GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

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.

Sequence variants affecting voice pitch in humans.

The genetic basis of the human vocal system is largely unknown, as are the sequence variants that give rise to individual differences in voice and speech. Here, we couple data on diversity in the sequence of the genome with voice and vowel acoustics in speech recordings from 12,901 Icelanders. We show how voice pitch and vowel acoustics vary across the life span and correlate with anthropometric, physiological, and cognitive traits. We found that voice pitch and vowel acoustics have a heritable component and discovered correlated common variants in ABCC9 that associate with voice pitch. The ABCC9 variants also associate with adrenal gene expression and cardiovascular traits. By showing that voice and vowel acoustics are influenced by genetics, we have taken important steps toward understanding the genetics and evolution of the human vocal system.

Developing and testing inter-rater reliability of a data collection tool for patient health records on end-of-life care of neurological patients in an acute hospital ward.

AIM: Develop and test a data collection tool-Neurological End-Of-Life Care Assessment Tool (NEOLCAT)-for extracting data from patient health records (PHRs) on end-of-life care of neurological patients in an acute hospital ward. DESIGN: Instrument development and inter-rater reliability (IRR) assessment. METHOD: NEOLCAT was constructed from patient care items obtained from clinical guidelines and literature on end-of-life care. Expert clinicians reviewed the items. Using percentage agreement and Fleiss' kappa we calculated IRR on 32 nominal items, out of 76 items. RESULTS: IRR of NEOLCAT showed 89% (range 83%-95%) overall categorical percentage agreement. The Fleiss' kappa categorical coefficient was 0.84 (range 0.71-0.91). There was fair or moderate agreement on six items, and moderate or almost perfect agreement on 26 items. CONCLUSION: The NEOLCAT shows promising psychometric properties for studying clinical components of care of neurological patients at the end-of-life on an acute hospital ward but could be further developed in future studies.

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.

Changes in vitamin D metabolites at the time of critical illness and 6 months later-A prospective observational study.

BACKGROUND: Despite multiple studies suggesting that low 25(OH)D-vitamin levels are associated with worse outcomes in critically ill individuals, attempts to mitigate the outcomes by fixed dose enteral supplementation unguided by baseline or target blood levels have been unsuccessful. Since a single measurement of 25(OH)D may not optimally reflect an individual's vitamin D status, we studied the plasma concentration of different vitamin D metabolites and their recovery during and following resolution of acute critical illness. METHODS: A prospective observational study including patients 18 years and older admitted to a mixed medical-surgical ICU in Reykjavik, Iceland, located at a high-northern altitude (64° N). Vitamin D metabolites were measured at three timepoints; On admission (S1), 3-5 days following admission (S2) and after recovery from acute illness (median 178 days) (S3). Concentrations of total 25(OH)D-vitamin, cholecalciferol (D3 ), total 24,25(OH)D-vitamin, vitamin D binding protein (VDBP) were measured with LC-tandem mass spectrometry (LC-MS/MS) and free 25-(OH)D was measured with enzyme-linked immunosorbent assay. RESULTS: Most individuals were vitamin D deficient when assessed during critical illness, with 25(OH)D-vitamin levels under 30 ng/ml for 37/40 individuals at timepoint S1 and 34/38 at S2. After recovery, 18/30 patients were deficient at S3. Levels of all vitamin D metabolites measured were low during critical illness but rose substantially following resolution of acute illness. No strong correlation was found between markers of acute illness severity or duration and resolution of vitamin D metabolites in the interval between acute illness and recovery. CONCLUSIONS: In critically ill patients, levels of multiple vitamin D metabolites are low but substantial recovery occurs following resolution of acute illness. It is unclear whether a single metabolite is sufficient to assess vitamin D status of critically ill patients and guide potential supplementation.

Penetrating stab injuries in Iceland: a whole-nation study on incidence and outcome in patients hospitalized for penetrating stab injuries.

