Author: "Jern, C" / Publication Year Range: Last 10 years - Searchworks@Jio Institute Digital Library Search Results

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225 results on '"Jern, C"'

1. Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆

Author: Frid, P., Xu, H., Mitchell, B.D., Drake, M., Wasselius, J., Gaynor, B., Ryan, K., Giese, A.K., Schirmer, M., Donahue, K.L., Irie, R., Bouts, M.J.R.J., McIntosh, E.C., Mocking, S.J.T., Dalca, A.V., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J.W., McArdle, P.F., Broderick, J.P., Jimenez-Conde, J., Jern, C., Kissela, B.M., Kleindorfer, D.O., Lemmens, R., Meschia, J.F., Rosand, J., Rundek, T., Sacco, R.L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B.B., Kittner, S.J., Petersson, J., Golland, P., Wu, O., Rost, N.S., and Lindgren, A.
Published: 2022
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2. Scaling behaviours of deep learning and linear algorithms for the prediction of stroke severity.

Author: Bourached, A, Bonkhoff, AK, Schirmer, MD, Regenhardt, RW, Bretzner, M, Hong, S, Dalca, AV, Giese, A-K, Winzeck, S, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Rhee, J, Kimchi, EY, Rost, NS, Bourached, A, Bonkhoff, AK, Schirmer, MD, Regenhardt, RW, Bretzner, M, Hong, S, Dalca, AV, Giese, A-K, Winzeck, S, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Rhee, J, Kimchi, EY, and Rost, NS
Abstract: Deep learning has allowed for remarkable progress in many medical scenarios. Deep learning prediction models often require 105-107 examples. It is currently unknown whether deep learning can also enhance predictions of symptoms post-stroke in real-world samples of stroke patients that are often several magnitudes smaller. Such stroke outcome predictions however could be particularly instrumental in guiding acute clinical and rehabilitation care decisions. We here compared the capacities of classically used linear and novel deep learning algorithms in their prediction of stroke severity. Our analyses relied on a total of 1430 patients assembled from the MRI-Genetics Interface Exploration collaboration and a Massachusetts General Hospital-based study. The outcome of interest was National Institutes of Health Stroke Scale-based stroke severity in the acute phase after ischaemic stroke onset, which we predict by means of MRI-derived lesion location. We automatically derived lesion segmentations from diffusion-weighted clinical MRI scans, performed spatial normalization and included a principal component analysis step, retaining 95% of the variance of the original data. We then repeatedly separated a train, validation and test set to investigate the effects of sample size; we subsampled the train set to 100, 300 and 900 and trained the algorithms to predict the stroke severity score for each sample size with regularized linear regression and an eight-layered neural network. We selected hyperparameters on the validation set. We evaluated model performance based on the explained variance (R2) in the test set. While linear regression performed significantly better for a sample size of 100 patients, deep learning started to significantly outperform linear regression when trained on 900 patients. Average prediction performance improved by ∼20% when increasing the sample size 9× [maximum for 100 patients: 0.279 ± 0.005 (R2, 95% confidence interval), 900 patients: 0.337 ± 0.006
Published: 2024

3. Genome‐wide analysis of genetic determinants of circulating factor VII‐activating protease (FSAP) activity

Author: Olsson, M., Stanne, T.M., Pedersen, A., Lorentzen, E., Kara, E., Martinez‐Palacian, A., Rønnow Sand, N.P., Jacobsen, A.F., Sandset, P.M., Sidelmann, J.J., Engström, G., Melander, O., Kanse, S.M., and Jern, C.
Published: 2018
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4. The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

Author: Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, AV, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Rost, NS, MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortium, Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, AV, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Rost, NS, and MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortium
Abstract: This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.
Published: 2023

5. Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke.

Author: Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Regenhardt, RW, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, J, Lindgren, AG, Jern, C, Golland, P, Kuchcinski, G, Rost, NS, Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Regenhardt, RW, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, J, Lindgren, AG, Jern, C, Golland, P, Kuchcinski, G, and Rost, NS
Abstract: BACKGROUND AND OBJECTIVES: While chronological age is one of the most influential determinants of post-stroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age". We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of stroke patients will be associated with cardiovascular risk factors and worse functional outcomes. METHODS: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison to chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs, and a logistic regression model of favorable functional outcomes taking RBA as input. RESULTS: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age=62.8 years, 42.0% females). T2-FLAIR radiomics predicted chronological ages (mean absolute error=6.9 years, r=0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted Odds-Ratios: 0.58, 0.76, 0.48, 0.55; all p-values<0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes. DISCUSSION: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.
Published: 2023

6. Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke

Author: Jaworek, T, Xu, H, Gaynor, BJ, Cole, JW, Rannikmae, K, Stanne, TM, Tomppo, L, Abedi, V, Amouyel, P, Armstrong, ND, Attia, J, Bell, S, Benavente, OR, Boncoraglio, GB, Butterworth, A, Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium, Carcel-Marquez, J, Chen, Z, Chong, M, Cruchaga, C, Cushman, M, Danesh, J, Debette, S, Duggan, DJ, Durda, JP, Engstrom, G, Enzinger, C, Faul, JD, Fecteau, NS, Fernandez-Cadenas, I, Gieger, C, Giese, A-K, Grewal, RP, Grittner, U, Havulinna, AS, Heitsch, L, Hochberg, MC, Holliday, E, Hu, J, Ilinca, A, INVENT Consortium, Irvin, MR, Jackson, RD, Jacob, MA, Janssen, RR, Jimenez-Conde, J, Johnson, JA, Kamatani, Y, Kardia, SL, Koido, M, Kubo, M, Lange, L, Lee, J-M, Lemmens, R, Levi, CR, Li, J, Li, L, Lin, K, Lopez, H, Luke, S, Maguire, J, McArdle, PF, McDonough, CW, Meschia, JF, Metso, T, Muller-Nurasyid, M, O'Connor, TD, O'Donnell, M, Peddareddygari, LR, Pera, J, Perry, JA, Peters, A, Putaala, J, Ray, D, Rexrode, K, Ribases, M, Rosand, J, Rothwell, PM, Rundek, T, Ryan, KA, Sacco, RL, Salomaa, V, Sanchez-Mora, C, Schmidt, R, Sharma, P, Slowik, A, Smith, JA, Smith, NL, Wassertheil-Smoller, S, Soederholm, M, Stine, OC, Strbian, D, Sudlow, CL, Tatlisumak, T, Terao, C, Thijs, V, Torres-Aguila, NP, Tregouet, D-A, Tuladhar, AM, Veldink, JH, Walters, RG, Weir, DR, Woo, D, Worrall, BB, Hong, CC, Ross, O, Zand, R, Leeuw, F-ED, Lindgren, AG, Pare, G, Anderson, CD, Markus, HS, Jern, C, Malik, R, Dichgans, M, Mitchell, BD, Kittner, SJ, and Early Onset Stroke Genetics Consortium of the International Stroke Genetics Consortium (ISGC)
Subjects: Neurology & Neurosurgery, 1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences
Abstract: BACKGROUND AND OBJECTIVES: Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke. METHODS: We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS. RESULTS: We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008). DISCUSSION: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
Published: 2022

7. Neglect and aphasia in the acute phase as predictors of functional outcome 7 years after ischemic stroke

Author: Gerafi, J., Samuelsson, H., Viken, J. I., Blomgren, C., Claesson, L., Kallio, S., Jern, C., Blomstrand, C., and Jood, K.
Published: 2017
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8. Global Differences in Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults-A Worldwide Meta-analysis: The GOAL Initiative

Author: Jacob, M.A., Ekker, M.S., Allach, Y., Cai, M., Aarnio, Karoliina, Arauz, A., Arnold, M., Bae, H.J., Bandeo, L., Barboza, M.A., Bolognese, M., Bonardo, P., Brouns, R., Chuluun, B., Chuluunbatar, E., Cordonnier, C., Dagvajantsan, B., Debette, S., Don, A., Enzinger, C., Ekizoglu, E., Fandler-Höfler, S., Fazekas, F., Fromm, A., Gattringer, T., Hora, T.F., Jern, C., Jood, K., Kim, Y.S., Kittner, S., Kleinig, T., Klijn, C.J.M., Kõrv, J., Kumar, V., Lee, K.J., Lee, Theo A.J. van der, Maaijwee, N.A.M.M., Martinez-Majander, N., Marto, J.P., Mehndiratta, M.M., Mifsud, V., Montanaro, V., Pacio, G., Patel, V.B., Phillips, M.C., Piechowski-Jozwiak, B., Pikula, A., Ruiz-Sandoval, J., Sarnowski, B., Swartz, R.H., Tan, K.S., Tanne, D., Tatlisumak, T., Thijs, V., Viana-Baptista, M., Vibo, R., Wu, T.Y., Yesilot, N., Waje-Andreassen, U., Pezzini, A., Putaala, J., Tuladhar, A.M., Leeuw, F.E. de, Jacob, M.A., Ekker, M.S., Allach, Y., Cai, M., Aarnio, Karoliina, Arauz, A., Arnold, M., Bae, H.J., Bandeo, L., Barboza, M.A., Bolognese, M., Bonardo, P., Brouns, R., Chuluun, B., Chuluunbatar, E., Cordonnier, C., Dagvajantsan, B., Debette, S., Don, A., Enzinger, C., Ekizoglu, E., Fandler-Höfler, S., Fazekas, F., Fromm, A., Gattringer, T., Hora, T.F., Jern, C., Jood, K., Kim, Y.S., Kittner, S., Kleinig, T., Klijn, C.J.M., Kõrv, J., Kumar, V., Lee, K.J., Lee, Theo A.J. van der, Maaijwee, N.A.M.M., Martinez-Majander, N., Marto, J.P., Mehndiratta, M.M., Mifsud, V., Montanaro, V., Pacio, G., Patel, V.B., Phillips, M.C., Piechowski-Jozwiak, B., Pikula, A., Ruiz-Sandoval, J., Sarnowski, B., Swartz, R.H., Tan, K.S., Tanne, D., Tatlisumak, T., Thijs, V., Viana-Baptista, M., Vibo, R., Wu, T.Y., Yesilot, N., Waje-Andreassen, U., Pezzini, A., Putaala, J., Tuladhar, A.M., and Leeuw, F.E. de
Abstract: Item does not contain fulltext, BACKGROUND AND OBJECTIVES: There is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide. METHODS: We performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18-50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression. RESULTS: We included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas "other determined stroke" and "undetermined stroke" were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42-4.36). DISCUSSION: Ethnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve h
Published: 2022

9. Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

Author: Frid, P, Xu, H, Mitchell, BD, Drake, M, Wasselius, J, Gaynor, B, Ryan, K, Giese, AK, Schirmer, M, Donahue, KL, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rosand, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Petersson, J, Golland, P, Wu, O, Rost, NS, Lindgren, A, Frid, P, Xu, H, Mitchell, BD, Drake, M, Wasselius, J, Gaynor, B, Ryan, K, Giese, AK, Schirmer, M, Donahue, KL, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rosand, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Petersson, J, Golland, P, Wu, O, Rost, NS, and Lindgren, A
Abstract: OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.
Published: 2022

