Postcoloniality without race? Racial exceptionalism and south-east European cultural studies

The black Dutch feminist Gloria Wekker, assembling past and present everyday expressions of racialized imagination which collectively undermine hegemonic beliefs that white Dutch society has no historic responsibility for racism, writes in her book White Innocence that ‘one can do postcolonial studies very well without ever critically addressing race’ (p. 175). Two and a half decades after the adaptation of postcolonial thought to explain aspects of cultural politics during the break-up of Yugoslavia created important tools for understanding the construction of national, regional and socio-economic identities around hierarchical notions of ‘Europe’ and ‘the Balkans’ in the Yugoslav region and beyond, Wekker’s observation is still largely true for south-east European studies, where no intervention establishing race and whiteness as categories of analysis has reframed the field like work by Maria Todorova on ‘balkanism’ or Milica Bakić-Hayden on ‘symbolic geographies’ and ‘nesting orientalism’ did in the early 1990s. Critical race theorists such as Charles Mills nevertheless argue that ‘race’ as a structure of thought and feeling that legitimised colonialism and slavery (and still informs structural white supremacy) involved precisely the kind of essentialised link between people and territory that south-east European cultural theory also critiques: the construction of spatialised hierarchies specifying which peoples and territories could have more or less access to civilisation and modernity. South-east European studies’ latent racial exceptionalism has some roots in the race-blind anti-colonial solidarities of state socialist internationalism (further intensified for Yugoslavia through the politics of Non-Alignment) but also, this paper suggests, in deeper associations between Europeanness, whiteness and modernity that remain part of the history of ‘Europe’ as an idea even if, by the end of the 20th century, they were silenced more often than voiced

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy

Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology