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7 results on '"Gaal, E.I."'

1. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Author

Hof, F.N. van 't, Ruigrok, Y.M., Lee, C.H., Ripke, S., Anderson, G., Baas, A.F., Blankensteijn, J.D., Bottinger, E.P., Bown, M.J., Broderick, J., Bijlenga, P., Carrell, D.S., Crawford, D.C., Crosslin, D.R., Ebeling, C., Eriksson, J.G., Fornage, M., Foroud, T., von Und Zu Fraunberg, M., Friedrich, C.M., Gaal, E.I., Gottesman, O., Guo, D.C., Harrison, S.C., Hernesniemi, J., Hofman, A., Inoue, I., Jaaskelainen, J.E., Jones, G.T., Kiemeney, L.A., Kivisaari, R., Ko, N., Koskinen, S., Kubo, M., Kullo, I.J., Kuivaniemi, H., Kurki, M.I., Laakso, A., Lai, D., Leal, S.M., Lehto, H., Lemaire, S.A., Low, S.K., Malinowski, J., McCarty, C.A., Milewicz, D.M., Mosley, T.H., Nakamura, Y., Nakaoka, H., Niemela, M., Pacheco, J., Peissig, P.L., Pera, J., Rasmussen-Torvik, L., Ritchie, M.D., Rivadeneira, F., Rij, A.M. van, Santos-Cortez, R.L., Saratzis, A., Slowik, A., Takahashi, A., Tromp, G., Uitterlinden, A.G., Verma, S.S., Vermeulen, S.H., Wang, G.T., Han, B., Rinkel, G.J., Bakker, P.I. de, Graaf, J. de, et al., Hof, F.N. van 't, Ruigrok, Y.M., Lee, C.H., Ripke, S., Anderson, G., Baas, A.F., Blankensteijn, J.D., Bottinger, E.P., Bown, M.J., Broderick, J., Bijlenga, P., Carrell, D.S., Crawford, D.C., Crosslin, D.R., Ebeling, C., Eriksson, J.G., Fornage, M., Foroud, T., von Und Zu Fraunberg, M., Friedrich, C.M., Gaal, E.I., Gottesman, O., Guo, D.C., Harrison, S.C., Hernesniemi, J., Hofman, A., Inoue, I., Jaaskelainen, J.E., Jones, G.T., Kiemeney, L.A., Kivisaari, R., Ko, N., Koskinen, S., Kubo, M., Kullo, I.J., Kuivaniemi, H., Kurki, M.I., Laakso, A., Lai, D., Leal, S.M., Lehto, H., Lemaire, S.A., Low, S.K., Malinowski, J., McCarty, C.A., Milewicz, D.M., Mosley, T.H., Nakamura, Y., Nakaoka, H., Niemela, M., Pacheco, J., Peissig, P.L., Pera, J., Rasmussen-Torvik, L., Ritchie, M.D., Rivadeneira, F., Rij, A.M. van, Santos-Cortez, R.L., Saratzis, A., Slowik, A., Takahashi, A., Tromp, G., Uitterlinden, A.G., Verma, S.S., Vermeulen, S.H., Wang, G.T., Han, B., Rinkel, G.J., Bakker, P.I. de, Graaf, J. de, and et al.

Abstract

Contains fulltext : 171496.pdf (publisher's version ) (Open Access), BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RESULTS: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1x10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1x10(-3)). CONCLUSIONS: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.

