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- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 3. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 9. |
- Watson, Hunna J., et al.
(författare)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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| 10. |
- Walton, Esther, et al.
(författare)
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Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa : A Coordinated Analysis by the ENIGMA Eating Disorders Working Group
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 92:9, s. 730-738
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and de-pendencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data.METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251).RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of un-dernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients.CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.
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- Kooij, Karlijn L., et al.
(författare)
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Fecal microbiota transplantation of patients with anorexia nervosa did not alter flexible behavior in rats
- 2024
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Ingår i: INTERNATIONAL JOURNAL OF EATING DISORDERS. - 0276-3478 .- 1098-108X.
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivePatients with anorexia nervosa (AN) are often anxious, display inflexible behavior and disrupted reward processing. Emerging evidence suggests that gut dysbiosis in patients contributes to the disease phenotype and progression.MethodsIn a preclinical study, we explored whether AN-derived microbiota impacts cognitive flexibility, anxiety, and dopamine signaling using fecal microbiota transplantation (FMT) in tyrosine hydroxylase-cre rats. We performed probabilistic reversal learning task (PRLT) at the baseline, after antibiotic treatment, and following FMT from patients with AN and controls. We assessed flexible behavior, task engagement, and ventral tegmental area (VTA) dopamine signaling during and in the absence of reward. Furthermore, anxiety-like behavior was evaluated with open field (OF) and elevated plus maze (EPM) tests.ResultsNeither antibiotic-induced dysbiosis nor AN FMT led to significant alterations in the number of reversals or lever press strategies after reinforced or nonreinforced lever presses (win and lose-stay) in the PRLT. However, the number of initiated trials decreased after antibiotic treatment while remaining unchanged after FMT. No significant differences were observed in VTA dopamine activity, anxiety measures in the OF and EPM tests. Microbiome analysis revealed limited overlap between the microbiota of the donors and recipients.DiscussionNo evidence was found that the microbiota of patients compared to controls, nor a depleted microbiome impacts cognitive flexibility. Nonetheless, antibiotic-induced dysbiosis resulted in reduced task engagement during the PRLT. The relatively low efficiency of the FMT is a limitation of our study and highlights the need for improved protocols to draw robust conclusions in future studies.Public SignificanceWhile our study did not reveal direct impacts of AN-associated gut microbiota on cognitive flexibility or anxiety behaviors in our preclinical model, we observed a decrease in task engagement after antibiotic-induced dysbiosis, underscoring that the presence of a gut microbiome matters. Our findings underscore the need for further refinement in FMT protocols to better elucidate the complex interplay between gut microbiota and behaviors characteristic of anorexia nervosa.
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| 13. |
- Verharen, J. P. H., et al.
(författare)
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Insensitivity to Losses: A Core Feature in Patients With Anorexia Nervosa?
- 2019
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Ingår i: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. - : Elsevier BV. - 2451-9022.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with anorexia nervosa (AN) demonstrate aberrations in choice behavior, including impairments in laboratory measures of decision making. Although a wealth of studies suggest that these aberrations arise from alterations in value processing, it remains unclear by which core component of value processing this is mediated. Methods: We fit trial-by-trial data of patients with AN (n = 60 first cohort, n = 216 second cohort) and healthy control participants (n = 55) performing the Iowa Gambling Task to a computational model based on prospect utility theory. We determined, per participant, the best-fit model parameters and compared these between the groups. Results: Analyses revealed a decreased estimate of model parameter λ in patients with AN, indicative of an attenuation of loss-aversive behavior in the Iowa Gambling Task. In comparison, measures of reward sensitivity, value-based learning, and exploration versus exploitation were unaltered in patients with AN. A measurement in a second independent cohort replicated the finding that loss aversion, typically observed in healthy individuals, is reduced in patients with AN. Conclusions: We show that patients with AN, in contrast to healthy control participants, demonstrate reduced loss-aversive behavior. This finding provides important fundamental insights into the decision-making capacity of patients with AN, suggesting alterations in the mechanisms involved in value processing related to negative feedback. © 2019
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| 14. |
- Adan, Roger A. H., et al.
(författare)
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Translational genetics; expectations for eating disorders and other psychiatric disorders : Translationele genetica: verwachtingen voor eetstoornissen en andere psychiatrische stoornissen
- 2022
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Ingår i: Tijdschrift voor Psychiatrie. - 0303-7339. ; 64:2022-5, s. 304-308
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Tidskriftsartikel (refereegranskat)abstract
- Background Translational (genetic) research focuses on the translation of preclinical research into practice. While many genetic studies have been conducted in recent years, the results do not simply translate to the clinic. Aim To visualize the steps through which translational genetic research contributes to the unraveling of the biological backgrounds of psychiatric disorders, in particular of eating disorders. Method Literature review. Results Genetic studies have unraveled a mechanism underlying the hunger and satiety system. There is hope that genome-wide studies of eating disorders will lead to identification of neural circuits in which associated genes cluster. New techniques, such as opto- and chemogenetics, provide the opportunity to define the precise role of these circuits in eating disorders. Conclusion New techniques in molecular neuroscience allow the unravelling of the complexity of how the brain works and some of those techniques (such as chemogenetics) are being further developed for application in humans. However, it will be years before we can definitively translate this into the treatment of psychiatric disorders.
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| 15. |
- Kooij, K. L., et al.
