ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage

Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD ha...
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Autor*in:	Natalia Cullell [verfasserIn] Cristina Gallego-Fábrega [verfasserIn] Jara Cárcel-Márquez [verfasserIn] Elena Muiño [verfasserIn] Laia Llucià-Carol [verfasserIn] Miquel Lledós [verfasserIn] Jesús M. Martín-Campos [verfasserIn] Jessica Molina [verfasserIn] Laura Casas [verfasserIn] Marta Almeria [verfasserIn] Israel Fernández-Cadenas [verfasserIn] Jerzy Krupinski [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS)

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 23(2022), 6, p 3161
Übergeordnetes Werk:	volume:23 ; year:2022 ; number:6, p 3161

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms23063161

Katalog-ID:	DOAJ027576884

Internformat


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520			\|a Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.
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allfields	10.3390/ijms23063161 doi (DE-627)DOAJ027576884 (DE-599)DOAJc5be74fb1093414e98c8cf6adb3a9967 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Natalia Cullell verfasserin aut ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS) Biology (General) Chemistry Cristina Gallego-Fábrega verfasserin aut Jara Cárcel-Márquez verfasserin aut Elena Muiño verfasserin aut Laia Llucià-Carol verfasserin aut Miquel Lledós verfasserin aut Jesús M. Martín-Campos verfasserin aut Jessica Molina verfasserin aut Laura Casas verfasserin aut Marta Almeria verfasserin aut Israel Fernández-Cadenas verfasserin aut Jerzy Krupinski verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 6, p 3161 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:6, p 3161 https://doi.org/10.3390/ijms23063161 kostenfrei https://doaj.org/article/c5be74fb1093414e98c8cf6adb3a9967 kostenfrei https://www.mdpi.com/1422-0067/23/6/3161 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 6, p 3161
spelling	10.3390/ijms23063161 doi (DE-627)DOAJ027576884 (DE-599)DOAJc5be74fb1093414e98c8cf6adb3a9967 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Natalia Cullell verfasserin aut ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS) Biology (General) Chemistry Cristina Gallego-Fábrega verfasserin aut Jara Cárcel-Márquez verfasserin aut Elena Muiño verfasserin aut Laia Llucià-Carol verfasserin aut Miquel Lledós verfasserin aut Jesús M. Martín-Campos verfasserin aut Jessica Molina verfasserin aut Laura Casas verfasserin aut Marta Almeria verfasserin aut Israel Fernández-Cadenas verfasserin aut Jerzy Krupinski verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 6, p 3161 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:6, p 3161 https://doi.org/10.3390/ijms23063161 kostenfrei https://doaj.org/article/c5be74fb1093414e98c8cf6adb3a9967 kostenfrei https://www.mdpi.com/1422-0067/23/6/3161 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 6, p 3161
allfields_unstemmed	10.3390/ijms23063161 doi (DE-627)DOAJ027576884 (DE-599)DOAJc5be74fb1093414e98c8cf6adb3a9967 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Natalia Cullell verfasserin aut ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS) Biology (General) Chemistry Cristina Gallego-Fábrega verfasserin aut Jara Cárcel-Márquez verfasserin aut Elena Muiño verfasserin aut Laia Llucià-Carol verfasserin aut Miquel Lledós verfasserin aut Jesús M. Martín-Campos verfasserin aut Jessica Molina verfasserin aut Laura Casas verfasserin aut Marta Almeria verfasserin aut Israel Fernández-Cadenas verfasserin aut Jerzy Krupinski verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 6, p 3161 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:6, p 3161 https://doi.org/10.3390/ijms23063161 kostenfrei https://doaj.org/article/c5be74fb1093414e98c8cf6adb3a9967 kostenfrei https://www.mdpi.com/1422-0067/23/6/3161 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 6, p 3161
allfieldsGer	10.3390/ijms23063161 doi (DE-627)DOAJ027576884 (DE-599)DOAJc5be74fb1093414e98c8cf6adb3a9967 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Natalia Cullell verfasserin aut ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS) Biology (General) Chemistry Cristina Gallego-Fábrega verfasserin aut Jara Cárcel-Márquez verfasserin aut Elena Muiño verfasserin aut Laia Llucià-Carol verfasserin aut Miquel Lledós verfasserin aut Jesús M. Martín-Campos verfasserin aut Jessica Molina verfasserin aut Laura Casas verfasserin aut Marta Almeria verfasserin aut Israel Fernández-Cadenas verfasserin aut Jerzy Krupinski verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 6, p 3161 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:6, p 3161 https://doi.org/10.3390/ijms23063161 kostenfrei https://doaj.org/article/c5be74fb1093414e98c8cf6adb3a9967 kostenfrei https://www.mdpi.com/1422-0067/23/6/3161 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 6, p 3161
