Polygenicity at the pathway level for anorexia nervosa

BackgroundEvidence from observational studies suggests an association between anxiety disorders and anorexia nervosa (AN), but causal inference is complicated by the potential for confounding in these studies. We triangulate evidence across a longitudinal study and a Mendelian randomization (MR) study, to evaluate whether there is support for anxiety disorder phenotypes exerting a causal effect on AN risk.MethodsStudy One assessed longitudinal associations of childhood worry and anxiety disorders with lifetime AN in the Avon Longitudinal Study of Parents and Children cohort. Study Two used two-sample MR to evaluate: causal effects of worry, and genetic liability to anxiety disorders, on AN risk; causal effects of genetic liability to AN on anxiety outcomes; and the causal influence of worry on anxiety disorder development. The independence of effects of worry, relative to depressed affect, on AN and anxiety disorder outcomes, was explored using multivariable MR. Analyses were completed using summary statistics from recent genome-wide association studies.ResultsStudy One did not support an association between worry and subsequent AN, but there was strong evidence for anxiety disorders predicting increased risk of AN. Study Two outcomes supported worry causally increasing AN risk, but did not support a causal effect of anxiety disorders on AN development, or of AN on anxiety disorders/worry. Findings also indicated that worry causally influences anxiety disorder development. Multivariable analysis estimates suggested the influence of worry on both AN and anxiety disorders was independent of depressed affect.ConclusionsOverall our results provide mixed evidence regarding the causal role of anxiety exposures in AN aetiology. The inconsistency between outcomes of Studies One and Two may be explained by limitations surrounding worry assessment in Study One, confounding of the anxiety disorder and AN association in observational research, and low power in MR analyses probing causal effects of genetic liability to anxiety disorders. The evidence for worry acting as a causal risk factor for anxiety disorders and AN supports targeting worry for prevention of both outcomes. Further research should clarify how a tendency to worry translates into AN risk, and whether anxiety disorder pathology exerts any causal effect on AN.

Anorexia nervosa (AN) is an eating disorder for which the underlying etiology remains mostly uncharacterized. Large-scale genetic studies of AN suggest a relationship between AN liability and cardiometabolic traits, such as lipid and glycemic biology, which may reveal novel treatment targets through pharmacological or nutritional interventions. However, the role of body mass index (BMI) in the diagnosis of AN presents a challenge in the interpretation of these genetic studies. Specifically, BMI is a heritable trait with a genetic architecture that is related to cardiometabolic traits. This becomes particularly salient with the emergence of an atypical AN diagnosis whereby individuals display behaviors consistent with AN, but their BMI remains within normal or higher ranges. In this review, we outline the evidence from genetic studies that support a role of cardiometabolic traits in risk for AN, as well as the unmet need to study cardiometabolic factors in atypical AN. We discuss the influence of selection for individuals with low BMI, particularly from large, international studies that rely on cohorts that used older diagnostic criteria together with efforts from the literature to disentangle these relationships. We conclude that there is at least some evidence that genetic susceptibility to lower BMI may impact the inferred cardiometabolic relationships with AN genetic liability; however, there remains genetic support for a role of metabolic factors in AN risk beyond what is directly attributable to weight-related diagnostic considerations alone. Finally, we provide recommendations for future genetic studies that explore cardiometabolic traits across the spectrum of eating disorders.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981–2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD [hazard ratio = 1.97, 95% confidence interval = 1.75–2.22] or ASD diagnosis [2.82, 2.48–3.19]. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44–100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal halfsibling with ASD had increased risk of AN [1.54, 1.33–1.78; 1.45, 1.08–1.94] compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk [1.06, 1.02–1.09]. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and a genetic association between ASD-PGS and AN were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Eating Disorders: What Are the Risks?

Perinatal factors seem to be implicated in the pathogenesis of anorexia nervosa (AN) and may be involved in the programming of stress response systems in humans. Our aim was to explore one of the possible pathways to explain the association between perinatal complications and a psychiatric disorder. In particular, we tested the hypothesis that neonatal immaturity may confer an enhanced vulnerability to AN after exposure to a severe stressful event, such as childhood abuse. The sample was composed of subjects who took part in a prevalence study carried out on a representative sample of the general population and cases of AN referred to an out-patient specialist unit. All subjects (n=663) were born in the two obstetric wards of Padua Hospital between 1971 and 1979. We analysed data using both a case-control and a cohort design. We found that functional signs of neonatal dysmaturity, but not a low birthweight or prematurity, had a significant additive interaction with childhood abuse in determining the risk for this illness. In normal subjects, but not in subjects with AN, neonatal dysmaturity was associated with being small, short or thin for gestational age at birth. The synergistic effect of neonatal dysmaturity and childhood abuse in increasing the risk for AN provides evidence for the hypothesis that a prenatal programming of stress response systems can result in an impairment of the individual's resilience to severe stressful events.

