Continuous turnover of neurons in the olfactory bulb is implicated in several key aspects of olfaction. There is a dramatic decline postnatally in the number of migratory neuroblasts en route to the ...olfactory bulb in humans, and it has been unclear to what extent the small number of neuroblasts at later stages contributes new neurons to the olfactory bulb. We have assessed the age of olfactory bulb neurons in humans by measuring the levels of nuclear bomb test-derived 14C in genomic DNA. We report that 14C concentrations correspond to the atmospheric levels at the time of birth of the individuals, establishing that there is very limited, if any, postnatal neurogenesis in the human olfactory bulb. This identifies a fundamental difference in the plasticity of the human brain compared to other mammals.
► Carbon dating establishes cell turnover dynamics in the human olfactory bulb ► The yearly exchange rate of nonneuronal cells is 2.0%–3.4% ► Olfactory bulb neurons are as old as the individual ► <1% of olfactory bulb neurons are exchanged over 100 years in humans
Bergmann et al. measure the cellular integration of 14C in olfactory bulb neurons from humans exposed to nuclear bomb tests. Results show that olfactory bulb neurons in humans are as old as the individual and argue that adult olfactory bulb neurogenesis is minimal in humans.
Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
We ...analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling.
Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones.
Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).
Abstract
Treatment response and resistance in major depressive disorder (MDD) are suggested to be heritable. Due to significant challenges in defining treatment-related phenotypes, our understanding ...of their genetic bases is limited. This study aimed to derive a stringent definition of treatment resistance and to investigate the genetic overlap between treatment response and resistance in MDD. Using electronic medical records on the use of antidepressants and electroconvulsive therapy (ECT) from Swedish registers, we derived the phenotype of treatment-resistant depression (TRD) and non-TRD within ~4500 individuals with MDD in three Swedish cohorts. Considering antidepressants and lithium are first-line treatment and augmentation used for MDD, respectively, we generated polygenic risk scores (PRS) of antidepressants and lithium response for individuals with MDD and evaluated their associations with treatment resistance by comparing TRD with non-TRD. Among 1778 ECT-treated MDD cases, nearly all (94%) used antidepressants before their first ECT and the vast majority had at least one (84%) or two (61%) antidepressants of adequate duration, suggesting these MDD cases receiving ECT were resistant to antidepressants. We did not observe a significant difference in the mean PRS of antidepressant response between TRD and non-TRD; however, we found that TRD cases had a significantly higher PRS of lithium response compared to non-TRD cases (OR = 1.10–1.12 under various definitions). The results support the evidence of heritable components in treatment-related phenotypes and highlight the overall genetic profile of lithium-sensitivity in TRD. This finding further provides a genetic explanation for lithium efficacy in treating TRD.
Pharmacological treatment, imaging, and neurochemistry studies identify altered dopamine signaling in bipolar disorder. Our previous work has shown higher concentration of homovanillic acid (HVA), ...the end metabolite of dopamine, in cerebrospinal fluid (CSF) from individuals with bipolar disorder compared to healthy controls. Here, we analyzed HVA concentrations from a follow-up visit in 103 adults with bipolar disorder and 57 controls from our first cohort. Further, we analyzed CSF monoamine metabolite concentrations in a second cohort of 152 adults with bipolar disorder and 55 controls. At the follow-up visit for the first cohort, HVA was higher in individuals with bipolar disorder (278 ± 102 nmol/L, p = 0.003) compared with controls (232 ± 83 nmol/L). In the second cohort, individuals with bipolar disorder had higher HVA (272 ± 97 nmol/L, p = 0.001) and lower 3-methoxy-4-hydroxyphenylglycol (MHPG, 40 ± 9 nmol/L, p = 0.002) concentrations than controls (HVA, 231 ± 71 nmol/L and MHPG, 45 ± 9 nmol/L). Baseline and follow-up measures of monoamine metabolites showed medium to high correlation to each other but did not predict course of illness. We failed to replicate the association of HVA concentration and psychotic symptoms but confirmed lower 5-hydroxyindoleacetic acid (5-HIAA) concentration in individuals treated with antidepressants. In conclusion, we confirmed high HVA concentration in CSF in patients with bipolar disorder compared to a control group. Previous work suggest that this is a feature shared with ADHD but distinct from schizophrenia and major depressive disorder. The role of increased HVA concentration in the course of illness in bipolar disorder remains unclear.