allfieldsSound	10.3390/ijms23063161 doi (DE-627)DOAJ027576884 (DE-599)DOAJc5be74fb1093414e98c8cf6adb3a9967 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Natalia Cullell verfasserin aut ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS) Biology (General) Chemistry Cristina Gallego-Fábrega verfasserin aut Jara Cárcel-Márquez verfasserin aut Elena Muiño verfasserin aut Laia Llucià-Carol verfasserin aut Miquel Lledós verfasserin aut Jesús M. Martín-Campos verfasserin aut Jessica Molina verfasserin aut Laura Casas verfasserin aut Marta Almeria verfasserin aut Israel Fernández-Cadenas verfasserin aut Jerzy Krupinski verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 23(2022), 6, p 3161 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:23 year:2022 number:6, p 3161 https://doi.org/10.3390/ijms23063161 kostenfrei https://doaj.org/article/c5be74fb1093414e98c8cf6adb3a9967 kostenfrei https://www.mdpi.com/1422-0067/23/6/3161 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 23 2022 6, p 3161
language	English
source	In International Journal of Molecular Sciences 23(2022), 6, p 3161 volume:23 year:2022 number:6, p 3161
sourceStr	In International Journal of Molecular Sciences 23(2022), 6, p 3161 volume:23 year:2022 number:6, p 3161
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS) Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Natalia Cullell @@aut@@ Cristina Gallego-Fábrega @@aut@@ Jara Cárcel-Márquez @@aut@@ Elena Muiño @@aut@@ Laia Llucià-Carol @@aut@@ Miquel Lledós @@aut@@ Jesús M. Martín-Campos @@aut@@ Jessica Molina @@aut@@ Laura Casas @@aut@@ Marta Almeria @@aut@@ Israel Fernández-Cadenas @@aut@@ Jerzy Krupinski @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ027576884
language_de	englisch
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Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). 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callnumber-first	Q - Science
author	Natalia Cullell
spellingShingle	Natalia Cullell misc QH301-705.5 misc QD1-999 misc small vessel disease misc small vessel stroke misc intracerebral haemorrhage misc PWAS misc proteome-wide association study misc genome-wide association study (GWAS) misc Biology (General) misc Chemistry ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage
authorStr	Natalia Cullell
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topic_title	QH301-705.5 QD1-999 ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage small vessel disease small vessel stroke intracerebral haemorrhage PWAS proteome-wide association study genome-wide association study (GWAS)
topic	misc QH301-705.5 misc QD1-999 misc small vessel disease misc small vessel stroke misc intracerebral haemorrhage misc PWAS misc proteome-wide association study misc genome-wide association study (GWAS) misc Biology (General) misc Chemistry
topic_unstemmed	misc QH301-705.5 misc QD1-999 misc small vessel disease misc small vessel stroke misc intracerebral haemorrhage misc PWAS misc proteome-wide association study misc genome-wide association study (GWAS) misc Biology (General) misc Chemistry
topic_browse	misc QH301-705.5 misc QD1-999 misc small vessel disease misc small vessel stroke misc intracerebral haemorrhage misc PWAS misc proteome-wide association study misc genome-wide association study (GWAS) misc Biology (General) misc Chemistry
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title	ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage
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title_full	ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage
author_sort	Natalia Cullell
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author_browse	Natalia Cullell Cristina Gallego-Fábrega Jara Cárcel-Márquez Elena Muiño Laia Llucià-Carol Miquel Lledós Jesús M. Martín-Campos Jessica Molina Laura Casas Marta Almeria Israel Fernández-Cadenas Jerzy Krupinski
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author-letter	Natalia Cullell
doi_str_mv	10.3390/ijms23063161
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title_sort	ica1l is associated with small vessel disease: a proteome-wide association study in small vessel stroke and intracerebral haemorrhage
callnumber	QH301-705.5
title_auth	ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage
abstract	Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.
abstractGer	Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.
abstract_unstemmed	Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). Our results show that the association of <i<ICA1L</i< with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.
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title_short	ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage
url	https://doi.org/10.3390/ijms23063161 https://doaj.org/article/c5be74fb1093414e98c8cf6adb3a9967 https://www.mdpi.com/1422-0067/23/6/3161 https://doaj.org/toc/1661-6596 https://doaj.org/toc/1422-0067
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Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (<i<q</i<-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and <i<p</i<-value = 9.6 × 10<sup<−6</sup<) and non-lobar ICH (z-score = −4.8 and <i<p</i<-value = 1.58 × 10<sup<−6</sup<) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (<i<p</i<-value = 3.66 × 10<sup<−5</sup<) and non-lobar ICH (<i<p</i<-value = 1.81 × 10<sup<−5</sup<). 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ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage

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