Many believe that the current application of modern logistics solutions in general and centralisation of distribution systems in particular is damaging from an environmental perspective. The reason for this claim is that when a distribution system is centralised, products need to be shipped over greater distances. This causes an increase in transport work, which in turn is believed to cause an increase in emissions. Further, the decision to centralise distribution can be characterised as a structural decision and earlier research has helped illustrate how such decisions have greater impact on the overall performance of a distribution system than decisions taken at subsequent levels (tactical and operative). The reason for this is that structural decisions help create new opportunities to make other logistical decisions that are beneficial for the performance of a distribution system, as measured in terms of costs and service. It is also acknowledged that there is a lack of research illustrating the actual environmental effects of centralisation. This area is the theme of this thesis and the overall purpose is to describe and analyse how centralisation of a distribution system can affect the environment. This purpose has been divided into two research questions, where the first one reads: - How does physical centralisation of a distribution system influence the environment? This question aims at investigating what effect centralisation has on the amount of emissions that are caused by transport in a distribution system. One of the main advantages with a centralised distribution system is that emergency deliveries are expected to decrease. This type of transport is often performed by airfreight, which is a mode of transport that is regarded to cause the largest amount of environmental stress among the four most commonly used transport modes. The argument that is made is that even though centralisation causes an increase in transport work, this must not necessarily mean that emissions increase. As indicated above, earlier studies on structural changes in distribution systems have shown that this type of decision creates new opportunities to make other decisions that are beneficial for the performance of a distribution system, albeit in terms of costs and service. The aim of the second research question is consequently to study this issue, but from an environmental perspective. This question therefore reads: - How do structural decisions in logistics create new opportunities to improve on the environmental performance of a distribution system? The results of the study show that it is not sufficient to only consider transport work and emergency deliveries when the environmental effect of a centralisation is to be evaluated. It has also been concluded that centralisation creates an opportunity to make improvements within the distribution system that can prove beneficial from an environmental perspective. In summary, three characteristics besides transport work and emergency deliveries were identified as being of importance when considering the environmental effects of a centralisation. These included centralised flow, modal change, and bargaining power. This model (see full pdf) does not aim to include all characteristics that can be relevant in an environmental evaluation of a centralisation, but rather those that have been found significant in this study. However, the model helps illustrate that there are many aspects that need to be considered in such an evaluation and that depending on the characteristics of the distribution system at hand the results can vary quite extensively.

BackgroundLong-term consequences of comorbid autism spectrum disorder (ASD) in individuals with anorexia nervosa (AN) are inadequately investigated.MethodsIn the 1980s, 51 adolescent-onset AN cases (AN group) and 51 matched controls (COMP group) were recruited from the community. They have been examined on five occasions. The four last assessments included the Morgan-Russell Outcome Assessment Schedule (MROAS) to assess eating disorder outcomes (weight, dieting, menstruation), and related problems including psychiatric, psychosexual and socioeconomic state. In the present study, at age 44, when 30 years had elapsed, MROAS data were compared with previous results. At age 16, 21, 24 and 32 years, all individuals had been assessed regarding ASD. At the 30-year follow-up, the impact of the ASD on the MROAS data was analysed.ResultsIn the AN group, all core anorectic symptoms (weight, dieting, menstruation) were on a par with the COMP group at the 30-year follow-up, but the positive outcomes were limited to those who had never had an ASD diagnosis. Psychiatric state was significantly worse in the AN group, particularly in the subgroup who had an ASD diagnosis assigned. The AN group—again particularly those with ASD—had a more negative attitude to sexual matters than the COMP group. The AN group had worse outcomes than the COMP group for ‘personal contacts’, ‘social contacts,’ and ‘employment record’ at the 30-year follow-up and the outcomes were worse the more often an ASD diagnosis had been assigned.LimitationsRare data collection points throughout 30 years (only 5 assessments). ASD was assessed in the first four studies but was not assessed again at the 30-year follow-up.ConclusionsMental health, psychosexual, and socioeconomic status were compromised up to 30 years after AN onset. Coexisting ASD contributed to the poor outcome. Core anorectic symptoms had “normalised” three decades after AN onset.Plain English summarySome individuals with anorexia nervosa (AN) also suffer from autism. In this study we have investigated outcome of AN 30 years after the onset of AN and whether the presence of autism affects the outcome. Since the 1980s we have followed 51 individuals with teenage-onset AN and 51 healthy controls. They have been examined on five occasions, and an instrument that measures symptoms of AN (weight, dieting, body image), psychiatric symptoms, ability to work, and relationships with partner, family, and friends has been used to assess outcome. Autism was assessed in the first four studies. Symptoms of AN had normalised at 30-year follow-up, but only among those without autism. Psychiatric symptoms, ability to work, and relationships were issues that persisted after 30 years in the AN group, and those who had both autism and a history of AN had even more pronounced problems in these areas. The AN group had a more negative attitude to sexual matters than the control group, the outcome was worse the more often an autism diagnosis had been assigned.ConclusionsMental health, psychosexual, and socioeconomic status are affected up to 30 years after AN onset, particularly among those with autism.

