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.

Aims Little is known about the effects of mental health conditions (MHC) on the utilization of oral anticoagulant (OAC) therapy in atrial fibrillation (AF) patients. We aimed to assess whether MHCs affect initiation of OAC therapy among AF patients with special focus on non-vitamin K-antagonist oral anticoagulants (NOAC). Methods and Results The FinACAF registry included all 239222 patients diagnosed with incident AF during 2007-2018 in Finland identified from national registries covering primary to tertiary care and drug purchases. Patients with previous depression, bipolar disorder, anxiety disorder or schizophrenia diagnosis or fulfilled psychiatric medication prescription within preceding year form AF diagnosis were classified to have any MHC. The main outcome was OAC initiation, defined as first fulfilled OAC prescription after AF diagnosis. The patients’ mean age was 72.7 years and 49.8% were female. The prevalence of any MHC was 19.9%. Lower proportion of patients with any MHC compared to those without MHCs were initiated with OAC therapy (64.9% vs. 73.3%, p&lt;0.001). Any MHC was associated with lower incidence of OAC initiation (adjusted subdistribution hazard ratio (aSHR) 0.867; 95%-confidence interval (CI) 0.856-0.880) as were depression (aSHR 0.868; 95%-CI 0.856-0.880), bipolar disorder (aSHR 0.838; 95%-CI 0.824-0.852), anxiety disorder (aSHR 0.840; 95%-CI 0.827-0.854) and schizophrenia (aSHR 0.838; 95%-CI 0.824-0.851) during entire follow-up. Any MHC remained associated with impaired incidence of OAC initiation also in the NOAC-era during 2015-2018 (aSHR 0.821; 95% CI 0.805-0.837). Conclusion MHCs are common among AF patients, and they are associated with lower rate of OAC initiation even during the NOAC-era.

Atrial fibrillation (AF) is a major cause of ischemic stroke and the number of AF patients is increasing. Thus, up-to-date multifaceted data about the characteristics of AF patients, their treatments, and outcomes are urgently needed. The Finnish anticoagulation in atrial fibrillation (FinACAF) study has collected comprehensive data on all Finnish AF patients from 1st January 2004 to 31st December 2018. The aim of this paper is to describe the study rationale, the process of integrating data from the applied resources and to define the study cohort. Using national unique personal identification number, individual patient data is linked from nationwide health care registries (primary, secondary, and tertiary care), drug purchases, education, and socio-economic status as well as places of domicile, incomes, and taxes. Six regional laboratory databases (~ 282,000, 77% of the patients) are also included. The study cohort comprises of a total of 411,000 patients. Since the introduction of the national primary care register in 2012, 9% of all AF patients were identified outside hospital care registers. The prevalence of AF in Finland—4.1% of whole population—is for the first time now established. The FinACAF study allows a unique possibility to investigate the epidemiology and socio-medico-economic impact of AF as well as the cost effectiveness of different AF management strategies in a completely unselected, nationwide population. This article provides the rationale and design of the study together with a summary of the characteristics of the cohort.