Published
2016

2. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Author

Hof, F.N. van 't, Ruigrok, Y.M., Lee, C.H., Ripke, S., Anderson, G., Baas, A.F., Blankensteijn, J.D., Bottinger, E.P., Bown, M.J., Broderick, J., Bijlenga, P., Carrell, D.S., Crawford, D.C., Crosslin, D.R., Ebeling, C., Eriksson, J.G., Fornage, M., Foroud, T., von Und Zu Fraunberg, M., Friedrich, C.M., Gaal, E.I., Gottesman, O., Guo, D.C., Harrison, S.C., Hernesniemi, J., Hofman, A., Inoue, I., Jaaskelainen, J.E., Jones, G.T., Kiemeney, L.A., Kivisaari, R., Ko, N., Koskinen, S., Kubo, M., Kullo, I.J., Kuivaniemi, H., Kurki, M.I., Laakso, A., Lai, D., Leal, S.M., Lehto, H., Lemaire, S.A., Low, S.K., Malinowski, J., McCarty, C.A., Milewicz, D.M., Mosley, T.H., Nakamura, Y., Nakaoka, H., Niemela, M., Pacheco, J., Peissig, P.L., Pera, J., Rasmussen-Torvik, L., Ritchie, M.D., Rivadeneira, F., Rij, A.M. van, Santos-Cortez, R.L., Saratzis, A., Slowik, A., Takahashi, A., Tromp, G., Uitterlinden, A.G., Verma, S.S., Vermeulen, S.H., Wang, G.T., Han, B., Rinkel, G.J., Bakker, P.I. de, Graaf, J. de, et al., Hof, F.N. van 't, Ruigrok, Y.M., Lee, C.H., Ripke, S., Anderson, G., Baas, A.F., Blankensteijn, J.D., Bottinger, E.P., Bown, M.J., Broderick, J., Bijlenga, P., Carrell, D.S., Crawford, D.C., Crosslin, D.R., Ebeling, C., Eriksson, J.G., Fornage, M., Foroud, T., von Und Zu Fraunberg, M., Friedrich, C.M., Gaal, E.I., Gottesman, O., Guo, D.C., Harrison, S.C., Hernesniemi, J., Hofman, A., Inoue, I., Jaaskelainen, J.E., Jones, G.T., Kiemeney, L.A., Kivisaari, R., Ko, N., Koskinen, S., Kubo, M., Kullo, I.J., Kuivaniemi, H., Kurki, M.I., Laakso, A., Lai, D., Leal, S.M., Lehto, H., Lemaire, S.A., Low, S.K., Malinowski, J., McCarty, C.A., Milewicz, D.M., Mosley, T.H., Nakamura, Y., Nakaoka, H., Niemela, M., Pacheco, J., Peissig, P.L., Pera, J., Rasmussen-Torvik, L., Ritchie, M.D., Rivadeneira, F., Rij, A.M. van, Santos-Cortez, R.L., Saratzis, A., Slowik, A., Takahashi, A., Tromp, G., Uitterlinden, A.G., Verma, S.S., Vermeulen, S.H., Wang, G.T., Han, B., Rinkel, G.J., Bakker, P.I. de, Graaf, J. de, and et al.

Abstract

Contains fulltext : 171496.pdf (publisher's version ) (Open Access), BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RESULTS: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1x10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1x10(-3)). CONCLUSIONS: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.

Published
2016

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

Author

Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., Jaaskelainen, J.E., Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., and Jaaskelainen, J.E.

Abstract

Contains fulltext : 138172.pdf (publisher's version ) (Open Access), 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 >2x 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 1.42x10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17x10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87x10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08x-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 1.87x10-12). 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.

Published
2014

4. Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7

Author

Foroud, T., Lai, D., Koller, D., Hof, F. Van't, Kurki, M.I., Anderson, C.S., Brown, R.D., Jr., Connolly, E.S., Jr., Eriksson, J.G., Flaherty, M., Fornage, M., Fraunberg, M. von Und Zu, Gaal, E.I., Laakso, A., Hernesniemi, J., Huston, J., Jaaskelainen, J.E., Kiemeney, L.A.L.M., Kivisaari, R., Kleindorfer, D., Ko, N., Lehto, H., Mackey, J., Meissner, I., Moomaw, C.J., Mosley, T.H., Moskala, M., Niemela, M., Palotie, A., Pera, J., Rinkel, G., Ripke, S., Rouleau, G., Ruigrok, Y., Sauerbeck, L., Slowik, A., Vermeulen, S., Woo, D., Worrall, B.B., Broderick, J., et al., Foroud, T., Lai, D., Koller, D., Hof, F. Van't, Kurki, M.I., Anderson, C.S., Brown, R.D., Jr., Connolly, E.S., Jr., Eriksson, J.G., Flaherty, M., Fornage, M., Fraunberg, M. von Und Zu, Gaal, E.I., Laakso, A., Hernesniemi, J., Huston, J., Jaaskelainen, J.E., Kiemeney, L.A.L.M., Kivisaari, R., Kleindorfer, D., Ko, N., Lehto, H., Mackey, J., Meissner, I., Moomaw, C.J., Mosley, T.H., Moskala, M., Niemela, M., Palotie, A., Pera, J., Rinkel, G., Ripke, S., Rouleau, G., Ruigrok, Y., Sauerbeck, L., Slowik, A., Vermeulen, S., Woo, D., Worrall, B.B., Broderick, J., and et al.

