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Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Homo sapiens is currently living in serious disharmony with the rest of the natural world. For our species to survive, and for our well-being, we must gather knowledge from multiple perspectives and actively engage in studies of planetary health. The enormous diversity of species, one of the most striking aspects of life on our planet, provides a source of solutions that have been developed through evolution by natural selection by animals living in extreme environments. The food system is central to finding solutions; our current global eating patterns have a negative impact on human health, driven climate change and loss of biodiversity. We propose that the use of solutions derived from nature, an approach termed biomimetics, could mitigate the effects of a changing climate on planetary health as well as human health. For example, activation of the transcription factor Nrf2 may play a role in protecting animals living in extreme environments, or animals exposed to heat stress, pollution and pesticides. In order to meet these challenges, we call for the creation of novel interdisciplinary planetary health research teams.
Autoimmune NMDA-R encephalitis (ANRE) shares clinical features with schizophrenia. Recent research also indicates that both disorders are associated with dysfunction of the N-Methyl-D-Aspartate glutamate receptors (NMDA-R) subunit 1.
We present the case of Ms A, 16 years old. Ms A presented with acute personality change, bizarre behaviour, delusional ideas and atypical seizures. She had a family history of psychotic disorders, and autistic traits diagnosed in childhood. She was initially diagnosed with a psychotic disorder. Delayed testing of CSF indicated ANRE. As the patient was a Jehovah's witness the treating team was unable to use gammaglobulin therapy; they instead relied on combined plasmapheresis and rituximab. To exclude the possibility that the affected members of this family shared a gene coding for an abnormal configuration of the NMDA receptor subunit 1 we sequenced the region of the GRIN1 gene in DNA extracted from blood in both Ms A and her grandmother.
Ms A’s condition improved dramatically, though her long-term memory is still demonstrably impaired. No genetic abnormality was detected.
This case emphasizes how important it is, for a first episode psychosis, to exclude ANRE and other autoimmune synaptic encephalitides, even in the face of significant family history, and if seronegative, the importance of testing for CSF autoantibodies.
Studies in Sweden and Australia have examined the relationship between number of CAG repeats in the androgen receptor gene and psychological traits — three Masculinity-Femininity (M-F) measures in Australia, and the Karolinska Scales of Personality (KSP) in Sweden. The present study derived M-F scales from the KSP items, and scales corresponding to several KSP scales from the items of the inventories used in Australia, to permit cross-validation of the Australian results in the Swedish sample, and vice versa. The derivation of scales was facilitated by the fact that items from both inventories had been used with a large twin sample in the US. Correlation of the derived scales with androgen receptor gene CAG-repeat scores for women in the Australian and Swedish samples failed to provide clear evidence of replication of either set of original correlations in the other sample, although there were a few hints of consistency. It was concluded that if the number of CAG repeats on this gene is related to psychological traits at all, the relationship is a weak one.
The Swedish Twin Registry was first established in the late 1950s. Today it includes more than 170,000 twins — in principle all twins born in Sweden since 1886. In this article we describe some ongoing and recently completed projects based on the registry. In particular, we describe recent efforts to screen all twins born between 1959 and 1985, and young twin pairs when they turn 9 and 12 years of age. For these studies, we present initial frequencies of common conditions and exposures.
The gender diagnosticity (GD) approach of Lippa (1995) was used to evaluate the relationship of within-sex differences in psychological masculinity–femininity to a genetic characteristic, the length of a repeated CAG sequence in the X-linked androgen receptor (AR) gene. Previously assessed adult samples in Australia and Sweden were used for this purpose. A weak relationship (correlations in the range .11 to .14) was obtained in both countries. Additional data from adolescent twins from Australia (12-, 14-, 16-year-olds) did not confirm such a relationship at those ages, especially for males. The fact that this sample consisted of twins permitted two kinds of within-pair comparisons: (1) Did the dizygotic twin who had the longer AR sequence have the higher GD score? (2) Was one twin's GD score more highly correlated with the other twin's AR score in MZ than in DZ pairs? The answer in both cases was negative. Clarification of these relationships will require large samples and measurements at additional ages.
The aim of the current study was to investigate the importance of genetic and environmental effects in the variation of body mass index, and to investigate linkage for obesity to previously reported candidate regions on chromosome 2 and 10. A sample of 1422 twin pairs from the population based Swedish Twin Registry was used in order to estimate the genetic and environmental effects in the variation of body mass index by means of structural equation modeling. A selection of those, 51 concordant and 155 discordant for obesity, was used for the linkage analysis by implementing the “combined” Haseman-Elston approach. Heritability of body mass index ranged from 59–70%, implying that genetic effects were of importance for the variation of obesity, and there were significant sex and age differences. Linkage could not be verified in candidate regions of chromosomes 2 and 10, indicating that these genetic variants have a significant effect in extreme obese populations rather than in moderately obese Caucasians. However, the results were sensitive to issues related to power, minor effects of the genes, ethnic differences and the complex mechanism underlying obesity.
Decagonal single quasicrystals of the composition Al70Ni15Co15 have been deformed in situ in a high-voltage transmission electron microscope at 730 °C along the 10-fold periodic axis to directly observe the dislocation motion. The deformation is carried by stress-assisted climb of dislocations with periodic Burgers vectors. These dislocations may also glide and move by a combination of glide and climb. Dislocations with Burgers vectors with components in the periodic and quasiperiodic directions probably move under the action of a chemical force. The observations are interpreted by a model established by P. Schall et al. under consideration of the activation parameters of macroscopic deformation and by analogies with the behavior of icosahedral quasicrystals.
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