ed7dbb9df8970e75c4986f9c5372a035 pmc_8951240.pdf 7967db49b782220aee9fb13a2ef94a852fac46a7 pmc_8951240.pdf 064cdfe21beb0353d30a211e93acbc9d4ca5fdcf60b8b05f35aa2d4ad4eb8c87 pmc_8951240.pdf Title: ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage Subject: 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 (q-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 p-value = 9.6 10-6) and non-lobar ICH (z-score = -4.8 and p-value = 1.58 10-6) 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 (p-value = 3.66 10-5) and non-lobar ICH (p-value = 1.81 10-5). Our results show that the association of ICA1L with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. Keywords: small vessel disease; small vessel stroke; intracerebral haemorrhage; PWAS; proteome-wide association study; genome-wide association study (GWAS) Author: 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 and Jerzy Krupinski Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Mar 15 13:00:40 2022 CET ModDate: Tue Mar 15 13:03:02 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2229676 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CMRYXI+VnURWPalladioL Type 1 Custom yes yes no 10 0 PGSAOM+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 WTDYSY+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 VUSMKW+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 EGFZUW+CMSY10 Type 1 Builtin yes yes no 28 0 CCDETI+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 40 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 44 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 48 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 60 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 63 0 FGILCW+URWPalladioL-BoldItal Type 1 Custom yes yes no 88 0 FOPBFA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 102 0 FOPBFB+PalatinoLinotype CID TrueType Identity-H yes yes yes 105 0 FOPBFC+PalatinoLinotype TrueType WinAnsi yes yes no 111 0 FOPBFE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 114 0 FOPBFA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 128 0 FOPBFB+PalatinoLinotype CID TrueType Identity-H yes yes yes 131 0 FOPBFC+PalatinoLinotype TrueType WinAnsi yes yes no 137 0 FOPBFE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 140 0 FOPBFA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 160 0 FOPBFC+PalatinoLinotype TrueType WinAnsi yes yes no 163 0 FOPBFE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 166 0 FOPBFA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 186 0 FOPBFB+PalatinoLinotype CID TrueType Identity-H yes yes yes 189 0 FOPBFC+PalatinoLinotype TrueType WinAnsi yes yes no 195 0 FOPBFE+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 198 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-05-20 02:23:52 CEST RepresentationInformation: pmc_8951240.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-04-26 18:00:02 CEST Size: 2229676 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 381 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4923ab24 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Children: Item: Title: Stringent Criterion PWAS Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: SMR and Conditional Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Open Criterion PWAS Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Proteome-Wide Associations Study (PWAS) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Colocalization Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Replication Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Summary-Based Mendelian Randomization (SMR) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Conditional Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Info: Title: ICA1L Is Associated with Small Vessel Disease: A Proteome-Wide Association Study in Small Vessel Stroke and Intracerebral Haemorrhage Author: 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 and Jerzy Krupinski Subject: 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 (q-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 p-value = 9.6 10-6) and non-lobar ICH (z-score = -4.8 and p-value = 1.58 10-6) 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 (p-value = 3.66 10-5) and non-lobar ICH (p-value = 1.81 10-5). Our results show that the association of ICA1L with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain. 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