10. Sex-specific lesion pattern of functional outcomes after stroke

Author: Bonkhoff, AK, Bretzner, M, Hong, S, Schirmer, MD, Cohen, A, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Fox, MD, Bzdok, D, Wu, O, Rost, NS, Bonkhoff, AK, Bretzner, M, Hong, S, Schirmer, MD, Cohen, A, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Fox, MD, Bzdok, D, Wu, O, and Rost, NS
Abstract: Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.
Published: 2022

11. International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Author: Lindgren, AG, Braun, RG, Juhl Majersik, J, Clatworthy, P, Mainali, S, Derdeyn, CP, Maguire, J, Jern, C, Rosand, J, Cole, JW, Lee, J-M, Khatri, P, Nyquist, P, Debette, S, Keat Wei, L, Rundek, T, Leifer, D, Thijs, V, Lemmens, R, Heitsch, L, Prasad, K, Jimenez Conde, J, Dichgans, M, Rost, NS, Cramer, SC, Bernhardt, J, Worrall, BB, Fernandez-Cadenas, I, Lindgren, AG, Braun, RG, Juhl Majersik, J, Clatworthy, P, Mainali, S, Derdeyn, CP, Maguire, J, Jern, C, Rosand, J, Cole, JW, Lee, J-M, Khatri, P, Nyquist, P, Debette, S, Keat Wei, L, Rundek, T, Leifer, D, Thijs, V, Lemmens, R, Heitsch, L, Prasad, K, Jimenez Conde, J, Dichgans, M, Rost, NS, Cramer, SC, Bernhardt, J, Worrall, BB, and Fernandez-Cadenas, I
Abstract: Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.
Published: 2022

12. Stroke genetics informs drug discovery and risk prediction across ancestries

Author: Mishra, A, Malik, R., Hachiya, T., Jürgenson, T., Namba, S., Posner, D.C., Kamanu, F.K., Koido, M., Grand, Q. Le, Shi, M., He, Y., Georgakis, M.K., Caro, I., Krebs, K., Liaw, Y.C., Vaura, F.C., Lin, K., Winsvold, B.S., Srinivasasainagendra, V., Parodi, L., Bae, H.J., Chauhan, G., Chong, M.R., Tomppo, L., Akinyemi, R., Roshchupkin, G.V., Habib, N., Jee, Y.H., Thomassen, J.Q., Abedi, V., Cárcel-Márquez, J., Nygaard, M., Leonard, H.L., Yang, C., Yonova-Doing, E., Knol, M.J., Lewis, A.J., Judy, R.L., Ago, T., Amouyel, P., Armstrong, N.D., Bakker, M.K., Bartz, T.M., Bennett, D.A., Bis, J.C., Bordes, C., Børte, S., Cain, A., Ridker, P.M., Cho, K., Chen, Z., Cruchaga, C., Cole, J.W., Jager, P.L., Cid, R. de, Endres, M., Ferreira, L.E., Geerlings, M.I., Gasca, N.C., Gudnason, V., Hata, J., He, J., Heath, A.K., Ho, Y.L., Havulinna, A.S., Hopewell, J.C., Hyacinth, H.I., Inouye, M., Jacob, M.A., Jeon, C.E., Jern, C., Kamouchi, M., Keene, K.L., Kitazono, T., Kittner, S.J., Konuma, T., Kumar, A., Lacaze, P., Launer, L.J., Lee, K.J., Lepik, K., Li, J, Li, L, Manichaikul, A., Markus, H.S., Marston, N.A., Meitinger, T., Mitchell, B.D., Montellano, F.A., Morisaki, T., Mosley, T.H., Nalls, M.A., Nordestgaard, B.G., O'Donnell, M.J., Okada, Y., Onland-Moret, N.C., Ovbiagele, B., Peters, A., Psaty, B.M., Rich, S.S., Tuladhar, A.M., Leeuw, F.E. de, Dichgans, M., Debette, S., Mishra, A, Malik, R., Hachiya, T., Jürgenson, T., Namba, S., Posner, D.C., Kamanu, F.K., Koido, M., Grand, Q. Le, Shi, M., He, Y., Georgakis, M.K., Caro, I., Krebs, K., Liaw, Y.C., Vaura, F.C., Lin, K., Winsvold, B.S., Srinivasasainagendra, V., Parodi, L., Bae, H.J., Chauhan, G., Chong, M.R., Tomppo, L., Akinyemi, R., Roshchupkin, G.V., Habib, N., Jee, Y.H., Thomassen, J.Q., Abedi, V., Cárcel-Márquez, J., Nygaard, M., Leonard, H.L., Yang, C., Yonova-Doing, E., Knol, M.J., Lewis, A.J., Judy, R.L., Ago, T., Amouyel, P., Armstrong, N.D., Bakker, M.K., Bartz, T.M., Bennett, D.A., Bis, J.C., Bordes, C., Børte, S., Cain, A., Ridker, P.M., Cho, K., Chen, Z., Cruchaga, C., Cole, J.W., Jager, P.L., Cid, R. de, Endres, M., Ferreira, L.E., Geerlings, M.I., Gasca, N.C., Gudnason, V., Hata, J., He, J., Heath, A.K., Ho, Y.L., Havulinna, A.S., Hopewell, J.C., Hyacinth, H.I., Inouye, M., Jacob, M.A., Jeon, C.E., Jern, C., Kamouchi, M., Keene, K.L., Kitazono, T., Kittner, S.J., Konuma, T., Kumar, A., Lacaze, P., Launer, L.J., Lee, K.J., Lepik, K., Li, J, Li, L, Manichaikul, A., Markus, H.S., Marston, N.A., Meitinger, T., Mitchell, B.D., Montellano, F.A., Morisaki, T., Mosley, T.H., Nalls, M.A., Nordestgaard, B.G., O'Donnell, M.J., Okada, Y., Onland-Moret, N.C., Ovbiagele, B., Peters, A., Psaty, B.M., Rich, S.S., Tuladhar, A.M., Leeuw, F.E. de, Dichgans, M., and Debette, S.
Abstract: Item does not contain fulltext, Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
Published: 2022

13. Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome.

Author: Bonkhoff, AK, Hong, S, Bretzner, M, Schirmer, MD, Regenhardt, RW, Arsava, EM, Donahue, K, Nardin, M, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, E, Attia, J, Benavente, O, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, S, Lemmens, R, Levi, C, McDonough, CW, Meschia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soederholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, P, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Golland, P, Bzdok, D, Wu, O, Rost, NS, Bonkhoff, AK, Hong, S, Bretzner, M, Schirmer, MD, Regenhardt, RW, Arsava, EM, Donahue, K, Nardin, M, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, E, Attia, J, Benavente, O, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, S, Lemmens, R, Levi, C, McDonough, CW, Meschia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soederholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, P, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Golland, P, Bzdok, D, Wu, O, and Rost, NS
Abstract: BACKGROUND AND OBJECTIVES: To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. METHODS: MR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. RESULTS: A total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific
Published: 2022

14. Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics

Author: Bonkhoff, AK, Ullberg, T, Bretzner, M, Hong, S, Schirmer, MD, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Frid, P, Rost, NS, Wasselius, J, Bonkhoff, AK, Ullberg, T, Bretzner, M, Hong, S, Schirmer, MD, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Frid, P, Rost, NS, and Wasselius, J
Abstract: BACKGROUND PURPOSE: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. MATERIALS AND METHODS: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. RESULTS: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only
Published: 2022

15. Stroke genetics informs drug discovery and risk prediction across ancestries (vol 611, pg 115, 2022)

Author: Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, and Debette, S
Published: 2022

16. L’âge cérébral radiomique prédit le pronostic fonctionnel après un avc ischémique.

Author: Bretzner, M, Bonkhoff, A, Schirmer, M, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, M, Rist, P, Nardin, M, Regenhardt, R, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, O, Cole, J, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Conde, JJ, Kittner, S, Lemmens, R, Levi, C, McArdle, P, McDonough, C, Meshia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, R, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, T, Strbian, D, Tatlisumak, T, Thijs, V, Vagala, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, B, Maguire, J, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, Rost, N, Bretzner, M, Bonkhoff, A, Schirmer, M, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, M, Rist, P, Nardin, M, Regenhardt, R, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, O, Cole, J, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Conde, JJ, Kittner, S, Lemmens, R, Levi, C, McArdle, P, McDonough, C, Meshia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, R, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, T, Strbian, D, Tatlisumak, T, Thijs, V, Vagala, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, B, Maguire, J, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, and Rost, N
Published: 2022

17. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries (Nature, (2022), 611, 7934, (115-123), 10.1038/s41586-022-05165-3)

Author: Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, YC, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, HJ, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, YL, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, KJ, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O’Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Mishra, A, Malik, R, Hachiya, T, Jürgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, YC, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, HJ, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Cárcel-Márquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Børte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, YL, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, KJ, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O’Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, and Rich, SS
Abstract: In the version of this article initially published, the name of the PRECISE4Q Consortium was misspelled as “PRECISEQ” and has now been amended in the HTML and PDF versions of the article. Further, data in the first column of Supplementary Table 55 were mistakenly shifted and have been corrected in the file accompanying the HTML version of the article.
Published: 2022

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

Author: Traylor, M, Persyn, E, Tomppo, L, Klasson, S, Abedi, V, Bakker, MK, Torres, N, Li, LX, Bell, S, Rutten-Jacobs, L, Tozer, DJ, Griessenauer, CJ, Zhang, YF, Pedersen, A, Sharma, P, Jimenez-Conde, J, Rundek, T, Grewal, RP, Lindgren, A, Meschia, JF, Salomaa, V, Havulinna, A, Kourkoulis, C, Crawford, K, Marini, S, Mitchell, BD, Kittner, SJ, Rosand, J, Dichgans, M, Jern, C, Strbian, D, Fernandez-Cadenas, I, Zand, R, Ruigrok, Y, Rost, N, Lemmens, R, Rothwell, PM, Anderson, CD, Wardlaw, J, Lewis, CM, Markus, HS, Helsinki Stroke Study, Dutch Parelsnoer Inst Cerebrovasc, Natl Inst Neurological Disorders, UK DNA Lacunar Stroke Study, Int Stroke Genetics Consortium, University of St Andrews. School of Biology, Bell, Steven [0000-0001-6774-3149], Tozer, Daniel [0000-0002-0404-3214], Markus, Hugh [0000-0002-9794-5996], Apollo - University of Cambridge Repository, HUS Neurocenter, Helsinki University Hospital Area, Neurologian yksikkö, Medicum, Institute for Molecular Medicine Finland, and University of Helsinki
Subjects: Oncology, PATHOGENESIS, LOCI, Genome-wide association study, Disease, VARIANTS, 3124 Neurology and psychiatry, SUBTYPES, 0302 clinical medicine, SMALL VESSEL DISEASE, Stroke, RISK, 0303 health sciences, Magnetic Resonance Imaging, 3. Good health, Europe, ISCHEMIC-STROKE, Meta-analysis, Medical genetics, Life Sciences & Biomedicine, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, medicine.medical_specialty, Lacunar stroke, Clinical Neurology, QH426 Genetics, CLASSIFICATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, QH426, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, business.industry, 3112 Neurosciences, Australia, DAS, medicine.disease, Hyperintensity, United States, ONSET, Stroke, Lacunar, RC0321, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Funding: This work, including collection and genotyping of the UK Young Lacunar Stroke DNA Study 2 (DNA Lacunar 2), was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate
Published: 2021
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19. EXPRESS: International Stroke Genetics Consortium Recommendations for Studies of Genetics of Stroke Outcome and Recovery