Macronutrient intake during the pre-onset, acute, and post weight-recovery period in women with anorexia nervosa: The national heart, lung, and blood institute growth and health study

The aim of this study was to assess prospectively the long-term outcome in a representative sample of teenage-onset anorexia nervosa (AN) in respect of psychiatric disorders and overall outcome. Fifty-one AN cases, recruited by community screening, with a mean age of onset of 14 years, was contrasted with 51 matched comparison cases at a mean age of 24 years (10 years after AN onset). All 102 cases had been examined at ages 16 and 21 years. At 24 years all probands were interviewed regarding psychiatric disorders (SCID-I) and overall outcome (Morgan-Russell assessment schedule, the GAF). There were no deaths at 10-year follow-up. One in four in the AN group had a persisting eating disorder (ED), including three who still had anorexia nervosa. Lifetime diagnoses of affective disorders and obsessive-compulsive disorder were over-represented in the AN group. Outcome according to Morgan-Russell was poor in 27%, intermediate in 29%, and good in 43%. According to the GAF, half the AN group had a poor psychosocial functioning. These were subjects with either a persisting ED or lifelong problems with social interaction or obsessive-compulsive behaviour. Ten-year outcome of teenage-onset AN is favourable in the majority of cases; most individuals have recovered from their ED and have no other axis I disorder. However, half the AN group reported poor psychosocial outcome, in most cases explained by a persisting ED or chronic obsessive-compulsive behaviour/social interaction problems.

Coronary artery disease (CAD) polygenic risk scores (PRS) enhance risk stratification, but it is unknown whether the degree varies across the spectrum of atherosclerotic cardiovascular disease (ASCVD). We compared the association of a CAD PRS and coronary events in patients with ASCVD and a prior ischemic event, ASCVD without event, and without overt ASCVD. Genotyped patients from 6 multinational cardiovascular trials were categorized into low (bottom 20%), intermediate (middle 60%), and high (top 20%) genetic risk using a genome-wide CAD PRS, then grouped by ASCVD status. The primary endpoint was any major coronary event, a composite of death from coronary disease, myocardial infarction, or coronary revascularization. 59,905 participants (mean age, 66 years; 71% male) were included; 47,456 (79%) had established ASCVD. Compared with low genetic risk, major coronary events were more frequent in high (HR, 2.06; 95%CI, 1.88-2.24; p<0.001) and intermediate (HR, 1.57; 95%CI, 1.45-1.70; p<0.001) genetic risk. Genetic risk was more strongly associated with major coronary events in patients without overt ASCVD (HR between high vs. low genetic risk, 4.63) than patients with ASCVD without (HR, 1.73) or with an ischemic event (HR, 1.63) (Pinteraction<0.001). Absolute risk difference between high and low genetic risk was comparable across ASCVD categories (5.0-7.0% difference at 3 years). A CAD PRS was associated with incident major coronary events in all ASCVD categories. Although genetics provided the strongest relative association in patients without established ASCVD, the absolute risk gradient was comparable for patients with and without ASCVD.