•Homo-vanillic acid (HVA), an end metabolite of dopamine, is increased in cerebrospinal fluid in individuals with bipolar disorder.•The end metabolites of serotonin and norepinephrine are not consistently altered in bipolar disorder.•HVA concentration remains high after a seven year follow-up period.•High HVA concentration was not associated with a worse outcome in bipolar disorder.
There is a long-standing belief that creativity is coupled with psychopathology.
To test this alleged association and to investigate whether any such association is the result of environmental or ...genetic factors.
We performed a nested case-control study based on Swedish registries. The likelihood of holding a creative occupation in individuals who had received in-patient treatment for schizophrenia, bipolar disorder or unipolar depression between 1973 and 2003 and their relatives without such a diagnosis was compared with that of controls.
Individuals with bipolar disorder and healthy siblings of people with schizophrenia or bipolar disorder were overrepresented in creative professions. People with schizophrenia had no increased rate of overall creative professions compared with controls, but an increased rate in the subgroup of artistic occupations. Neither individuals with unipolar depression nor their siblings differed from controls regarding creative professions.
A familial cosegregation of both schizophrenia and bipolar disorder with creativity is suggested.
ObjectiveTo compare problems reported in the five EQ-5D-3L dimensions and EQ VAS scores at baseline and at 1-year follow-up among different patient groups and specific diagnoses in 11 National ...Quality Registers (NQRs) and to compare these with the general population.DesignLongitudinal, descriptive study.Participants2 66 241 patients from 11 NQRs and 49 169 participants from the general population were included in the study.Primary and secondary outcome measuresProportions of problems reported in the five EQ-5D-3L dimensions, EQ VAS scores of participants’ own health and proportions of participants and mean/median EQ VAS score in the Paretian Classification of Health Change (PCHC) categories.ResultsIn most of the included registers, and the general population, problems with pain/discomfort were the most frequently reported at baseline and at 1-year follow-up. Mean EQ VAS score (SD) ranged from 45.2 (22.4) among disc hernia patients to 88.1 (15.3) in wrist and hand fracture patients at baseline. They ranged from 48.9 (20.9) in pulmonary fibrosis patients to 83.3 (17.4) in wrist and hand fracture patients at follow-up. The improved category of PCHC, improvement in at least one dimension without deterioration in any other, accounted for the highest proportion in several diagnoses, corresponding with highest improvement in mean EQ VAS score.ConclusionsThe study documented self-reported health of several different patient groups using the EQ-5D-3L in comparing with the general population. This demonstrated the important role of patient-reported outcomes in routine clinical care, to assess and follow-up health status and progress within different groups of patients. The EQ-5D-3L descriptive system and EQ VAS have an important role in providing a ‘common denominator’, allowing comparisons across NQRs and specific diagnoses.Trial registration numberClinicalTrials.gov (NCT04359628).
An association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link ...are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09-0.19) and identify a shared locus at 19p13 (GATAD2A) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms.
Attention-deficit hyperactivity disorder (ADHD) is associated with bipolar disorder and schizophrenia, and it has been suggested that combined bipolar disorder and ADHD is aetiologically distinct ...from the pure disorders.
To clarify whether ADHD shares genetic and environmental factors with bipolar disorder and schizophrenia.
By linking longitudinal Swedish national registers, we identified 61 187 persons with ADHD (the proband group) and their first- and second-degree relatives, and matched them with a control group of people without ADHD and their corresponding relatives. Conditional logistic regression was used to determine the risks of bipolar disorder and schizophrenia in the relatives of the two groups.
First-degree relatives of the ADHD proband group were at increased risk of both bipolar disorder (odds ratio (OR) = 1.84-2.54 for parents, offspring and full siblings) and schizophrenia (OR = 1.71-2.22 for parents, offspring and full siblings). The risks of bipolar disorder and schizophrenia among second-degree relatives were substantially lower than among full siblings.
These findings suggest that the co-occurrence of ADHD and bipolar disorder as well as ADHD and schizophrenia is due to shared genetic factors, rather than representing completely aetiologically distinct subsyndromes.
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