Abstract

Item does not contain fulltext, BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0x10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14x10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91x10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.

Published
2014

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

Author

Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., Jaaskelainen, J.E., Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., and Jaaskelainen, J.E.

Abstract

Contains fulltext : 138172.pdf (publisher's version ) (Open Access), 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 >2x 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 1.42x10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17x10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87x10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08x-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 1.87x10-12). 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.

Published
2014

6. Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7

Author

Foroud, T., Lai, D., Koller, D., Hof, F. Van't, Kurki, M.I., Anderson, C.S., Brown, R.D., Jr., Connolly, E.S., Jr., Eriksson, J.G., Flaherty, M., Fornage, M., Fraunberg, M. von Und Zu, Gaal, E.I., Laakso, A., Hernesniemi, J., Huston, J., Jaaskelainen, J.E., Kiemeney, L.A.L.M., Kivisaari, R., Kleindorfer, D., Ko, N., Lehto, H., Mackey, J., Meissner, I., Moomaw, C.J., Mosley, T.H., Moskala, M., Niemela, M., Palotie, A., Pera, J., Rinkel, G., Ripke, S., Rouleau, G., Ruigrok, Y., Sauerbeck, L., Slowik, A., Vermeulen, S., Woo, D., Worrall, B.B., Broderick, J., et al., Foroud, T., Lai, D., Koller, D., Hof, F. Van't, Kurki, M.I., Anderson, C.S., Brown, R.D., Jr., Connolly, E.S., Jr., Eriksson, J.G., Flaherty, M., Fornage, M., Fraunberg, M. von Und Zu, Gaal, E.I., Laakso, A., Hernesniemi, J., Huston, J., Jaaskelainen, J.E., Kiemeney, L.A.L.M., Kivisaari, R., Kleindorfer, D., Ko, N., Lehto, H., Mackey, J., Meissner, I., Moomaw, C.J., Mosley, T.H., Moskala, M., Niemela, M., Palotie, A., Pera, J., Rinkel, G., Ripke, S., Rouleau, G., Ruigrok, Y., Sauerbeck, L., Slowik, A., Vermeulen, S., Woo, D., Worrall, B.B., Broderick, J., and et al.

Abstract

Item does not contain fulltext, BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0x10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14x10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91x10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.

Published
2014

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

Author

Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., Jaaskelainen, J.E., Kurki, M.I., Gaal, E.I., Kettunen, J., Lappalainen, T., Menelaou, A., Anttila, V., Hof, F.N. van 't, Fraunberg, M. von Und Zu, Helisalmi, S., Hiltunen, M., Lehto, H., Laakso, A., Kivisaari, R., Koivisto, T., Ronkainen, A., Rinne, J., Kiemeney, B., Vermeulen, S., Kaunisto, M.A., Eriksson, J.G., Aromaa, A., Perola, M., Lehtimaki, T., Raitakari, O.T., Salomaa, V., Gunel, M., Dermitzakis, E.T., Ruigrok, Y.M., Rinkel, G.J., Niemela, M., Hernesniemi, J., Ripatti, S., Bakker, P.I. de, Palotie, A., and Jaaskelainen, J.E.

Abstract

Contains fulltext : 138172.pdf (publisher's version ) (Open Access), 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 >2x 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 1.42x10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17x10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87x10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08x-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 1.87x10-12). 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.

Published
2014

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