Anorexia nervosa (AN) is a psychiatric disorder with a high mortality rate and significant prevalence in the paediatric population. Preliminary reports during the COVID-19 pandemic suggested an increased incidence of AN among children and adolescents. The objective of this study was to analyse new cases of AN before, during, and after the pandemic, with a particular focus on the physical manifestations of the disease. This single-centre, retrospective study included new AN cases from the hospital database of a regional paediatric hospital (a reference centre for AN) between 2013 and 2023. Data analysed included the duration of the disease, body mass index (BMI), weight loss, length of hospitalisation, laboratory markers (leukopenia, anaemia, hypoproteinaemia, hyperferritinaemia, hypophosphataemia, dyslipidaemia, and hypothyroxinaemia) and clinical features of malnutrition (such as amenorrhea bradycardia, pericardial effusion, and cortical/subcortical atrophy). This study was conducted in a Polish regional hospital. We analysed 228 hospitalized female patients aged 10 to 18 years diagnosed with AN, focusing on clinical characteristics, biochemical markers, and the impact of the COVID-19 pandemic. The COVID-19 pandemic was shown to have a significant impact, with longer hospitalisations observed during and after the pandemic and a lower BMI on admission post-pandemic compared to pre-pandemic. In addition, nutritional treatment became more prevalent over time while biochemical markers such as anaemia, hypothyroidism, hypophosphataemia, and dyslipidaemia were statistically more common post-pandemic. This study demonstrates a significant impact of the COVID-19 pandemic on the clinical course and hospitalisation patterns of paediatric patients with AN. These findings suggest that the pandemic may have exacerbated disease severity and altered treatment approaches, emphasizing the need for enhanced clinical management and follow-up strategies for AN in the paediatric population during such health crises.

Potential effects of prenatal sex hormones on later eating disorders in offspring have been investigated with two indirect methods (finger length ratio, opposite- versus same-sex twins). We utilized a direct, prospective method, examining the association between prenatal sex-hormones in maternal sera and the risk of bulimia nervosa (BN) and anorexia nervosa (AN) among daughters. Females with BN (55), AN (150), sister controls without eating disorders (one per case), and population controls (one per case) were derived from Finnish registers. Maternal gestational testosterone and estradiol levels were assayed from archived specimens stored in a national serum biobank. When females with BN were compared to their sister controls, those with higher gestational testosterone levels were at an increased risk of BN. No significant associations with BN were found when the comparison was made to population controls, and when estradiol levels and testosterone/estrogen ratio were assessed. We neither found associations between gestational sex-hormone levels and the risk of AN. Among females with familial liability for BN, higher gestational testosterone exposure may have a role in later development of BN, whereas lower testosterone exposure may have a protective effect. We found no evidence for the involvement of gestational sex-hormones in the etiology of AN.

Association of 5-HTR2A -1438A/G polymorphism with anorexia nervosa and bulimia nervosa: A meta-analysis

The literature contains several cases of anorexia nervosa (AN) patients with prolonged QTc interval. However, the risk of prolonged QTc interval is controversial and the risk of cardiac events in AN patients has yet to be investigated. We estimated the difference in mean QTc interval and relative risk of borderline prolonged QTc (>440 ms) and prolonged QTc (>460 ms) between 430 adult women AN patients and 123 healthy controls using 3 correction formulas. In a follow-up study, we estimated the risk of a primary end point (a composite of ventricular tachycardia, aborted cardiac arrest, and cardiac arrest) in AN patients compared with a population-based cohort derived from the Danish Civil Register. Mean QTc for AN patients was 408 ms (Hodges), 402 ms (Fridericia), and 399 ms (Bazett). Hodges' found a slightly increased mean QTc (6.8 ms, 95% confidence interval, 1.6-12.0; P=0.01) and percentage with QTc >440 ms in AN patients (relative risk, 3.7, 95% confidence interval, 1.4-10.3; P=0.01), not observed with Fridericia's and Bazett's formulas. There was no difference in the risk of QTc >460 ms between AN patients and healthy controls. During a median follow-up of 10.1 years, AN patients had an increased risk of the primary end point compared with the population-based cohort (hazard ratio, 10.4, 95% confidence interval, 2.6-41.6; P=0.001). However, absolute numbers were small with cumulative incidences of 0.5% and 0.07%, respectively, after 10 years. No events occurred in any AN patient with QTc >440 ms. All-cause mortality was also significantly increased in AN patients compared with the population-based cohort (hazard ratio, 11.2, 95% confidence interval, 5.1-24.5; P<0.001). Overall, there was no difference in mean QTc interval or risk of prolonged QTc between AN patients and healthy controls. However, AN patients had a notably increased all-cause mortality, as well as an increased risk of cardiac events, which was not related to the baseline QTc interval.

Common genetic background in anorexia nervosa and obsessive compulsive disorder: Preliminary results from an association study