Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Do fig wasps produce mixed paternity clutches?

Pollinating fig wasps (Hymenoptera, Agaonidae) have been the focus of numerous studies examining sex ratio evolution. Recently, molecular genetic techniques have been introduced that assume single matings in fig wasps, yet their mating biology has not been investigated genetically. We used recently developed microsatellite markers to investigate whether a pollinating fig wasp (Liporrhopalum tentacularis Grandi) produces single or mixed paternity clutches. The clutches of 12 females which had had the opportunity to mate with males of different genotypes were investigated. The results suggest that, at least in this species of fig wasp, single paternity clutches are the norm. Based on our behavioural observations, this appears to be due to mating with a single male rather than sperm competition. [KEYWORDS: Hymenoptera ; Liporrhopalum ; mating system ; microsatellites ; paternity ; sex ratio]

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies

CHEOPS geometric albedo of the hot Jupiter HD 209458 b

Stars and planetary system

Fundamental effective temperature measurements for eclipsing binary stars - III.: SPIRou near-infrared spectroscopy and CHEOPS photometry of the benchmark G0V star EBLM J0113+31

Stars and planetary system

The geometric albedo of the hot Jupiter HD 189733b measured with CHEOPS

Context. Measurements of the occultation of an exoplanet at visible wavelengths allow us to determine the reflective properties of a planetary atmosphere. The observed occultation depth can be translated into a geometric albedo. This in turn aids in characterising the structure and composition of an atmosphere by providing additional information on the wavelength-dependent reflective qualities of the aerosols in the atmosphere. Aims. Our aim is to provide a precise measurement of the geometric albedo of the gas giant HD 189733b by measuring the occultation depth in the broad optical bandpass of CHEOPS (350-1100 nm). Methods. We analysed 13 observations of the occultation of HD 189733b performed by CHEOPS utilising the Python package PyCHEOPS. The resulting occultation depth is then used to infer the geometric albedo accounting for the contribution of thermal emission from the planet. We also aid the analysis by refining the transit parameters combining observations made by the TESS and CHEOPS space telescopes. Results. We report the detection of an 24.7 ± 4.5 ppm occultation in the CHEOPS observations. This occultation depth corresponds to a geometric albedo of 0.076 ± 0.016. Our measurement is consistent with models assuming the atmosphere of the planet to be cloud-free at the scattering level and absorption in the CHEOPS band to be dominated by the resonant Na doublet. Taking into account previous optical-light occultation observations obtained with the Hubble Space Telescope, both measurements combined are consistent with a super-stellar Na elemental abundance in the dayside atmosphere of HD 189733b. We further constrain the planetary Bond albedo to between 0.013 and 0.42 at 3σconfidence. Conclusions. We find that the reflective properties of the HD 189733b dayside atmosphere are consistent with a cloud-free atmosphere having a super-stellar metal content. When compared to an analogous CHEOPS measurement for HD 209458b, our data hint at a slightly lower geometric albedo for HD 189733b (0.076 ± 0.016) than for HD 209458b (0.096 ± 0.016), or a higher atmospheric Na content in the same modelling framework. While our constraint on the Bond albedo is consistent with previously published values, we note that the higher-end values of ∼0.4, as derived previously from infrared phase curves, would also require peculiarly high reflectance in the infrared, which again would make it more difficult to disentangle reflected and emitted light in the total observed flux, and therefore to correctly account for reflected light in the interpretation of those phase curves. Lower reported values for the Bond albedos are less affected by this ambiguity