Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. 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 analysis3, 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 approach4, 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 ancestry5. 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.

Word count abstract: 248 (max. 250) Word count manuscript text: 4977 (max. 5000) Vonk-Psycholinguistic features in PPA 2 AbstractObjective: To determine the effect of three psycholinguistic variables-lexical frequency, age of acquisition, and neighborhood density-on lexical-semantic processing in individuals with non-fluent, logopenic, and semantic primary progressive aphasia (PPA). Identifying the scope and independence of these features can provide valuable information about the organization of words in our mind and brain. Method:We administered a lexical-decision task-with words carefully selected to permit distinguishing lexical frequency, age of acquisition, and orthographic neighborhood density effects-to 41 individuals with the three variants of PPA (13 non-fluent, 14 logopenic, and 14 semantic) and 25 controls. Results:Of the psycholinguistic variables studied, lexical frequency had the largest influence on lexicalsemantic processing, but age of acquisition and neighborhood density also played an independent role.The effect of these latter two features differed across PPA variants and is consistent with the atrophy pattern of each variant. That is, individuals with non-fluent and logopenic PPA experienced a neighborhood density effect consistent with the role of inferior frontal and temporoparietal regions in lexical analysis and word form processing. By contrast, individuals with semantic PPA experienced an age of acquisition effect consistent with the role of the anterior temporal lobe in semantic processing. Conclusions:The findings are in line with a hierarchical mental lexicon structure with a conceptual (semantic) versus lexeme (word-form) level, such that a selective deficit at one of these levels of the mental lexicon manifests differently in lexical-semantic processing performance, consistent with the affected language-specific brain region in each PPA variant.

No abstract

No abstract

No abstract