The SCN1A rs6732655 enigma – a reply

rs6732655. I acknowledge that the title of this blog post looks like my keyboard is broken, but please bear with me. Last month, I blogged about a recent genome-wide association by the BioBank Japan (BBJ), discussing the evidence for a Single Nucleotide Polymorphism (SNP) in the vicinity of the SCN1A gene (rs6732655). In a prior study, the SNP in question was initially found to be associated with epilepsy and I discussed the fact that this SNP, albeit not significant by itself, was also seen at a higher frequency in cases than in controls in the epilepsy cohort of the BBJ study. I received some comments regarding this post and it was pointed out that my reasoning was incorrect given that rs6732655 was not nominally significant in the BBJ study. Therefore, this study was not a replication study in itself. Let me retrace my steps and revisit where my hunch came from to write the initial blog post. Continue reading

Common genetic risk factors for epilepsy in the Japanese population

GWAS. While our blog mainly deals with monogenic epilepsies, assessing common genetic risk factors through genome-wide association studies has been an established way of understanding potential genetic contributors to both common and rare disorders. More recently, polygenic risk scores have entered the stage, composite measures of many common variants which explain a significant proportion of the overall population risk for epilepsy. However, a major limitation of many genome-wide association studies has been the focus on populations of European ancestry. So far, very few studies have examined common genetic risk factors in the epilepsies in non-European populations. In a recent publication examining results from the BioBank Japan Project, 42 disorders were examined in more than 200,000 individuals, including the epilepsies. While no single epilepsy variant stood out, the study provides an interesting confirmation of a previously known common risk factors for the epilepsies. Continue reading

The second ILAE GWAS or why 30% of genetic generalized epilepsy is explained

Genome-wide association. While most of the neurogenetics community was focused on exome sequencing and the discovery of novel monogenic forms of epilepsy in the last few years, something quite remarkable had happened in the background. Common variants and genome-wide association studies have made a remarkable comeback. The ILAE Consortium for Complex Epilepsy had slowly worked on increasing sample sizes over time, and the second analysis of common variants in common epilepsies was published in late 2018. Sample sizes have almost doubled since the first study in 2014, and as a result, the number of genome-wide significant loci has tripled. However, the most intriguing finding was something that completely caught me by surprise – more than 30% of the heritability of the genetic generalized epilepsies is explained through common variants, approaching the numbers we see in epileptic encephalopathies explained by monogenic causes. This is one more reason to discuss the recent ILAE GWAS in more detail. Continue reading

A polygenic trickle of common variants in neurodevelopmental disorders

Common variants. In addition to the gradual increase in gene discovery due to exome sequencing, there is a field of human genetics developing in parallel that we have not paid much attention to recently. The role of common genetic variants or Single Nucleotide Polymorphisms (SNP) was initially limited to genome-wide association studies, looking at single variants individually. However, more recently, common variants have been assessed jointly in various diseases, resulting in so-called polygenic scores. In a recent publication in Nature, the polygenic contribution to neurodevelopmental disorders is evaluated. Interestingly, there seems to be a very robust contribution of common variants in neurodevelopmental disorders, even in patients with known de novo variants. Here is a brief discussion on why common variants start getting interesting for the neurogenetics field again. Continue reading