BACKGROUND: Studies on penetrating injuries in Europe are scarce and often represent data from single institutions. The aim of this study was to describe the incidence and demographic features of patients hospitalized for stab injury in a whole nation. MATERIALS AND METHODS: This was a retrospective nationwide population-based study on all consecutive adult patients who were hospitalized in Iceland following knife and machete-related injuries, 2000-2015. Age-standardized incidence was calculated and Injury Severity Score (ISS) was used to assess severity of injury. RESULTS: Altogether, 73 patients (mean age 32.6 years, 90.4% males) were admitted during the 16-year study period, giving an age-standardized incidence of 1.54/100,000 inhabitants. The incidence did not vary significantly during the study period (P = 0.826). Most cases were assaults (95.9%) occurring at home or in public streets, and involved the chest (n = 32), abdomen (n = 26), upper limbs (n = 26), head/neck/face (n = 21), lower limbs (n = 10), and the back (n = 6). Median ISS was 9, with 14 patients (19.2%) having severe injuries (defined as ISS > 15). The median length of hospital stay was 2 days (range 0-53). Forty-seven patients (64.4%) underwent surgery and 26 of them (35.6%) required admission to an intensive care unit (ICU), all with ISS scores above 15. Three patients did not survive for 30 days (4.1%); all of them had severe injuries (ISS 17, 25, and 75). CONCLUSION: Stab injuries that require hospital admission are rare in Iceland, and their incidence has remained relatively stable. One in every five patients sustained severe injuries, two-thirds of whom were treated with surgical interventions, and roughly one-third required ICU care. Although some patients were severely injured with high injury scores, their 30-day mortality was still low in comparison to other studies.

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.

Truncating mutations in RBM12 are associated with psychosis.

Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T (P = 2.2 × 10-4), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis (P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile (P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease.

Selection against variants in the genome associated with educational attainment.

Epidemiological and genetic association studies show that genetics play an important role in the attainment of education. Here, we investigate the effect of this genetic component on the reproductive history of 109,120 Icelanders and the consequent impact on the gene pool over time. We show that an educational attainment polygenic score, POLYEDU, constructed from results of a recent study is associated with delayed reproduction (P < 10-100) and fewer children overall. The effect is stronger for women and remains highly significant after adjusting for educational attainment. Based on 129,808 Icelanders born between 1910 and 1990, we find that the average POLYEDU has been declining at a rate of ∼0.010 standard units per decade, which is substantial on an evolutionary timescale. Most importantly, because POLYEDU only captures a fraction of the overall underlying genetic component the latter could be declining at a rate that is two to three times faster.

A sequence variant associating with educational attainment also affects childhood cognition.

Only a few common variants in the sequence of the genome have been shown to impact cognitive traits. Here we demonstrate that polygenic scores of educational attainment predict specific aspects of childhood cognition, as measured with IQ. Recently, three sequence variants were shown to associate with educational attainment, a confluence phenotype of genetic and environmental factors contributing to academic success. We show that one of these variants associating with educational attainment, rs4851266-T, also associates with Verbal IQ in dyslexic children (P = 4.3 × 10-4, ß = 0.16 s.d.). The effect of 0.16 s.d. corresponds to 1.4 IQ points for heterozygotes and 2.8 IQ points for homozygotes. We verified this association in independent samples consisting of adults (P = 8.3 × 10-5, ß = 0.12 s.d., combined P = 2.2 x 10-7, ß = 0.14 s.d.). Childhood cognition is unlikely to be affected by education attained later in life, and the variant explains a greater fraction of the variance in verbal IQ than in educational attainment (0.7% vs 0.12%,. P = 1.0 × 10-5).

CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in vitro and induce differentiation and a proinflammatory response.

A mutation in the human cystatin C gene leads to familial cerebral amyloid angiopathy. This disease is known as "hereditary cerebral hemorrhage with amyloidosis-Icelandic type" or "hereditary cystatin C amyloid angiopathy." The mutant cystatin C protein forms aggregates and amyloid, within the central nervous system almost exclusively in connection with the vascular system. It was not known whether immune cells could remove mutant cystatin C protein aggregates. Ex vivo mutant cystatin C protein aggregates, both in solution and dried onto a glass surface, induced adhesion to the substrate, differentiated the THP-1 monocyte cell line and led to a proinflammatory response. Aggregates were also taken up by both THP-1 cells and THP-1 derived macrophages. These are the same responses induced by other amyloidogenic protein species, such as amyloid ß protein and amylin, supporting the model of all amyloidogenic proteins being toxic due to common structural motifs. Proinflammatory response induced by the ex vivo mutant cystatin C protein aggregates suggests that vascular inflammation plays an important role in hereditary cerebral hemorrhage with amyloidosis-Icelandic type. Ex vivo protein aggregates of cystatin C might better model cellular behavior than in vitro-generated aggregates or supplement in vitro material.

Survival and neurodevelopmental outcome of ELBW children at 5 years of age: comparison of two cohorts born 10 years apart.

