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

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.

Physical and cognitive impact following SARS-CoV-2 infection in a large population-based case-control study.

BACKGROUND: Persistent symptoms are common after SARS-CoV-2 infection but correlation with objective measures is unclear. METHODS: We invited all 3098 adults who tested SARS-CoV-2 positive in Iceland before October 2020 to the deCODE Health Study. We compared multiple symptoms and physical measures between 1706 Icelanders with confirmed prior infection (cases) who participated, and 619 contemporary and 13,779 historical controls. Cases participated in the study 5-18 months after infection. RESULTS: Here we report that 41 of 88 symptoms are associated with prior infection, most significantly disturbed smell and taste, memory disturbance, and dyspnea. Measured objectively, cases had poorer smell and taste results, less grip strength, and poorer memory recall. Differences in grip strength and memory recall were small. No other objective measure associated with prior infection including heart rate, blood pressure, postural orthostatic tachycardia, oxygen saturation, exercise tolerance, hearing, and traditional inflammatory, cardiac, liver, and kidney blood biomarkers. There was no evidence of more anxiety or depression among cases. We estimate the prevalence of long Covid to be 7% at a median of 8 months after infection. CONCLUSIONS: We confirm that diverse symptoms are common months after SARS-CoV-2 infection but find few differences between cases and controls in objective parameters measured. These discrepancies between symptoms and physical measures suggest a more complicated contribution to symptoms related to prior infection than is captured with conventional tests. Traditional clinical assessment is not expected to be particularly informative in relating symptoms to a past SARS-CoV-2 infection.

Persistent symptoms are commonly reported after SARS-CoV-2 infection, and this is often described as long Covid. We compared different symptoms reported following SARS-CoV- 2 infection with the results obtained during various medical evaluations that are often used to assess health, such as blood tests, smell tests, taste tests, hearing tests, etc. We compared symptoms and test results between 1,706 Icelanders who had been infected previously with SARS-CoV-2 infection (cases) and 14,398 individuals who had not been infected (controls). Out of 88 assessed symptoms, 41 were more common in cases than controls. However, relatively few differences were seen in the results obtained from the various medical evaluations (cases had poorer smell and taste test results, slightly less grip strength, and slightly poorer memory recall than controls). The differences seen between symptoms and results of medical evaluations suggests that conventional clinical tests may not be informative in relating symptoms to a past SARS-CoV-2 infection.

Thirty novel sequence variants impacting human intracranial volume.

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 (n = 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 GLI3 and CDK6 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.

MAP1B mutations cause intellectual disability and extensive white matter deficit.

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 (ß = -2.1SD, P = 5.1 × 10-8), 47% less corpus callosum (CC) volume (ß = -2.4SD, P = 5.5 × 10-10) and lower brain-wide fractional anisotropy (P = 6.7 × 10-4). 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.

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

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.

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

We conducted a search for rare, functional variants altering susceptibility to Alzheimer's disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimer's disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10(-13)) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10(-15)).

Isolation and characterization of a thermostable RNA ligase 1 from a Thermus scotoductus bacteriophage TS2126 with good single-stranded DNA ligation properties.

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.