Author: Lindgren, A, Braun, R, Majersik, JJ, Clatworthy, P, Mainali, S, Derdeyn, CP, Maguire, JM, Jern, C, Rosand, J, Cole, JW, Lee, J-M, Khatri, P, Nyquist, PA, Debette, SP, Keat Wei, L, Rundek, T, Leifer, D, Thijs, V, Lemmens, R, Heitsch, L, Prasad, K, Jimenez-Conde, J, Dichgans, M, Rost, NS, Cramer, SC, Bernhardt, J, Worrall, BB, and Cadenas, I
Subjects: Neurology & Neurosurgery, cardiovascular diseases, 1103 Clinical Sciences, 1109 Neurosciences
Abstract: Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.
Published: 2021

20. Technological readiness and implementation of genomic‐driven precision medicine for complex diseases

Author: Franks, P. W., primary, Melén, E., additional, Friedman, M., additional, Sundström, J., additional, Kockum, I., additional, Klareskog, L., additional, Almqvist, C., additional, Bergen, S. E., additional, Czene, K., additional, Hägg, S., additional, Hall, P., additional, Johnell, K., additional, Malarstig, A., additional, Catrina, A., additional, Hagström, H., additional, Benson, M., additional, Gustav Smith, J., additional, Gomez, M. F, additional, Orho‐Melander, M., additional, Jacobsson, B., additional, Halfvarson, J., additional, Repsilber, D., additional, Oresic, M., additional, Jern, C., additional, Melin, B., additional, Ohlsson, C., additional, Fall, T., additional, Rönnblom, L., additional, Wadelius, M., additional, Nordmark, G., additional, Johansson, Å., additional, Rosenquist, R., additional, and Sullivan, P. F., additional
Published: 2021
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21. Technological readiness and implementation of genomic-driven precision medicine for complex diseases

Author: Franks, P. W., Melén, E., Friedman, M., Sundström, J., Kockum, I., Klareskog, L., Almqvist, C., Bergen, S. E., Czene, K., Hägg, S., Hall, P., Johnell, K., Malarstig, A., Catrina, A., Hagström, H., Benson, M., Gustav Smith, J., Gomez, M. F., Orho-Melander, M., Jacobsson, B., Halfvarson, Jonas, Repsilber, Dirk, Oresic, Matej, Jern, C., Melin, B., Ohlsson, C., Fall, T., Rönnblom, L., Wadelius, M., Nordmark, G., Johansson, Å., Rosenquist, R., Sullivan, P. F., Franks, P. W., Melén, E., Friedman, M., Sundström, J., Kockum, I., Klareskog, L., Almqvist, C., Bergen, S. E., Czene, K., Hägg, S., Hall, P., Johnell, K., Malarstig, A., Catrina, A., Hagström, H., Benson, M., Gustav Smith, J., Gomez, M. F., Orho-Melander, M., Jacobsson, B., Halfvarson, Jonas, Repsilber, Dirk, Oresic, Matej, Jern, C., Melin, B., Ohlsson, C., Fall, T., Rönnblom, L., Wadelius, M., Nordmark, G., Johansson, Å., Rosenquist, R., and Sullivan, P. F.
Abstract: The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data., Funding Agencies:SciLifeLab United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH)MH077139 MH1095320European Commission 610307 733161 825843European Research Council (ERC)European Commission CoG-2015_681742_NASCENTStrategic Research Area Epidemiology at Karolinska Institutet Vth 80-year Foundation Clinical Research Support (Avtal om Läkarutbildning och Forskning) Swedish government County councils ALF-agreement IMI2 Joint Undertaking 115974European Federation of Pharmaceutical Industries and Associations with JDRF H2020 Program ERA PerMed JTC 2018 Call (VR) 2018-05619
Published: 2021
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22. MRI Radiomic Signature of White Matter Hyperintensities Is Associated With Clinical Phenotypes

Author: Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, KL, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Marinescu, R, Wang, C, Regenhardt, RW, Leclerc, X, Lopes, R, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, JM, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, Rost, NS, Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, KL, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Marinescu, R, Wang, C, Regenhardt, RW, Leclerc, X, Lopes, R, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, JM, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, and Rost, NS
Abstract: OBJECTIVE: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes. METHODS: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA). RESULTS: Radiomic features were predictive of WMH burden (R 2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-values CV 1 - 6 < 0.001, p-value CV 7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes. CONCLUSION: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of
Published: 2021

23. Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis

Author: Ken-Dror, G, Cotlarciuc, I, Martinelli, I, Grandone, E, Hiltunen, S, Lindgren, E, Margaglione, M, Duchez, VLC, Triquenot, AB, Zedde, M, Mancuso, M, Ruigrok, YM, Marjot, T, Worrall, B, Majersik, JJ, Metso, TM, Putaala, J, Haapaniemi, E, Zuurbier, SM, Brouwer, MC, Passamonti, SM, Abbattista, M, Bucciarelli, P, Mitchell, BD, Kittner, SJ, Lemmens, R, Jern, C, Pappalardo, E, Costa, P, Colombi, M, de Sousa, DA, Rodrigues, S, Canhao, P, Tkach, A, Santacroce, R, Favuzzi, G, Arauz, A, Colaizzo, D, Spengos, K, Hodge, A, Ditta, R, Pezzini, A, Debette, S, Coutinho, JM, Thijs, V, Jood, K, Pare, G, Tatlisumak, T, Ferro, JM, Sharma, P, Ken-Dror, G, Cotlarciuc, I, Martinelli, I, Grandone, E, Hiltunen, S, Lindgren, E, Margaglione, M, Duchez, VLC, Triquenot, AB, Zedde, M, Mancuso, M, Ruigrok, YM, Marjot, T, Worrall, B, Majersik, JJ, Metso, TM, Putaala, J, Haapaniemi, E, Zuurbier, SM, Brouwer, MC, Passamonti, SM, Abbattista, M, Bucciarelli, P, Mitchell, BD, Kittner, SJ, Lemmens, R, Jern, C, Pappalardo, E, Costa, P, Colombi, M, de Sousa, DA, Rodrigues, S, Canhao, P, Tkach, A, Santacroce, R, Favuzzi, G, Arauz, A, Colaizzo, D, Spengos, K, Hodge, A, Ditta, R, Pezzini, A, Debette, S, Coutinho, JM, Thijs, V, Jood, K, Pare, G, Tatlisumak, T, Ferro, JM, and Sharma, P
Abstract: OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.
Published: 2021

24. Outcome after acute ischemic stroke is linked to sex-specific lesion patterns

Author: Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Brudfors, M, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Bzdok, D, Wu, O, Rost, NS, Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Brudfors, M, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Bzdok, D, Wu, O, and Rost, NS
Abstract: Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.
Published: 2021

25. Genetic Predisposition to Mosaic Chromosomal Loss Is Associated With Functional Outcome After Ischemic Stroke.

Author: Johansson, M, Pedersen, A, Cole, JW, Lagging, C, Lindgren, A, Maguire, JM, Rost, NS, Söderholm, M, Worrall, BB, Stanne, TM, Jern, C, Johansson, M, Pedersen, A, Cole, JW, Lagging, C, Lindgren, A, Maguire, JM, Rost, NS, Söderholm, M, Worrall, BB, Stanne, TM, and Jern, C
Abstract: Background and Objectives: To test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set. Methods: We used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately. Results: Increasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03-1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08-1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95-1.14), and we observed no significant genotype-sex interaction. Discussion: In this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration.
Published: 2021

26. Apolipoprotein E e4 associates to age of ischemic stroke onset but not to stroke outcome

Author: Lagging, C, Lorentzen, E, Pedersen, A, Stanne, TM, Soderholm, M, Maguire, JM, Lindgren, A, and Jern, C
Subjects: Genetics & Heredity
Published: 2019

27. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes (vol 50, pg 524, 2018)

Author: Malik, R, Chauhan, G, Traylor, M, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, A-K, Van der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, TM, Benavente, OR, Bevan, S, Boncoraglio, GB, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, W-M, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, DeStefano, AL, Den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, F-C, Hyacinth, IH, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jimenez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, J-M, Lemmens, R, Leys, D, Lewis, CM, Lin, W-Y, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmae, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, Rothwell, PM, Rotter, JI, Rundek, T, Sacco, RL, Sakaue, S, Sale, MM, Salomaa, V, Sapkota, BR, Schmidt, R, Schmidt, CO, Schminke, U, Sharma, P, Slowik, A, Sudlow, CLM, Tanislav, C, Tatlisumak, T, Taylor, KD, Thijs, VNS, Thorleifsson, G, Thorsteinsdottir, U, Tiedt, S, Trompet, S, Tzourio, C, Van Duijn, CM, Walters, M, Wareham, NJ, Wassertheil-Smoller, S, Wilson, JG, Wiggins, KL, Yang, Q, Yusuf, S, Bis, JC, Pastinen, T, Ruusalepp, A, Schadt, EE, Koplev, S, Bjorkegren, JLM, Codoni, V, Civelek, M, Smith, NL, Tregouet, DA, Christophersen, IE, Roselli, C, Lubitz, SA, Ellinor, PT, Tai, ES, Kooner, JS, Kato, N, He, J, Van der Harst, P, Elliott, P, Chambers, JC, Takeuchi, F, Johnson, AD, Sanghera, DK, Melander, O, Jern, C, Strbian, D, Fernandez-Cadenas, I, Longstreth, WT, Rolfs, A, Hata, J, Woo, D, Rosand, J, Pare, G, Hopewell, JC, Saleheen, D, Stefansson, K, Worrall, BB, Kittner, SJ, Seshadri, S, Fornage, M, Markus, HS, Howson, JMM, Kamatani, Y, Debette, S, and Dichgans, M
Subjects: Genetics & Heredity, International Genomics of Blood Pressure (iGEN-BP) Consortium, COMPASS Consortium, MEGASTROKE Consortium, Science & Technology, UK Young Lacunar DNA Study, AFGen Consortium, INVENT Consortium, STARNET, 06 Biological Sciences, METASTROKE Consortium, EPIC-CVD Consortium, BioBank Japan Cooperative Hospital Group, International Stroke Genetics Consortium (ISGC), NINDS Stroke Genetics Network (SiGN), Neurology Working Group of the CHARGE Consortium, EPIC-InterAct Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Life Sciences & Biomedicine, 11 Medical and Health Sciences, Developmental Biology
Published: 2019