AIM: To examine survival and outcome of extremely low-birth-weight (ELBW) children (birth weight < 1000 g) in two 5-year periods, 10 years apart. METHODS: In a retrospective population-based study, information on all ELBW children born in Iceland in 1991-1995 and in 2001-2005 was obtained from the National Birth Registry, hospital charts and medical records. The two periods were compared. RESULTS: In 1991-1995, 102 of 22.261 newborn children (0.5%) were extremely low birth weight compared with 70 of 20.923 newborns (0.33%) in 2001-2005 (p = 0.04). At 5 years of age, 52% (35/67) of live-born children born in 1991-1995 were alive compared with 63% (31/49) of children born in 2001 - 2005 (p = 0.2). Six ELBW children (17%) born 1991-1995 were diagnosed with disabilities at 5 years of age, three with major neurodevelopmental disabilities compared with six (19%) born 2001-2005, thereof one with severe neurodevelopmental disabilities (p = 0.57). CONCLUSION: The incidence of childhood disabilities in ELBW children in Iceland remains stable despite an increase in survival rate. The severity of neurodevelopmental disabilities has decreased.

Costs and outcomes of abdominal, vaginal, laparoscopic and robotic hysterectomies.

BACKGROUND AND OBJECTIVES: To estimate the incidence of operative complications and compare operative cost and overall cost of different methods of benign hysterectomy including abdominal, vaginal, laparoscopic, and robotic techniques. METHODS: We performed a retrospective cohort analysis (Canadian Task Force classification II-2) of all patients who underwent a hysterectomy for benign reasons in 2009 at a single urban academic tertiary care center using the χ(2) test and Student t test. A multivariate regression analysis was also performed for predictors of costs. Cost data were gathered from the hospital's billing system; the remainder of data was extracted from patient's medical records. RESULTS: In 2009, 688 patients underwent a benign hysterectomy; 185 (26.9%) hysterectomies were abdominal, 135 (19.6%) vaginal, 352 (51.5%) laparoscopic, and 14 (2.0%) robotic. The rate of intraoperative complication was 1.7% for abdominal, 0.8% for vaginal, 0.3% for laparoscopic, and 0 for robotic. Mean total patient costs were $43,622 for abdominal, $31,934 for vaginal, $38,312 for laparoscopic, and $49,526 for robotic hysterectomies. Costs were significantly influenced by method of hysterectomy, operative time, and length of stay. CONCLUSION: Though complication rates did not vary significantly among minimally invasive methods of hysterectomy, patient costs were significantly influenced by the method of hysterectomy.

The Feasibility of Societal Cost Equivalence between Robotic Hysterectomy and Alternate Hysterectomy Methods for Endometrial Cancer.

Objectives. We assess whether it is feasible for robotic hysterectomy for endometrial cancer to be less expensive to society than traditional laparoscopic hysterectomy or abdominal hysterectomy. Methods. We performed a retrospective cohort analysis of patient characteristics, operative times, complications, and hospital charges from all (n = 234) endometrial cancer patients who underwent hysterectomy in 2009 at our hospital. Per patient costs of each hysterectomy method were examined from the societal perspective. Sensitivity analysis and Monte Carlo simulation were performed using a cost-minimization model. Results. 40 (17.1%) of hysterectomies for endometrial cancer were robotic, 91 (38.9%), were abdominal, and 103 (44.0%) were laparoscopic. 96.3% of the variation in operative cost between patients was predicted by operative time (R = 0.963, P < 0.01). Mean operative time for robotic hysterectomy was significantly longer than other methods (P < 0.01). Abdominal hysterectomy was consistently the most expensive while the traditional laparoscopic approach was consistently least expensive. The threshold in operative time that makes robotic hysterectomy cost equivalent to the abdominal approach is within the range of our experience. Conclusion. It is feasible for robotic hysterectomy to be less expensive than abdominal hysterectomy, but unlikely for robotic hysterectomy to be less expensive than traditional laparoscopy.

Prospective evaluation of quality of life in total versus supracervical laparoscopic hysterectomy.

STUDY OBJECTIVE: To evaluate and compare recovery times and quality of life (QOL) in patients undergoing a total laparoscopic hysterectomy (TLH) and laparoscopic supracervical hysterectomy (LSH). DESIGN: Patients underwent either a TLH or LSH. After surgery, patients maintained a daily log documenting pain, nausea, use of pain medications, and return to daily activities. They also completed a QOL questionnaire (SF-36) before and after surgery. DESIGN CLASSIFICATION: Prospective cohort study (Canadian Task Force Classification II-1). SETTING: University teaching hospital. PATIENTS: A total of 122 women undergoing laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: A total of 122 women underwent TLH (n = 71) or LSH (n = 51) for benign indications from February 2008 to January 2010. There was a significantly higher postoperative improvement of QOL scores in the LSH group in 6 of 10 questionnaire categories and summary scores, including physical functioning (p =.03), role physical (p =.002), and bodily pain (p =.03). There were no significant differences in use of pain medications, level of pain, level of nausea, or return to normal activities. CONCLUSION: LSH appears to provide greater improvement in short-term postoperative QOL compared with TLH. No significant differences were found in postoperative pain or return to daily activities.