(författare)
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Intranasal administration of olanzapine has beneficial outcome in a rat activity-based anorexia model
- 2023
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Ingår i: European Neuropsychopharmacology. - 0924-977X. ; 71, s. 65-74
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Tidskriftsartikel (refereegranskat)abstract
- The atypical antipsychotic drug olanzapine is prescribed despite clinical studies on olanzap-ine treatment showing mixed results on treatment efficacy in anorexia nervosa. We investi-gated the effect of systemic and intranasal administration of olanzapine in the activity-based anorexia (ABA) model. Rats were habituated to a running wheel and exposed to the ABA model while treated with olanzapine. During ABA rats had 1.5 h of daily access to food and ad libi-tum access to a running wheel for seven consecutive days. Olanzapine was administered via an osmotic minipump (1, 2.75, and 7.5 mg/kg) or intranasally 2 h before dark onset (1 and 2.75 mg/kg). We monitored body weight, food intake, wheel revolutions, body temperature, and adipose tissue.We found 2.75 and 7.5 mg/kg systemic olanzapine decreased wheel revolutions during ABA. Relative adipose tissue mass was increased in the 7.5 mg/kg olanzapine-treated group while body weight, food intake, and body temperature were unaltered by the systemic olanzapine. 1 and 2.75 mg/kg intranasal olanzapine diminished wheel revolutions and body temperature during the first 2 h after administration. The intranasal olanzapine-treated rats had a higher body weight at the end of ABA. We find that olanzapine has beneficial outcomes in the ABA via two administration routes by acting mainly on running wheel activity. Intranasal olanzapine showed a rapid effect in the first hours after administration in reducing locomotor activity. We recommend further explor-ing intranasal administration of olanzapine in anorectic patients to assist them in coping with restlessness.(c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
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| 17. |
- Gilsbach, Susanne, et al.
(författare)
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Increase in admission rates and symptom severity of childhood and adolescent anorexia nervosa in Europe during the COVID-19 pandemic: data from specialized eating disorder units in different European countries
- 2022
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Ingår i: Child and Adolescent Psychiatry and Mental Health. - : Springer Science and Business Media LLC. - 1753-2000. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background The COVID-19 pandemic, associated with confinement and social isolation, seems to have impacted the course of many mental disorders in children and adolescents. An increase in hospital admission rates for juvenile anorexia nervosa (AN) has been documented in many regions of the world. However, data from Europe are scarce. Methods We asked clinicians in specialized eating disorder units in hospitals of maximum care in France, Germany, Italy, Spain, Sweden, and the Netherlands to report on (i) overall (inpatient and outpatient) and (ii) inpatient admission rates for adolescents with AN during 2019 and 2020. Additionally, a modified version of the COVID Isolation Eating Scale (CIES) was used to assess the child and adolescent psychiatrists’ estimations of a possible increase in symptom severity in children and adolescents with AN during the COVID-19 pandemic and to (iii) inquire about the contributing factors perceived by the caring professionals. Results Four out of six representatives of European hospitals described a higher rate of overall admissions during the pandemic. Three hospitals out of six reported an increase in inpatient admissions, and two centres had constant high numbers of admissions of both outpatients and inpatients. The clinicians perceived a higher symptom severity in 2020 than in 2019, especially involving more frequent use of social media, longer duration of exercising, and more restrictive eating. They supposed an increase in social media consumption, a perceived “loss of control”, and a lack of in-person assessments and weight controls as the main contributing factors for the deterioration in AN numbers and symptomatology. Conclusions The COVID-19 pandemic seems to have had a deep impact on symptom severity in AN, which is mirrored by a large increase in admission rates across Europe. An increase in exercise, social media consumption, a perceived “loss of control”, and a lack of face-to-face health care seem to have contributed to this development. Further investigation is required to identify which factors may lead to the increase in incidence and deterioration of childhood and adolescent AN. Possible preventive means for the future could include educating paediatricians and health care workers about AN, regular weight assessment, and home-based treatments.
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| 18. |
- Hortensius, Lisa M., et al.
(författare)
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Serum docosahexaenoic acid levels are associated with brain volumes in extremely preterm born infants
- 2021
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Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 90:6, s. 1177-1185
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Tidskriftsartikel (refereegranskat)abstract
- Background: Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for fetal brain growth and development. Our aim was to evaluate the association between serum DHA and AA levels and brain volumes in extremely preterm infants. Methods: Infants born at <28 weeks gestational age in 2013–2015, a cohort derived from a randomized controlled trial comparing two types of parenteral lipid emulsions, were included (n = 90). Serum DHA and AA levels were measured at postnatal days 1, 7, 14, and 28, and the area under the curve was calculated. Magnetic resonance (MR) imaging was performed at term-equivalent age (n = 66), and volumes of six brain regions were automatically generated. Results: After MR image quality assessment and area under the curve calculation, 48 infants were included (gestational age mean [SD] 25.5 [1.4] weeks). DHA levels were positively associated with total brain (B = 7.966, p = 0.012), cortical gray matter (B = 3.653, p = 0.036), deep gray matter (B = 0.439, p = 0.014), cerebellar (B = 0.932, p = 0.003), and white matter volume (B = 3.373, p = 0.022). AA levels showed no association with brain volumes. Conclusions: Serum DHA levels during the first 28 postnatal days were positively associated with volumes of several brain structures in extremely preterm infants at term-equivalent age. Impact: Higher serum levels of DHA in the first 28 postnatal days are positively associated with brain volumes at term-equivalent age in extremely preterm born infants.Especially the most immature infants suffer from low DHA levels in the first 28 postnatal days, with little increase over time.Future research is needed to explore whether postnatal fatty acid supplementation can improve brain development and may serve as a nutritional preventive and therapeutic treatment option in extremely preterm infants.
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