28. Genetically determined risk of depression and functional outcome after ischemic stroke

Author: Gill, D, James, NE, Monori, G, Lorentzen, E, Fernandez-Cadenas, I, Lemmens, R, Thijs, V, Rost, NS, Scott, R, Hankey, GJ, Lindgren, A, Jern, C, Maguire, JM, and International Stroke Genetics Consortium and the GISCOME Network
Subjects: Science & Technology, Neurology & Neurosurgery, Clinical Neurology, morbidity, 1103 Clinical Sciences, stroke, Peripheral Vascular Disease, depression, International Stroke Genetics Consortium and the GISCOME Network, Cardiovascular System & Cardiology, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 1102 Cardiorespiratory Medicine and Haematology
Abstract: Background and Purpose- Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods- Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results- There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions- We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possible effect on functional outcome after ischemic stroke. Given the widespread prevalence of depression-related morbidity, these findings could have implications for prognostication and personalized rehabilitation after stroke.
Published: 2019

29. Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study

Author: Frid, P, Drake, M, Giese, AK, Wasselius, J, Schirmer, MD, Donahue, KL, Cloonan, L, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Sridharan, R, Xu, H, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Mitchell, BD, Petersson, J, Rosand, J, Golland, P, Wu, O, Rost, NS, Lindgren, A, Frid, P, Drake, M, Giese, AK, Wasselius, J, Schirmer, MD, Donahue, KL, Cloonan, L, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Sridharan, R, Xu, H, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Mitchell, BD, Petersson, J, Rosand, J, Golland, P, Wu, O, Rost, NS, and Lindgren, A
Abstract: OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.
Published: 2020

30. Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study

Author: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Frid, Petrea, Drake, Mattias, Giese, A. K., Wasselius, J., Schirmer, Markus, Donahue, K. L., Cloonan, L., Irie, R., Bouts, M. J. R. J., McIntosh, E. C., Mocking, S. J. T., Dalca, Adrian Vasile, Sridharan, Ramesh, Xu, H., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J. W., McArdle, P. F., Broderick, J. P., Jimenez-Conde, J., Jern, C., Kissela, B. M., Kleindorfer, D. O., Lemmens, R., Meschia, J. F., Rundek, T., Sacco, R. L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B. B., Kittner, S. J., Mitchell, B. D., Petersson, J., Rosand, J., Golland, Polina, Wu, O., Rost, N. S., Lindgren, A., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Frid, Petrea, Drake, Mattias, Giese, A. K., Wasselius, J., Schirmer, Markus, Donahue, K. L., Cloonan, L., Irie, R., Bouts, M. J. R. J., McIntosh, E. C., Mocking, S. J. T., Dalca, Adrian Vasile, Sridharan, Ramesh, Xu, H., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J. W., McArdle, P. F., Broderick, J. P., Jimenez-Conde, J., Jern, C., Kissela, B. M., Kleindorfer, D. O., Lemmens, R., Meschia, J. F., Rundek, T., Sacco, R. L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B. B., Kittner, S. J., Mitchell, B. D., Petersson, J., Rosand, J., Golland, Polina, Wu, O., Rost, N. S., and Lindgren, A.
Abstract: Objective Posterior circulation ischemic stroke (PCiS) constitutes 20–30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. Methods Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. Results PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04–1.61; male sex, OR = 1.46; 95% CI 1.21–1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. Conclusion Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS., National Institutes of Health NIBIB (Grant P41EB015902)
Published: 2020

31. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author: Chauhan, G., Adams, H.H.H., Satizabal, C.L., Bis, J.C., Teumer, A., Sargurupremraj, M., Hofer, E., Trompet, S., Hilal, S., Smith, A.V., Jian, X.Q., Malik, R., Traylor, M., Pulit, S.L., Amouyel, P., Mazoyer, B., Zhu, Y.C., Kaffashian, S., Schilling, S., Beecham, G.W., Montine, T.J., Schellenberg, G.D., Kjartansson, O., Gudnason, V., Knopman, D.S., Griswold, M.E., Windham, B.G., Gottesman, R.F., Mosley, T.H., Schmidt, R., Saba, Y., Schmidt, H., Takeuchi, F., Yamaguchi, S., Nabika, T., Kato, N., Rajan, K.B., Aggarwal, N.T., Jager, P.L. de, Evans, D.A., Psaty, B.M., Rotter, J.I., Rice, K., Lopez, O.L., Liao, J.M., Chen, C., Cheng, C.Y., Wong, T.Y., Ikram, M.K., Lee, S.J. van der, Amin, N., Chouraki, V., DeStefano, A.L., Aparicio, H.J., Romero, J.R., Maillard, P., DeCarli, C., Wardlaw, J.M., Hernandez, M.D.V., Luciano, M., Liewald, D., Deary, I.J., Starr, J.M., Bastin, M.E., Maniega, S.M., Slagboom, P.E., Beekman, M., Deelen, J., Uh, H.W., Lemmens, R., Brodaty, H., Wright, M.J., Ames, D., Boncoraglio, G.B., Hopewell, J.C., Beecham, A.H., Blanton, S.H., Wright, C.B., Sacco, R.L., Wen, W., Thalamuthu, A., Armstrong, N.J., Chong, E., Schofield, P.R., Kwok, J.B., Grond, J. van der, Stott, D.J., Ford, I., Jukema, J.W., Vernooij, M.W., Hofman, A., Uitterlinden, A.G., Lugt, A. van der, Wittfeld, K., Grabe, H.J., Hosten, N., Sarnowski, B. von, Volker, U., Levi, C., Jimenez-Conde, J., Sharma, P., Sudlow, C.L.M., Rosand, J., Woo, D., Cole, J.W., Meschia, J.F., Slowik, A., Thijs, V., Lindgren, A., Melander, O., Grewal, R.P., Rundek, T., Rexrode, K., Rothwell, P.M., Arnett, D.K., Jern, C., Johnson, J.A., Benavente, O.R., Wasssertheil-Smoller, S., Lee, J.M., Wong, Q., Mitchell, B.D., Rich, S.S., McArdle, P.F., Geerlings, M.I., Graaf, Y. van der, Bakker, P.I.W. de, Asselbergs, F.W., Srikanth, V., Thomson, R., McWhirter, R., Moran, C., Callisaya, M., Phan, T., Rutten-Jacobs, L.C.A., Bevan, S., Tzourio, C., Mather, K.A., Sachdev, P.S., Duijn, C.M. van, Worrall, B.B., Dichgans, M., Kittner, S.J., Markus, H.S., Ikram, M.A., Fornage, M., Launer, L.J., Seshadri, S., Longstreth, W.T., Debette, S., Stroke Genetics Network SiGN, ISGC, METASTROKE, ADGC, and CHARGE Consortium
Subjects: Meta-analysis, Mendelian Randomization, Blood Pressure, Polymorphisms, Genome-wide Association, Silent, Insights, Small Vessel Disease, Matter Hyperintensity Volume, Ischemic Stroke, Doenças Cardio e Cérebro-vasculares
Abstract: Collaborators (845): Astrid M. Vicente Free PMC article:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905/ Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI. info:eu-repo/semantics/publishedVersion
Published: 2019

32. Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study

Author: Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaëlsson, K, Markus, HS, Malik, R, Chauhan, G, Sargurupremraj, M, Okada, Y, Mishra, A, Rutten-Jacobs, L, Giese, AK, Van Der Laan, SW, Gretarsdottir, S, Anderson, CD, Chong, M, Adams, HHH, Ago, T, Almgren, P, Amouyel, P, Ay, H, Bartz, RM, Benavente, OR, Bevan, S, Brown, RD, Butterworth, AS, Carrera, C, Carty, CL, Chasman, DI, Chen, WM, Cole, JW, Correa, A, Cotlarciuc, I, Cruchaga, C, Danesh, J, De Bakker, PIW, Destefano, AL, Hoed, MD, Duan, Q, Engelter, ST, Falcone, GJ, Gottesman, RF, Grewal, RP, Gudnason, V, Gustafsson, S, Haessler, J, Harris, TB, Hassan, A, Havulinna, AS, Heckbert, SR, Holliday, EG, Howard, G, Hsu, FC, Hyacinth, HI, Ikram, MA, Ingelsson, E, Irvin, MR, Jian, X, Jiménez-Conde, J, Johnson, JA, Jukema, JW, Kanai, M, Keene, KL, Kissela, BM, Kleindorfer, DO, Kooperberg, C, Kubo, M, Lange, LA, Langefeld, CD, Langenberg, C, Launer, LJ, Lee, JM, Lemmens, R, Leys, D, Lewis, CM, Lin, WY, Lindgren, AG, Lorentzen, E, Magnusson, PK, Maguire, J, Manichaikul, A, McArdle, PF, Meschia, JF, Mitchell, BD, Mosley, TH, Nalls, MA, Ninomiya, T, O'Donnell, MJ, Psaty, BM, Pulit, SL, Rannikmäe, K, Reiner, AP, Rexrode, KM, Rice, K, Rich, SS, Ridker, PM, Rost, NS, and Rothwell, PM
Subjects: Stroke, Neurology & Neurosurgery, Intracranial Embolism, Humans, Calcium, Magnesium, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Brain Ischemia
Abstract: © 2019 American Academy of Neurology. ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2018

33. Global Outcome Assessment Life-long after stroke in young adults initiative-the GOAL initiative: study protocol and rationale of a multicentre retrospective individual patient data meta-analysis

Author: Ekker, M.S., Jacob, M.A., Dongen, M.M.E. van, Aarnio, K., Annamalai, A., Arauz, A., Arnold, M., Barboza, M., Bolognese, M., Brouns, R., Chuluun, B., Chuluunbaatar, E., Dagvajantsan, B., Debette, S., Don, A., Enzinger, C., Ekizoglu, E., Fandler-Hofler, S., Fazekas, F., Fromm, A., Gattringer, T., Gulli, G., Hoffmann, M., Hora, T., Jern, C., Jood, K., Kamouchi, M., Kim, Y.S., Kitazono, T., Kittner, S., Kleinig, T., Klijn, K., Korv, J., Lee, T.H., Leys, D., Maaijwee, N., Martinez-Majander, N., Marto, J.P., Mehndiratta, M., Mifsud, V., Montanaro, V., Owolabi, M.O., Patel, V., Phillips, M., Piechowski-Iozwiak, B., Pikula, A., Ruiz-Sandoval, J.L., Sarnowski, B., Schreuder, F.H.B.M., Swartz, R., Tan, K.S., Tanne, D., Tatlisumak, T., Thijs, V., Tuladhar, A., Viana-Baptista, M., Vibo, R., Wu, T., Yesilot, N., Waje-Andreassen, U., Pezzini, A., Putaala, J., Leeuw, F.E. de, Ekker, M.S., Jacob, M.A., Dongen, M.M.E. van, Aarnio, K., Annamalai, A., Arauz, A., Arnold, M., Barboza, M., Bolognese, M., Brouns, R., Chuluun, B., Chuluunbaatar, E., Dagvajantsan, B., Debette, S., Don, A., Enzinger, C., Ekizoglu, E., Fandler-Hofler, S., Fazekas, F., Fromm, A., Gattringer, T., Gulli, G., Hoffmann, M., Hora, T., Jern, C., Jood, K., Kamouchi, M., Kim, Y.S., Kitazono, T., Kittner, S., Kleinig, T., Klijn, K., Korv, J., Lee, T.H., Leys, D., Maaijwee, N., Martinez-Majander, N., Marto, J.P., Mehndiratta, M., Mifsud, V., Montanaro, V., Owolabi, M.O., Patel, V., Phillips, M., Piechowski-Iozwiak, B., Pikula, A., Ruiz-Sandoval, J.L., Sarnowski, B., Schreuder, F.H.B.M., Swartz, R., Tan, K.S., Tanne, D., Tatlisumak, T., Thijs, V., Tuladhar, A., Viana-Baptista, M., Vibo, R., Wu, T., Yesilot, N., Waje-Andreassen, U., Pezzini, A., Putaala, J., and Leeuw, F.E. de
Abstract: Contains fulltext : 215629.pdf (publisher's version ) (Open Access), INTRODUCTION: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients. METHODS AND ANALYSIS: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence. ETHICS AND DISSEMINATION: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.
Published: 2019

34. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Author: Aparicio H.J., Del C. Valdes Hernandez M., Luciano M., Liewald D., Deary I.J., Starr J.M., Bastin M.E., Maniega S.M., Slagboom P.E., Beekman M., Deelen J., Uh H.-W., Lemmens R., Brodaty H., Wright M.J., Ames D., Boncoraglio G.B., Hopewell J.C., Beecham A.H., Blanton S.H., Wright C.B., Sacco R.L., Wen W., Thalamuthu A., Armstrong N.J., Chong E., Schofield P.R., Kwok J.B., van der Grond J., Stott D.J., Ford I., Jukema J.W., Vernooij M.W., Hofman A., Uitterlinden A.G., van der Lugt A., Wittfeld K., Grabe H.J., Hosten N., von Sarnowski B., Volker U., Levi C., Jimenez-Conde J., Sharma P., Sudlow C.L.M., Rosand J., Woo D., Cole J.W., Meschia J.F., Slowik A., Thijs V., Lindgren A., Melander O., Grewal R.P., Rundek T., Rexrode K., Rothwell P.M., Arnett D.K., Jern C., Johnson J.A., Benavente O.R., Wasssertheil-Smoller S., Lee J.-M., Wong Q., Mitchell B.D., Rich S.S., McArdle P.F., Geerlings M.I., van der Graaf Y., de Bakker P.I.W., Asselbergs F.W., Srikanth V., Thomson R., McWhirter R., Moran C., Callisaya M., Phan T., Rutten-Jacobs L.C.A., Bevan S., Tzourio C., Mather K.A., Sachdev P.S., van Duijn C.M., Worrall B.B., Dichgans M., Kittner S.J., Markus H.S., Ikram M.A., Fornage M., Launer L.J., Seshadri S., Longstreth W.T., Debette S., Chauhan G., Adams H.H.H., Satizabal C.L., Bis J.C., Teumer A., Sargurupremraj M., Hofer E., Trompet S., Hilal S., Smith A.V., Jian X., Malik R., Traylor M., Pulit S.L., Amouyel P., Mazoyer B., Zhu Y.-C., Kaffashian S., Schilling S., Beecham G.W., Montine T.J., Schellenberg G.D., Kjartansson O., Gudnason V., Knopman D.S., Griswold M.E., Windham B.G., Gottesman R.F., Mosley T.H., Schmidt R., Saba Y., Schmidt H., Takeuchi F., Yamaguchi S., Nabika T., Kato N., Rajan K.B., Aggarwal N.T., De Jager P.L., Evans D.A., Psaty B.M., Rotter J.I., Rice K., Lopez O.L., Liao J., Chen C., Cheng C.-Y., Wong T.Y., Ikram M.K., van der Lee S.J., Amin N., Chouraki V., Destefano A.L., Romero J.R., Maillard P., Decarli C., Wardlaw J.M., Aparicio H.J., Del C. Valdes Hernandez M., Luciano M., Liewald D., Deary I.J., Starr J.M., Bastin M.E., Maniega S.M., Slagboom P.E., Beekman M., Deelen J., Uh H.-W., Lemmens R., Brodaty H., Wright M.J., Ames D., Boncoraglio G.B., Hopewell J.C., Beecham A.H., Blanton S.H., Wright C.B., Sacco R.L., Wen W., Thalamuthu A., Armstrong N.J., Chong E., Schofield P.R., Kwok J.B., van der Grond J., Stott D.J., Ford I., Jukema J.W., Vernooij M.W., Hofman A., Uitterlinden A.G., van der Lugt A., Wittfeld K., Grabe H.J., Hosten N., von Sarnowski B., Volker U., Levi C., Jimenez-Conde J., Sharma P., Sudlow C.L.M., Rosand J., Woo D., Cole J.W., Meschia J.F., Slowik A., Thijs V., Lindgren A., Melander O., Grewal R.P., Rundek T., Rexrode K., Rothwell P.M., Arnett D.K., Jern C., Johnson J.A., Benavente O.R., Wasssertheil-Smoller S., Lee J.-M., Wong Q., Mitchell B.D., Rich S.S., McArdle P.F., Geerlings M.I., van der Graaf Y., de Bakker P.I.W., Asselbergs F.W., Srikanth V., Thomson R., McWhirter R., Moran C., Callisaya M., Phan T., Rutten-Jacobs L.C.A., Bevan S., Tzourio C., Mather K.A., Sachdev P.S., van Duijn C.M., Worrall B.B., Dichgans M., Kittner S.J., Markus H.S., Ikram M.A., Fornage M., Launer L.J., Seshadri S., Longstreth W.T., Debette S., Chauhan G., Adams H.H.H., Satizabal C.L., Bis J.C., Teumer A., Sargurupremraj M., Hofer E., Trompet S., Hilal S., Smith A.V., Jian X., Malik R., Traylor M., Pulit S.L., Amouyel P., Mazoyer B., Zhu Y.-C., Kaffashian S., Schilling S., Beecham G.W., Montine T.J., Schellenberg G.D., Kjartansson O., Gudnason V., Knopman D.S., Griswold M.E., Windham B.G., Gottesman R.F., Mosley T.H., Schmidt R., Saba Y., Schmidt H., Takeuchi F., Yamaguchi S., Nabika T., Kato N., Rajan K.B., Aggarwal N.T., De Jager P.L., Evans D.A., Psaty B.M., Rotter J.I., Rice K., Lopez O.L., Liao J., Chen C., Cheng C.-Y., Wong T.Y., Ikram M.K., van der Lee S.J., Amin N., Chouraki V., Destefano A.L., Romero J.R., Maillard P., Decarli C., and Wardlaw J.M.
Abstract: Objective To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 x 10-8; and LINC00539/ZDHHC20, p = 5.82 x 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 x 10-25; p [SSBI] = 5.23 x 10-14 for hypertension), smoking (p[BI]= 4.4 x 10-10; p [SSBI] = 1.2 x 10 -4), diabetes (p[BI] = 1.7 x 10 -8; p [SSBI] = 2.8 x 10 -3), previous cardiovascular disease (p [BI] = 1.0 x 10-18; p [SSBI] = 2.3 x 10-7), stroke (p [BI] = 3.9 x 10-69; p [SSBI] = 3.2 x 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 x 10-157; p [SSBI] = 3.16 x 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p <= 0.0022), without indication of directional pleiotropy. Conclusion In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significa
Published: 2019

35. White matter hyperintensity quantification in large-scale clinical acute ischemic stroke cohorts - The MRI-GENIE study

Author: Schirmer, MD, Dalca, A, Sridharan, R, Giese, A-K, Donahue, KL, Nardin, MJ, Mocking, SJT, McIntosh, EC, Frid, P, Wasselius, J, Cole, JW, Holmegaard, L, Jern, C, Jimenez-Conde, J, Lemmens, R, Lindgren, AG, Meschia, JF, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Vagal, A, Xu, H, Kittner, SJ, McArdle, PF, Mitchell, BD, Rosand, J, Worrall, BB, Wu, O, Golland, P, Rost, NS, Schirmer, MD, Dalca, A, Sridharan, R, Giese, A-K, Donahue, KL, Nardin, MJ, Mocking, SJT, McIntosh, EC, Frid, P, Wasselius, J, Cole, JW, Holmegaard, L, Jern, C, Jimenez-Conde, J, Lemmens, R, Lindgren, AG, Meschia, JF, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Vagal, A, Xu, H, Kittner, SJ, McArdle, PF, Mitchell, BD, Rosand, J, Worrall, BB, Wu, O, Golland, P, and Rost, NS
Abstract: White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of sub
Published: 2019

36. Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Author: Chauhan, G, Adams, HHH, Satizabal, CL, Bis, JC, Teumer, A, Sargurupremraj, M, Hofer, E, Trompet, S, Hilal, S, Smith, AV, Jian, X, Malik, R, Traylor, M, Pulit, SL, Amouyel, P, Mazoyer, B, Zhu, Y-C, Kaffashian, S, Schilling, S, Beecham, GW, Montine, TJ, Schellenberg, GD, Kjartansson, O, Gudnason, V, Knopman, DS, Griswold, ME, Windham, BG, Gottesman, RF, Mosley, TH, Schmidt, R, Saba, Y, Schmidt, H, Takeuchi, F, Yamaguchi, S, Nabika, T, Kato, N, Rajan, KB, Aggarwal, NT, De Jager, PL, Evans, DA, Psaty, BM, Rotter, JI, Rice, K, Lopez, OL, Liao, J, Chen, C, Cheng, C-Y, Wong, TY, Ikram, MK, van der Lee, SJ, Amin, N, Chouraki, V, DeStefano, AL, Aparicio, HJ, Romero, JR, Maillard, P, DeCarli, C, Wardlaw, JM, Hernandez, MDCV, Luciano, M, Liewald, D, Deary, IJ, Starr, JM, Bastin, ME, Maniega, SM, Slagboom, PE, Beekman, M, Deelen, J, Uh, H-W, Lemmens, R, Brodaty, H, Wright, MJ, Ames, D, Boncoraglio, GB, Hopewell, JC, Beecham, AH, Blanton, SH, Wright, CB, Sacco, RL, Wen, W, Thalamuthu, A, Armstrong, NJ, Chong, E, Schofield, PR, Kwok, JB, van der Grond, J, Stott, DJ, Ford, I, Jukema, JW, Vernooij, MW, Hofman, A, Uitterlinden, AG, van der Lugt, A, Wittfeld, K, Grabe, HJ, Hosten, N, von Sarnowski, B, Voelker, U, Levi, C, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rosand, J, Woo, D, Cole, JW, Meschia, JF, Slowik, A, Thijs, V, Lindgren, A, Melander, O, Grewal, RP, Rundek, T, Rexrode, K, Rothwell, PM, Arnett, DK, Jern, C, Johnson, JA, Benavente, OR, Wasssertheil-Smoller, S, Lee, J-M, Wong, Q, Mitchell, BD, Rich, SS, McArdle, PF, Geerlings, MI, van der Graaf, Y, de Bakker, PIW, Asselbergs, FW, Srikanth, V, Thomson, R, McWhirter, R, Moran, C, Callisaya, M, Thanh, P, Rutten-Jacobs, LCA, Bevan, S, Tzourio, C, Mather, KA, Sachdev, PS, van Duijn, CM, Worrall, BB, Dichgans, M, Kittner, SJ, Markus, HS, Ikram, MA, Fornage, M, Launer, LJ, Seshadri, S, Longstreth, WT, Debette, S, Chauhan, G, Adams, HHH, Satizabal, CL, Bis, JC, Teumer, A, Sargurupremraj, M, Hofer, E, Trompet, S, Hilal, S, Smith, AV, Jian, X, Malik, R, Traylor, M, Pulit, SL, Amouyel, P, Mazoyer, B, Zhu, Y-C, Kaffashian, S, Schilling, S, Beecham, GW, Montine, TJ, Schellenberg, GD, Kjartansson, O, Gudnason, V, Knopman, DS, Griswold, ME, Windham, BG, Gottesman, RF, Mosley, TH, Schmidt, R, Saba, Y, Schmidt, H, Takeuchi, F, Yamaguchi, S, Nabika, T, Kato, N, Rajan, KB, Aggarwal, NT, De Jager, PL, Evans, DA, Psaty, BM, Rotter, JI, Rice, K, Lopez, OL, Liao, J, Chen, C, Cheng, C-Y, Wong, TY, Ikram, MK, van der Lee, SJ, Amin, N, Chouraki, V, DeStefano, AL, Aparicio, HJ, Romero, JR, Maillard, P, DeCarli, C, Wardlaw, JM, Hernandez, MDCV, Luciano, M, Liewald, D, Deary, IJ, Starr, JM, Bastin, ME, Maniega, SM, Slagboom, PE, Beekman, M, Deelen, J, Uh, H-W, Lemmens, R, Brodaty, H, Wright, MJ, Ames, D, Boncoraglio, GB, Hopewell, JC, Beecham, AH, Blanton, SH, Wright, CB, Sacco, RL, Wen, W, Thalamuthu, A, Armstrong, NJ, Chong, E, Schofield, PR, Kwok, JB, van der Grond, J, Stott, DJ, Ford, I, Jukema, JW, Vernooij, MW, Hofman, A, Uitterlinden, AG, van der Lugt, A, Wittfeld, K, Grabe, HJ, Hosten, N, von Sarnowski, B, Voelker, U, Levi, C, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rosand, J, Woo, D, Cole, JW, Meschia, JF, Slowik, A, Thijs, V, Lindgren, A, Melander, O, Grewal, RP, Rundek, T, Rexrode, K, Rothwell, PM, Arnett, DK, Jern, C, Johnson, JA, Benavente, OR, Wasssertheil-Smoller, S, Lee, J-M, Wong, Q, Mitchell, BD, Rich, SS, McArdle, PF, Geerlings, MI, van der Graaf, Y, de Bakker, PIW, Asselbergs, FW, Srikanth, V, Thomson, R, McWhirter, R, Moran, C, Callisaya, M, Thanh, P, Rutten-Jacobs, LCA, Bevan, S, Tzourio, C, Mather, KA, Sachdev, PS, van Duijn, CM, Worrall, BB, Dichgans, M, Kittner, SJ, Markus, HS, Ikram, MA, Fornage, M, Launer, LJ, Seshadri, S, Longstreth, WT, and Debette, S
Abstract: OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most si
Published: 2019

37. APOE epsilon 4 is associated with younger age at ischemic stroke onset but not with stroke outcome

Author: Lagging, C, Lorentzen, E, Stanne, TM, Pedersen, A, Soderholm, M, Cole, JW, Jood, K, Lemmens, R, Phuah, C-L, Rost, NS, Thijs, V, Woo, D, Maguire, JM, Lindgren, A, Jern, C, Lagging, C, Lorentzen, E, Stanne, TM, Pedersen, A, Soderholm, M, Cole, JW, Jood, K, Lemmens, R, Phuah, C-L, Rost, NS, Thijs, V, Woo, D, Maguire, JM, Lindgren, A, and Jern, C
Published: 2019

38. Serum magnesium and calcium levels in relation to ischemic stroke Mendelian randomization study

Author: Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaelsson, K, Markus, HS, Larsson, SC, Traylor, M, Burgess, S, Boncoraglio, GB, Jern, C, Michaelsson, K, and Markus, HS
Abstract: OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2019

39. Genome-wide association meta-analysis of functional outcome after ischemic stroke

Author: Soderholm, M, Pedersen, A, Lorentzen, E, Stanne, TM, Bevan, S, Olsson, M, Cole, JW, Fernandez-Cadenas, I, Hankey, GJ, Jimenez-Conde, J, Jood, K, Lee, J-M, Lemmens, R, Levi, C, Mitchell, BD, Norrving, B, Rannikmaee, K, Rost, NS, Rosand, J, Rothwell, PM, Scott, R, Strbian, D, Sturm, JW, Sudlow, C, Traylor, M, Thijs, V, Tatlisumak, T, Woo, D, Worrall, BB, Maguire, JM, Lindgren, A, Jern, C, Soderholm, M, Pedersen, A, Lorentzen, E, Stanne, TM, Bevan, S, Olsson, M, Cole, JW, Fernandez-Cadenas, I, Hankey, GJ, Jimenez-Conde, J, Jood, K, Lee, J-M, Lemmens, R, Levi, C, Mitchell, BD, Norrving, B, Rannikmaee, K, Rost, NS, Rosand, J, Rothwell, PM, Scott, R, Strbian, D, Sturm, JW, Sudlow, C, Traylor, M, Thijs, V, Tatlisumak, T, Woo, D, Worrall, BB, Maguire, JM, Lindgren, A, and Jern, C
Abstract: OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10-8. RESULTS: We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10-9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1). CONCLUSIONS: In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
Published: 2019

40. Global Outcome Assessment Life-long after stroke in young adults initiative-the GOAL initiative: study protocol and rationale of a multicentre retrospective individual patient data meta-analysis

Author: Ekker, MS, Jacob, MA, van Dongen, MME, Aarnio, K, Annamalai, AK, Arauz, A, Arnold, M, Barboza, MA, Bolognese, M, Brouns, R, Chuluun, B, Chuluunbaatar, E, Dagvajantsan, B, Debette, S, Don, A, Enzinger, C, Ekizoglu, E, Fandler-Hoefler, S, Fazekas, F, Fromm, A, Gattringer, T, Gulli, G, Hoffmann, M, Hora, TF, Jern, C, Jood, K, Kamouchi, M, Kim, YS, Kitazono, T, Kittner, SJ, Kleinig, TJ, Klijn, CJM, Korv, J, Lee, T-H, Leys, D, Maaijwee, NAM, Martinez-Majander, N, Marto, JP, Mehndiratta, MM, Mifsud, V, Montanaro, VV, Owolabi, MO, Patel, VB, Phillips, MC, Piechowski-Iozwiak, B, Pikula, A, Luis Ruiz-Sandoval, J, Sarnowski, B, Schreuder, FHBM, Swartz, RH, Tan, KS, Tanne, D, Tatlisumak, T, Thijs, V, Tuladhar, AM, Viana-Baptista, M, Vibo, R, Wu, TY, Yesilot, N, Waje-Andreassen, U, Pezzini, A, Putaala, J, de Leeuw, F-E, Ekker, MS, Jacob, MA, van Dongen, MME, Aarnio, K, Annamalai, AK, Arauz, A, Arnold, M, Barboza, MA, Bolognese, M, Brouns, R, Chuluun, B, Chuluunbaatar, E, Dagvajantsan, B, Debette, S, Don, A, Enzinger, C, Ekizoglu, E, Fandler-Hoefler, S, Fazekas, F, Fromm, A, Gattringer, T, Gulli, G, Hoffmann, M, Hora, TF, Jern, C, Jood, K, Kamouchi, M, Kim, YS, Kitazono, T, Kittner, SJ, Kleinig, TJ, Klijn, CJM, Korv, J, Lee, T-H, Leys, D, Maaijwee, NAM, Martinez-Majander, N, Marto, JP, Mehndiratta, MM, Mifsud, V, Montanaro, VV, Owolabi, MO, Patel, VB, Phillips, MC, Piechowski-Iozwiak, B, Pikula, A, Luis Ruiz-Sandoval, J, Sarnowski, B, Schreuder, FHBM, Swartz, RH, Tan, KS, Tanne, D, Tatlisumak, T, Thijs, V, Tuladhar, AM, Viana-Baptista, M, Vibo, R, Wu, TY, Yesilot, N, Waje-Andreassen, U, Pezzini, A, Putaala, J, and de Leeuw, F-E
Abstract: INTRODUCTION: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients. METHODS AND ANALYSIS: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence. ETHICS AND DISSEMINATION: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.
Published: 2019

41. Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke

Author: Pfeiffer, D, Chen, B, Schlicht, K, Ginsbach, P, Abboud, S, Bersano, A, Bevan, S, Brandt, T, Caso, V, Debette, S, Erhart, P, Freitag-Wolf, S, Giacalone, G, Grau, AJ, Hayani, E, Jern, C, Jiménez-Conde, J, Kloss, M, Krawczak, M, Lee, JM, Lemmens, R, Leys, D, Lichy, C, Maguire, JM, Martin, JJ, Metso, AJ, Metso, TM, Mitchell, BD, Pezzini, A, Rosand, J, Rost, NS, Stenman, M, Tatlisumak, T, Thijs, V, Touzé, E, Traenka, C, Werner, I, Woo, D, Del Zotto, E, Engelter, ST, Kittner, SJ, Cole, JW, Grond-Ginsbach, C, Lyrer, PA, Lindgren, A, Pfeiffer, D, Chen, B, Schlicht, K, Ginsbach, P, Abboud, S, Bersano, A, Bevan, S, Brandt, T, Caso, V, Debette, S, Erhart, P, Freitag-Wolf, S, Giacalone, G, Grau, AJ, Hayani, E, Jern, C, Jiménez-Conde, J, Kloss, M, Krawczak, M, Lee, JM, Lemmens, R, Leys, D, Lichy, C, Maguire, JM, Martin, JJ, Metso, AJ, Metso, TM, Mitchell, BD, Pezzini, A, Rosand, J, Rost, NS, Stenman, M, Tatlisumak, T, Thijs, V, Touzé, E, Traenka, C, Werner, I, Woo, D, Del Zotto, E, Engelter, ST, Kittner, SJ, Cole, JW, Grond-Ginsbach, C, Lyrer, PA, and Lindgren, A
Abstract: Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this associ
Published: 2019

