Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Traylor, Matthew; Persyn, Elodie; Tomppo, Liisa; Klasson, Sofia; Abedi, Vida; Bakker, Mark K; Torres, Nuria; Li, Linxin; Bell, Steven; Rutten-Jacobs, Loes C.A.; Tozer, Daniel J.; Griessenauer, Christoph J.; Zhang, Yanfei; Pedersén, Annie; Sharma, Pankaj; Jiménez‐Conde, Jordi; Rundek, Tatjana; Grewal, Raji P.; Lindgren, Arne; Meschia, James F.; Salomaa, Veikko; Havulinna, Aki S.; Kourkoulis, Christina; Crawford, Katherine; Marini, Sandro; Mitchell, Braxton D.; Kittner, Steven J.; Rosand, Jonathan; Dichgans, Martin; Jern, Christina; Strbian, Daniel; Fernández‐Cadenas, Israel; Zand, Ramin; Ruigrok, Ynte M.; Rost, Natalia S.; Lemmens, Robin; Rothwell, Peter M.; Anderson, Christopher; Wardlaw, Joanna M.; Lewis, Cathryn M.; Markus, Hugh S.; Investigators, UK Dna Lacunar Stroke Study

doi:10.1016/s1474-4422(21)00031-4

Cited by 134 publications

(137 citation statements)

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“…One approach used to prioritize the likely causal gene within an associated locus with multiple genes is the use of a transcriptome-wide association study (TWAS) [ 27 ]. The TWAS from the SVS GWAS results found that the expression of SLC25A44 in the arteries and the 2q33·2 locus ( CARF , FAM117B , ICA1L , and NBEAL1 ) in the arteries and brain was causally associated with an SVS risk [ 23 ]. Very similar results regarding the 2q33·2 locus were previously obtained by Persyn et al and Sargurupremraj et al in their TWAS of WMH [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, these loci presented a nominal association ( p -value < 5 × 10 −3 ) with non-lobar ICH and SVS in the corresponding GWAS but not at a genome-wide level [ 4 ]. Three different GWAS in SVS have identified significant associations with this phenotype in 16q24.2 ( ZCCHC14 ) [ 6 ], 2q33.2 ( ICA1L and WDR12 ) [ 22 ], ULK4 ; SPI1-SLC39A13-PSMC3-RAPSN , and ZBTB14-EPB41L3 [ 23 ]. Recently, an MTAG combining SVS and WMH allowed for the identification of seven loci associated with SVS for the first time but some of them were previously associated with ICH ( SLC25A44-PMF1-BGLAP , LOX-ZNF474-LOC100505841 , FOXF2 FOXQ1 , SH3PXD2A , VTA1-GPR126 , HTRA1-ARMS2 , and COL4A2 ) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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

Cullell

Gallego-Fábrega²,

Cárcel‐Márquez

et al. 2022

IJMS

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Cullell

Gallego-Fábrega²,

Cárcel‐Márquez

et al. 2022

IJMS

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“…Additionally, SH3PXD2A is nearby a sentinel locus for atrial fibrillation 80 and the KDELR3 region is associated with Electrocardiogram T-peak to T-end 81 , suggesting a role for heart rhythm and contractility in African ancestry blood pressure traits. SH3PXD2A is also within loci associated with intraocular pressure, cerebral small vessel disease, and white matter hyperintensities, all closely related to blood pressure levels [82][83][84] . MBTPS1 has also been implicated in stroke 85 .…”

Section: Discussionmentioning

confidence: 99%

African ancestry genome-wide association study of blood pressure and hypertension identifies 25 novel loci through predicted gene expression

Hellwege

Liang

Giri

et al. 2022

Preprint

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African Americans (AAs) experience a high burden of hypertension but have been underrepresented in genetic studies of blood pressure. We performed common and rare variant genome-wide association studies (GWAS) of systolic (SBP) and diastolic (DBP) blood pressure, pulse pressure and hypertension in 95,457 AAs from the Million Veteran Program and Continental Origins and Genetic Epidemiology Network (COGENT) consortium with replication in up to 41,014 African-ancestry participants. GWAS meta-analysis confirmed 26 previously reported loci including 15 with SBP, four with DBP, 10 with pulse pressure and five with hypertension. Predicted gene expression analysis identified 25 genes newly associated with blood pressure. We provide validated African-ancestry polygenic scores for SBP and DBP that are strongly associated with hypertension. This work provides evidence for similar genetic architectures of hypertension and blood pressure across racial/ethnic groups and demonstrates the utility of predicted expression analysis in identifying novel genes beyond GWAS alone.

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“…Clinical characteristics of the stroke cases are shown in eTable 2. Genotypes for all studies except Helsinki were imputed using the TOPMed reference panel on the University of Michigan Imputation Server 17 . The Helsinki Study imputed genotypes using a Finnish population-specific reference panel and the BEAGLE software.…”

Section: Methodsmentioning

confidence: 99%

Genetic Contributions to Early and Late Onset Ischemic Stroke

Jaworek¹,

Xu²,

Gaynor³

et al. 2021

Preprint

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ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

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Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Cited by 134 publications

References 83 publications

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

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

African ancestry genome-wide association study of blood pressure and hypertension identifies 25 novel loci through predicted gene expression

Genetic Contributions to Early and Late Onset Ischemic Stroke

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