GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Correction: Genetic diversity in the major capsid L1 protein of HPV-16 and HPV-18 in the Netherlands

In the Data Availability statement and the Materials and Methods section, the GenBank accession number KU70477 appears incorrectly. The correct accession number should be KU707477

Genetic Diversity in the Major Capsid L1 Protein of HPV-16 and HPV-18 in the Netherlands

Objectives Intratypic molecular variants of human papillomavirus (HPV) type-16 and -18 exist. In the Netherlands, a bivalent vaccine, composed of recombinant L1 proteins from HPV-16 and -18, is used to prevent cervical cancer since 2009. Long-term vaccination could lead to changes in HPV-16 and -18 virus population, thereby hampering vaccination strategies. We determined the genetic diversity of the L1 gene in HPV-16 and -18 viral strains circulating in the Netherlands at the start of vaccination in order to understand the baseline genetic diversity in the Dutch population. Methods DNA sequences of the L1 gene were determined in HPV-16 (n = 241) and HPV-18 (n = 108) positive anogenital samples collected in 2009 and 2011 among Dutch 16- to 24-year old female and male attendees of the sexually transmitted infection (STI) clinics. Phylogenetic analysis was performed and sequences were compared to reference sequences HPV-16 (AF536179) and HPV-18 (X05015) using BioNumerics 7.1. Results For HPV-16, ninety-five single nucleotide polymorphism (SNPs) were identified, twenty seven (28%) were non-synonymous variations. For HPV-18, seventy-one SNPs were identified, twenty-nine (41%) were non-synonymous. The majority of the non-silent variations were located in sequences encoding alpha helix, beta sheet or surface loops, in particular in the immunodominant FG loop, and may influence the protein secondary structure and immune recognition. Conclusions This study provides unique pre-vaccination/baseline data on the genetic L1 diversity of HPV- 16 and -18 viruses circulating in the Netherlands among adolescents and young adults

Non-synonymous nucleotide sequence variations of HPV-18 L1.

<p>Non-synonymous nucleotide sequence variations of HPV-18 L1.</p

Maximum parsimony tree based on nucleotide sequences of L1 HPV-18 gene.

<p>Study sequences of 108 HPV-18 positive samples collected in 2009 and 2011 are shown in blue. Reference sequences of European/A lineages (GenBank reference X05015, AY262282 (sublineage A1), EF202146 (sublineage A2), EF202147 (sublineage A3), EF202151 (sublineage A4), CQ180787 (sublineage A5)), African/B lineages (GenBank references EF202153, EF202154, EF202155 (sublineage B1)) KC470225 (sublineage B2) EF202152 (sublineage B3), and reference for lineage C (KC47229) are shown in green, brown and pink respectively. HPV-18 variant used in the vaccine (GenBank reference AY863161) is shown in red. The number given in each circle indicates the number of viral strains with the same sequence.</p

Maximum parsimony tree based on nucleotide sequences of L1 HPV-16 gene.

<p>Study sequences of 241 HPV-16 positive samples collected in 2009 and 2011 are shown in blue. Reference sequences of European/A lineages (GenBank reference AF536179 K02718 = NC001526, HQ644236, AF534061) are shown in green, African/B lineages (GenBank references AF472508, HQ644298 and AF536180) in brown. African-2/C lineage GenBank reference AF472509 is shown in pink. References sequences from lineage D are shown in purple HQ644257 (sublineage D1-North American), AY686579-(sublineage D2, Asian-American) AF402678 (sublineage D3, Asian-American). HPV-16 variant used in the vaccine (GenBank reference AF043286) is shown in red. The number given in each circle indicates the number of viral strains with the same sequence.</p

Characteristics of study population.

<p>Characteristics of study population.</p

Clinical and genetic analysis of a family with two rare reflex epilepsies

Purpose: To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. Method: Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. Results: The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalised PPRs were found in seven members (six above 50 yrs of age) with myoclonus during the PPR. Evolution was typical: sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 yrs. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129 C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. Conclusion: This family presents a combination of two rare reflex epilepsies. Genetic analysis favours four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features is warranted

Clinical and genetic analysis of a family with two rare reflex epilepsies

Purpose To determine clinical phenotypes, evolution and genetic background of a large family with a combination of two unusual forms of reflex epilepsies. Method Phenotyping was performed in eighteen family members (10 F, 8 M) including standardized EEG recordings with intermittent photic stimulation (IPS). Genetic analyses (linkage scans, Whole Exome Sequencing (WES) and Functional studies) were performed using photoparoxysmal EEG responses (PPRs) as affection status. Results The proband suffered from speaking induced jaw-jerks and increasing limb jerks evoked by flickering sunlight since about 50 years of age. Three of her family members had the same phenotype. Generalized PPRs were found in seven members (six above 50 years of age) with myoclonus during the PPR. Evolution was typical: Sensitivity to lights with migraine-like complaints around adolescence, followed by jerks evoked by lights and spontaneously with dropping of objects, and strong increase of light sensitivity and onset of talking induced jaw jerks around 50 years. Linkage analysis showed suggestive evidence for linkage to four genomic regions. All photosensitive family members shared a heterozygous R129C mutation in the SCNM1 gene that regulates splicing of voltage gated ion channels. Mutation screening of 134 unrelated PPR patients and 95 healthy controls, did not replicate these findings. Conclusion This family presents a combination of two rare reflex epilepsies. Genetic analysis favors four genomic regions and points to a shared SCNM1 mutation that was not replicated in a general cohort of photosensitive subjects. Further genetic studies in families with similar combination of features are warranted