42. Genetically Determined Risk of Depression and Functional Outcome after Ischemic Stroke: Mendelian Randomization Study

Author: Gill, D, James, NE, Monori, G, Lorentzen, E, Fernandez-Cadenas, I, Lemmens, R, Thijs, V, Rost, NS, Scott, R, Hankey, GJ, Lindgren, A, Jern, C, Maguire, JM, Gill, D, James, NE, Monori, G, Lorentzen, E, Fernandez-Cadenas, I, Lemmens, R, Thijs, V, Rost, NS, Scott, R, Hankey, GJ, Lindgren, A, Jern, C, and Maguire, JM
Abstract: © 2019 American Heart Association, Inc. Background and Purpose-Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods-Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results-There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions-We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent
Published: 2019

43. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Author: Cole, J, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y, O'Connell, J, Bevan, S, Malik, R, Ahmed, N, Amouyel, P, Anjum, S, Bis, J, Crosslin, D, Danesh, J, Engelter, S, Fornage, M, Frossard, P, Gieger, C, Giese, A, Grond-Ginsbach, C, Ho, W, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, W, Mahmood, K, Meisinger, C, Metso, T, Mosley, T, Müller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Słowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, V, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Isgc, Metastroke Consortium Of The, Consortium, Wtccc-2, Stine, O, Kittner, S, Mitchell, B, Cole, John W [0000-0001-9263-8930], Gaynor, Brady [0000-0002-4142-0613], Pezzini, Alessandro [0000-0001-8629-3315], Thijs, Vincent N [0000-0002-6614-8417], Apollo - University of Cambridge Repository, Faculty of Medicine, Neurologian yksikkö, Clinicum, Department of Neurosciences, HUS Neurocenter, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, Male, Thrombomodulin, Social Sciences, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular Medicine, Vascular Medicine, 3124 Neurology and psychiatry, Brain Ischemia, Brain ischemia, 0302 clinical medicine, Sociology, Consortia, YOUNG-ADULTS, Medicine and Health Sciences, Medicine, FACTOR-V-LEIDEN, Ethnicities, Age of Onset, African American people, POPULATION, education.field_of_study, Endothelial protein C receptor, Multidisciplinary, Endothelial Protein C Receptor, Genomics, Middle Aged, Population groupings, 3. Good health, Stroke, Hemorrhagic Stroke, VINTAGE, Neurology, Cardiovascular Diseases, Female, Research Article, Adult, medicine.medical_specialty, Adolescent, Science, Cerebrovascular Diseases, Population, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, CLASSIFICATION, White People, MECHANISMS, Molecular Genetics, 03 medical and health sciences, Young Adult, Internal medicine, Factor V Leiden, Genome-Wide Association Studies, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, education, Molecular Biology, POLYMORPHISMS, METAANALYSIS, Genetic Association Studies, Ischemic Stroke, business.industry, MORTALITY, Case-control study, 3112 Neurosciences, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, Genome Analysis, Black or African American, MYOCARDIAL-INFARCTION, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Age of onset, People and places, business, 030217 neurology & neurosurgery
Abstract: Background and purpose Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin−protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. Methods Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15–49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age Results Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. Conclusion PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.
Published: 2018
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44. Common coding variant in SERPINA1 increases the risk for large artery stroke

Author: Malik, R, Dau, T, Gonik, M, Sivakumar, A, Deredge, DJ, Edeleva, EV, Götzfried, J, Van Der Laan, SW, Pasterkamp, G, Beaufort, N, Seixas, S, Bevan, S, Lincz, LF, Holliday, EG, Burgess, AI, Rannikmäe, K, Minnerup, J, Kriebel, J, Waldenberger, M, Müller-Nurasyid, M, Lichtner, P, Saleheen, D, Woo, D, Debette, S, Maguire, J, Cole, JW, Majersik, J, Jimenez-Conde, J, Lee, JM, Rost, N, Pare, G, Jern, C, Lindgren, AG, Cardenas, IF, Rothwell, PM, Levi, C, Attia, J, Sudlow, CLM, Braun, D, Markus, HS, Wintrode, PL, Berger, K, Jenne, DE, and Dichgans, M
Subjects: Repressor Proteins, Stroke, alpha 1-Antitrypsin, Humans, Deuterium Exchange Measurement, Leukocyte Elastase, 3' Untranslated Regions, Polymorphism, Single Nucleotide, Histone Deacetylases, Mass Spectrometry, Genetic Association Studies, Plaque, Atherosclerotic
Abstract: Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3?-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.
Published: 2017

45. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Author: Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), Morris, R.W. (Richard), Franceschini, N. (Nora), Giambartolomei, C. (Claudia), Vries, P.S. (Paul) de, Finan, C. (Chris), Bis, J.C. (Joshua), Huntley, R.P. (Rachael P.), Lovering, R.C. (Ruth C.), Tajuddin, S.M. (Salman M.), Winkler, T.W. (Thomas W.), Graff, M. (Misa), Kavousi, M. (Maryam), Dale, C. (Caroline), Smith, A.V. (Albert), Hofer, E. (Edith), Leeuwen, E.M. (Elisa) van, Nolte, I.M. (Ilja), Lu, L. (Lingyi), Scholz, M. (Markus), Sargurupremraj, M. (Muralidharan), Pitkanen, N. (Niina), Franzén, O. (Oscar), Joshi, P.K. (Peter), Noordam, R. (Raymond), Marioni, R.E. (Riccardo), Hwang, S.-J. (Shih-Jen), Musani, S.K. (Solomon K.), Schminke, U. (Ulf), Palmas, W. (Walter), Isaacs, A.J. (Aaron), Correa, D.D., Zonderman, A.B., Hofman, A. (Albert), Teumer, A. (Alexander), Cox, A.J. (Amanda J.), Uitterlinden, A.G. (André), Wong, A. (Andrew), Smit, A.J. (Andries), Newman, A.B. (Anne B.), Britton, A.R., Ruusalepp, A. (Arno), Sennblad, B. (Bengt), Hedblad, B. (Bo), Pasaniuc, B. (Bogdan), Penninx, B.W.J.H. (Brenda), Langefeld, C.D. (Carl D.), Wassel, C.L. (Christina), Tzourio, C. (Christophe), Fava, C. (Cristiano), Baldassarre, D. (Damiano), O’Leary, D.H. (Daniel H.), Teupser, D. (Daniel), Kuh, D. (Diana), Tremoli, E. (Elena), Mannarino, E. (Elmo), Grossi, E. (Enzo), Boerwinkle, E.A. (Eric), Schadt, E.E. (Eric E.), Ingelsson, E. (Erik), Veglia, F. (Fabrizio), Rivadeneira Ramirez, F. (Fernando), Beutner, F. (Frank), Chauhan, G. (Ganesh), Heiss, G. (Gerardo), Snieder, H. (Harold), Campbell, H. (Harry), Völzke, H. (Henry), Markus, H.S. (Hugh), Deary, I.J. (Ian), Jukema, J.W. (Jan Wouter), Graaf, J. (Jacqueline) de, Price, J. (Jacqueline), Pott, J. (Janne), Hopewell, J., Liang, J. (Jingjing), Thiery, J.P. (Joachim), Engmann, J. (Jorgen), Gertow, K. (Karl), Rice, K.M. (Kenneth), Taylor, K.D. (Kent), Dhana, K. (Klodian), Kiemeney, L.A.L.M. (Lambertus A. L. M.), Kao, W.H.L. (Wen), Raffield, L.M. (Laura M.), Launer, L.J. (Lenore), Holdt, L.M. (Lesca), Dörr, M. (Marcus), Kubisch, C. (Christian), Traylor, M. (Matthew), Sitzer, M. (Matthias), Kumari, M. (Meena), Kivimaki, M. (Mika), Nalls, M.A. (Michael), Melander, O. (Olle), Raitakari, O. (Olli), Franco, O.H. (Oscar), Rueda-Ochoa, O.L. (Oscar), Roussos, A. (Alexandra), Whincup, P.H. (Peter), Amouyel, P. (Philippe), Giral, P. (Philippe), Anugu, P. (Pramod), Wong, Q. (Quenna), Malik, R. (Rainer), Rauramaa, R. (Rainer), Burkhardt, R. (Ralph), Hardy, R. (Rebecca), Schmidt, R. (Reinhold), Mutsert, R. (Reneé) de, Strawbridge, R.J. (Rona), Wannamethee, S.G. (Goya), Hägg, S. (Sara), Shah, S. (Sonia), McLachlan, S. (Stela), Trompet, S. (Stella), Seshadri, S. (Sudha), Kurl, S. (Sudhir), Heckbert, S.R. (Susan), Ring, S.M. (Susan), Harris, T.B. (Tamara B.), Lehtimäki, T. (Terho), Galesloot, T.E. (Tessel), Shah, T. (Tina), Faire, U. (Ulf) de, Plagnol, V. (Vincent), Rosamond, W.D. (Wayne), Post, W.S. (Wendy S.), Zhu, X. (Xiaofeng), Zhang, X. (Xiaoling), Guo, X. (Xiuqing), Saba, Y. (Yasaman), Okada, Y. (Yukinori), Mishra, A. (Aniket), Rutten-Jacobs, L. (Loes), Giese, A.-K. (Anne-Katrin), van der Laan, S.W. (Sander W.), Gretarsdottir, S. (Solveig), Anderson, C.D. (Christopher D.), Chong, M. (Michael), Adams, H.H.H. (Hieab), Ago, T. (Tetsuro), Almgren, P. (Peter), Ay, H. (Hakan), Bartz, T.M. (Traci M.), Benavente, O.R. (Oscar R.), Bevan, S. (Steve), Boncoraglio, G. (Giorgio Battista), Brown, R.D. (Robert D.), Butterworth, A.S. (Adam S.), Carrera, C. (Caty), Carty, C.L. (Cara L.), Chasman, D.I. (Daniel), Chen, W-M., Cole, J.W. (John W.), Cotlarciuc, I. (Ioana), Cruchaga, C. (Carlos), Danesh, J. (John), Bakker, P.I.W. (Paul) de, DeStefano, A.L. (Anita), Hoed, M. (Marcel) den, Duan, Q. (Qing), Engelter, S.T. (Stefan), Falcone, G.J. (Guido J.), Gottesman, R.F. (Rebecca), Grewal, R.P. (Raji P.), Gustafsson, S. (Stefan), Haessler, J. (Jeff), Harris, T.B. (Tamara), Hassan, A. (Ahamad), Havulinna, A.S. (Aki), Holliday, E.G. (Elizabeth), Howard, G. (George), Hsu, F.-C. (Fang-Chi), Hyacinth, H.I. (Hyacinth I.), Ikram, M.A. (Arfan), Irvin, M.R. (Marguerite R.), Jian, X. (Xueqiu), Jimenez-Conde, J. (Jordi), Johnson, J.A. (Julie A.), Jukema, J.W. (J. Wouter), Kanai, M. (Masahiro), Keene, K.L. (Keith), Kissela, B.M. (Brett M.), Kleindorfer, D.O. (Dawn O.), Kooperberg, C. (Charles), Kubo, M. (Michiaki), Lange, L.A. (Leslie), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Lee, J.-M. (Jin-Moo), Lemmens, R. (Robin), Leys, D. (Didier), Lewis, C.M. (Cathryn), Lin, W.-Y. (Wei-Yu), Lindgren, A.G. (Arne G.), Lorentzen, E. (Erik), Magnusson, P.K. (Patrik), Maguire, J.M. (Jane), Manichaikul, A. (Ani), McArdle, P.F. (Patrick), Meschia, J.F. (James F.), Mosley, T.H. (Thomas H.), Ninomiya, T. (Toshiharu), O’Donnell, M.J. (Martin J.), Pulit, S.L. (Sara), Rannikmäe, K. (Kristiina), Reiner, A.P. (Alexander P.), Rexrode, K. (Kathryn), Rich, S.S. (Stephen), Ridker, P.M. (Paul), Rost, N.S. (Natalia), Rothwell, P.M. (Peter), Rundek, T. (Tatjana), Muir, K.W. (Keith), Sakaue, S. (Saori), Sale, M.M. (Michele M.), Salomaa, V. (Veikko), Sapkota, B.R. (Bishwa R.), Schmidt, C.O. (Carsten O.), Sharma, P. (Pankaj), Slowik, A. (Agnieszka), Sudlow, C. (Cathie), Tanislav, C. (Christian), Tatlisumak, T. (Turgut), Thijs, V. (Vincent), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Tiedt, S. (Steffen), Walters, M. (Matthew), Wareham, N.J. (Nick), Wassertheil-Smoller, S. (Sylvia), Wiggins, K.L. (Kerri), Yang, Q. (Qiong Fang), Yusuf, S. (Salim), Pastinen, T. (Tomi), Schadt, E.E. (Eric), Koplev, S. (Simon), Codoni, V. (Veronica), Civelek, M. (Mete), Smith, N.L. (Nicholas), Tregouet, D.-A. (David-Alexandre), Christophersen, I.E. (Ingrid E.), Roselli, C. (Carolina), Lubitz, S.A. (Steven A.), Ellinor, P.T. (Patrick), Tai, E.S. (E. Shyong), Kooner, J.S. (Jaspal S.), Kato, N. (Norihiro), He, J. (Jiang), Harst, P. (Pim) van der, Elliott, P. (Paul), Chambers, J.C. (John C.), Takeuchi, F. (Fumihiko), Johnson, A.D. (Andrew), Sanghera, D.K. (Dharambir K.), Jern, C. (Christina), Strbian, D. (Daniel), Fernandez-Cadenas, I. (Israel), Longstreth Jr, W.T., Rolfs, A. (Arndt), Hata, J. (Jun), Woo, D. (Daniel), Rosand, J. (Jonathan), Pare, G. (Guillame), Saleheen, D. (Danish), Zwart, J-A. (John-Anker), Worrall, B.B. (Bradford B.), Kittner, T. (Thomas), Howson, J.M.M. (Joanna M. M.), Kamatani, Y. (Yoichiro), Dehghan, A. (Abbas), Seldenrijk, K.A. (Kees), Morrison, A.C. (Alanna), Hamsten, A. (Anders), Psaty, B.M. (Bruce), Duijn, C.M. (Cornelia) van, Lawlor, D.A. (Debbie), Mook-Kanamori, D.O. (Dennis O.), Bowden, D.W. (Donald), Schmidt, H. (Helena), Wilson, J.F. (James F.), Wilson, J.F. (James), Rotter, J.I. (Jerome I.), Wardlaw, J.M. (J.), Deanfield, J. (John), Halcox, J. (Julian), Lyytikäinen, L.-P. (Leo-Pekka), Loeffler, M. (Markus), Evans, M.K. (Michele), Debette, S. (Stéphanie), Humphries, S.E. (Steve), Völker, U. (Uwe), Gudnason, V. (Vilmundur), Hingorani, A. (Aroon), Björkegren, J.L.M. (Johan L.M.), Casas, J.P. (Juan), Ódonnell, C.J. (Christopher), and Morris, R.W. (Richard)
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Published: 2018
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46. Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke

Author: Ko, S-B, Cole, JW, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y-C, O'Connell, J, Bevan, S, Malik, R, Ahmed, NU, Amouyel, P, Anjum, S, Bis, JC, Crosslin, D, Danesh, J, Engelter, ST, Fornage, M, Frossard, P, Gieger, C, Giese, A-K, Grond-Ginsbach, C, Ho, WK, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley, T, Mueller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Slowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, VN, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Stine, OC, Kittner, SJ, Mitchell, BD, Ko, S-B, Cole, JW, Xu, H, Ryan, K, Jaworek, T, Dueker, N, McArdle, P, Gaynor, B, Cheng, Y-C, O'Connell, J, Bevan, S, Malik, R, Ahmed, NU, Amouyel, P, Anjum, S, Bis, JC, Crosslin, D, Danesh, J, Engelter, ST, Fornage, M, Frossard, P, Gieger, C, Giese, A-K, Grond-Ginsbach, C, Ho, WK, Holliday, E, Hopewell, J, Hussain, M, Iqbal, W, Jabeen, S, Jannes, J, Kamal, A, Kamatani, Y, Kanse, S, Kloss, M, Lathrop, M, Leys, D, Lindgren, A, Longstreth, WT, Mahmood, K, Meisinger, C, Metso, TM, Mosley, T, Mueller-Nurasyid, M, Norrving, B, Parati, E, Peters, A, Pezzini, A, Quereshi, I, Rasheed, A, Rauf, A, Salam, T, Shen, J, Slowik, A, Stanne, T, Strauch, K, Tatlisumak, T, Thijs, VN, Tiedt, S, Traylor, M, Waldenberger, M, Walters, M, Zhao, W, Boncoraglio, G, Debette, S, Jern, C, Levi, C, Markus, H, Meschia, J, Rolfs, A, Rothwell, P, Saleheen, D, Seshadri, S, Sharma, P, Sudlow, C, Worrall, B, Stine, OC, Kittner, SJ, and Mitchell, BD
Abstract: BACKGROUND AND PURPOSE: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. METHODS: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. RESULTS: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. CONCLUSION: PROCR polymorphisms are as
Published: 2018

47. Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Author: Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, Sheth, K, Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, and Sheth, K
Abstract: OBJECTIVE: We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. METHODS: We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. RESULTS: We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10-4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10-48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1). CONCLUSIONS: Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
Published: 2018

48. Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

Author: Traylor, M, Zhang, Cr, Adib Samii, P, Devan, Wj, Parsons, Oe, Lanfranconi, S, Gregory, S, Cloonan, L, Falcone, Gj, Radmanesh, F, Fitzpatrick, K, Kanakis, A, Barrick, Tr, Moynihan, B, Lewis, Cm, Boncoraglio, Gb, Lemmens, R, Thijs, V, Sudlow, C, Wardlaw, J, Rothwell, Pm, Meschia, Jf, Worrall, Bb, Levi, C, Bevan, S, Furie, Kl, Dichgans, M, Rosand, J, Markus, Hs, Rost, N, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, Th, Chang, Kc, Elkind, M, Goldstein, L, James, Ml, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, Kj, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Ahmadi, K, Opherk, C, Duering, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller Myhsok, B, Meschia, J, Brott, T, Pare, G, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Yvonne Chan, Yf, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Ke, Le, Lee, Wl, Tan, Ek, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Sheu, W, Chiou, Hy, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Martín, Jj, Klijn, K, Van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, Alessandro, Padovani, Alessandro, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Rannikmae, K, Silliman, S, Mcdonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, Mcardle, P, Chang, Yc, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, Ak, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, Jm, and Sheth, K.
Subjects: Cerebral Small Vessel Diseases, Genetic Predisposition to Disease, Genetic Testing, Humans, Polymorphism, Single Nucleotide, Risk Factors, Stroke, White Matter, Genome-Wide Association Study, Neurology (clinical), Single Nucleotide, C420 Human Genetics, Article, C431 Medical Genetics, C400 Genetics, Polymorphism, C440 Molecular Genetics
Abstract: Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.
Published: 2016
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49. Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study

Author: Rosand, J, Mitchell, BD, Ay, H, de Bakker, PIW, Gwinn, K, Kittner, SJ, Lindgren, A, Meschia, JF, Pulit, SL, Sudlow, CLM, Thijs, V, Woo, D, Worrall, BB, Arnett, DK, Benavente, O, Cole, JW, Dichgans, M, Grewal, RP, Jern, C, Conde, JJ, Johnson, JA, Lee, J-M, Levi, C, Markus, HS, Melander, O, Rexrode, K, Rothwell, PM, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, and Wasssertheil-Smoller, S
Subjects: Adult, Aged, 80 and over, Neurology & Neurosurgery, Adolescent, Tetraspanins, Nerve Tissue Proteins, Middle Aged, Brain Ischemia, Cohort Studies, Stroke, Young Adult, Genetic Loci, Case-Control Studies, Humans, Aged, Genome-Wide Association Study
Published: 2015

50. Neglect and aphasia in the acute phase as predictors of functional outcome 7 years after ischemic stroke

Author: Gerafi, Joel, Samuelsson, H., Viken, J. I., Blomgren, C., Claesson, L., Kallio, Sakari, Jern, C., Blomstrand, C., Jood, K., Gerafi, Joel, Samuelsson, H., Viken, J. I., Blomgren, C., Claesson, L., Kallio, Sakari, Jern, C., Blomstrand, C., and Jood, K.
Abstract: Background and purpose: Visuospatial inattention (VSI) and languageimpairment (LI) are often present early after stroke and associations with an unfavorable short-term functional outcome have been reported. The purpose of this study was to investigate whether a screening of VSI and LI as indicators of cortical symptoms early after stroke could predict long-term functional outcomes. Methods: A consecutive cohort of 375 patients with ischemic stroke was assessed for the occurrence of VSI at a median of 7 days after admission (interquartile range, 1–5 days) using the Star Cancellation Test and for LI (within the ﬁrst 7 days) with the language item in the Scandinavian StrokeScale. Seven years later, functional outcomes were assessed by the modiﬁed Rankin scale and Frenchay Activities Index in 235 survivors without recurrent stroke. Relationships between baseline predictors and functional outcome at 7 years were analyzed with bivariate correlations and multiple categorical regressions with optimal scaling. Results: The regression model signiﬁcantly explained variance in the modiﬁed Rankin scale (R2= 0.435, P < 0.001) and identiﬁed VSI (P=0.001) and neurological deﬁcits (P < 0.001; Scandinavian Stroke Scale score without the language item) as the signiﬁcant independent predictors. The model for FrenchayActivities Index was also signiﬁcant (R2= 0.269, P < 0.001) with VSI(P = 0.035) and neurological deﬁcits (P < 0.001) as signiﬁcant independent predictors. Conclusions: Visuospatial inattention at acute stroke has an independent impact on long-term functional outcomes. Early recognition may enable targeted rehabilitative interventions., First published: 12 August 2017
Published: 2017
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