®Google Scholar

Jiang Y, Zhang M, He H, Chen J, Zeng H, Li J, et al. MicroRNA/mRNA profiling and regulatory network of intracranial aneurysm. BMC Med Genomics. 2013;6:36.

 PubMed Web of Science ®Google Scholar

Pera J, Korostynski M, Golda S, Piechota M, Dzbek J, Krzyszkowski T, et al. Gene expression profiling of blood in ruptured intracranial aneurysms: in search of biomarkers. J Cereb Blood Flow Metab. 2013;33:1025–31.

 Google Scholar

Wei L, Gao YJ, Wei SP, Zhang YF, Zhang WF, Jiang JX, et al. Transcriptome network-based method to identify genes associated with unruptured intracranial aneurysms. Genet Mol Res. 2013;12: 3263–73.

 Google Scholar

Chen L, Wan JQ, Zhou JP, Fan YL, Jiang JY. Gene expression analysis of ruptured and un-ruptured saccular intracranial aneurysm. Eur Rev Med Pharmacol Sci. 2013;17:1374–81.

 Google Scholar