Abstract Background Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease ...pathogenesis. In a previous small-scale copy number variation study of a GTS cohort ( n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase ( AADAC ), were observed and merited further investigations. Methods We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC , identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. Results In the Danish cohort, we identified eight patients with overlapping deletions of AADAC . Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association ( p = 4.4 × 10−4 ; odds ratio = 1.9; 95% confidence interval = 1.33–2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. Conclusions AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.
Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an important step towards understanding the pathophysiology of these disorders. Whole-genome sequencing of ...31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree (genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter (WM) volume (β = -2.1SD, P = 5.1 × 10
), 47% less corpus callosum (CC) volume (β = -2.4SD, P = 5.5 × 10
) and lower brain-wide fractional anisotropy (P = 6.7 × 10
). In summary, we show that loss of MAP1B function affects general cognitive ability through a profound, brain-wide WM deficit with likely disordered or compromised axons.
We generated two polygenic scores, one capturing verbal and the other spatial aspects of cognitive ability, using UK Biobank data and studied their effects on various diseases and other traits in the ...Icelandic population. The score tagging spatial ability associated with higher body mass index (β = 0.032, p = 3.2 × 10−13), but lower risk of schizophrenia (OR = 0.82, p = 8.8 × 10−9) and other mental disorders. Furthermore, it associated with less openness, a personality trait reflecting curiosity and creativity (β = −0.023, p = 1.3 × 10−4). Conversely, the score tagging verbal ability associated with lower body mass index (β = −0.023, p = 1.6 × 10−7) and more openness (β = 0.045, p = 3.5 × 10−14), but did not associate with risk of schizophrenia (OR = 0.97, p = 0.42). Furthermore, applying genomic structural equation modeling, we observed that the genetic component of verbal ability associated positively with the genetic component of schizophrenia after conditioning on the g factor (bg = 0.193, p = 5.4 × 10−4). Thus, at the genetic level, verbal and spatial ability exhibit contrasting associations with indicators of mental and physical health, as well as with personality.
•Verbal and spatial ability exhibit contrasting associations with health.•Spatial ability shares sequence variants with greater body mass index.•After adjusting for g, verbal ability shares sequence variants with schizophrenia.
Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We ...performed a genome-wide association study meta-analysis of intracranial volume (
= 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including
and
that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder.
We have recently sequenced the genome of a novel thermophilic bacteriophage designated as TS2126 that infects the thermophilic eubacterium Thermus scotoductus. One of the annotated open reading ...frames (ORFs) shows homology to T4 RNA ligase 1, an enzyme of great importance in molecular biology, owing to its ability to ligate single-stranded nucleic acids. The ORF was cloned, and recombinant protein was expressed, purified and characterized. The recombinant enzyme ligates single-stranded nucleic acids in an ATP-dependent manner and is moderately thermostable. The recombinant enzyme exhibits extremely high activity and high ligation efficiency. It can be used for various molecular biology applications including RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE). The TS2126 RNA ligase catalyzed both inter- and intra-molecular single-stranded DNA ligation to >50% completion in a matter of hours at an elevated temperature, although favoring intra-molecular ligation on RNA and single-stranded DNA substrates. The properties of TS2126 RNA ligase 1 makes it very attractive for processes like adaptor ligation, and single-stranded solid phase gene synthesis.
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.
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