Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

Humanitarianisms in context

This introduction describes the rapidly expanding history of non-state humanitarianism in terms of three themes. First, it argues that we should think about humanitarianism less in terms of ruptures or breaks, and focus more on the moments of acceleration and the continuities that shaped that narrative: how the relationships among local, national and international discourses were played out in the shift between imperial and post-colonial worlds, in the dialogue between religious and secular traditions, and in the transformative processes of decolonization, de-regulation and globalization. Second, we suggest the need to re-think the geography of non-state humanitarianism. Drawing attention to the transnational contexts and traditions in which ideas of humanitarianism have been articulated not only adds to our understanding of transnational action and the strength of global civil society beyond the West, we argue, it allows us to better appreciate the myriad languages and practices of humanitarianism employed in a global context. Finally, this introduction also re-visits the question of motivation. By looking beyond the state, we argue, we can better understand the variety of motives that shaped the act of giving: from compassion to capturing markets, the search for efficiency, and the construction of local, national and international identities.2017-09-1