A burden of rare copy number variants in obsessive-compulsive disorder.

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, P = 1.77 × 10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P = 2.58 × 10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR = 1.19, P = 3.08 × 10-4), particularly deletions impacting loss-of-function intolerant genes (pLI >0.995, OR = 4.12, P = 2.54 × 10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60 × 10-3). In cases where sufficient clinical data were available (n = 1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P < 0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P = 0.02). The results demonstrate a contribution of rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.

Behavioral separation of liking and wanting in response to olfactory and visual food cues.

In real-world settings, food rewards are processed in parallel across several sensory modalities, but paradigms that compare contributions of different modalities are lacking. While odor perception in particular is frequently implicated in appetite regulation, the mechanisms by which food odors differentially evoke experiences of wanting and liking remain poorly understood. This study addressed this gap by dissociating liking from wanting responses for olfactory stimuli, and establishing commonalities and differences relative to the visual modality. In two separate experiments, participants (n1=37, n2=43) rated content-matched batteries of odors and pictures, respectively, for their ability to elicit pleasure (liking) and the desire to eat (wanting). A third experiment (n3=39) utilized a combined olfactory-visual paradigm to test the separation of these dimensions in a multisensory context. Our results show that participants differentiated clearly and reliably between liking and wanting for both odors and pictures, as demonstrated by a high difference score between the two in non-food (high liking, low wanting), but not in food (both high) or disgusting stimuli (both low), and high within-session retest reliability. Higher variability for olfactory relative to visual assessments was observed and likely reflects well-established difficulties with odor object identification. Taken together, our study demonstrates that olfactory stimuli can be used in experimental settings to evoke separable experiences of liking and wanting for food and non-food stimuli. Manipulating these components independently across sensory modalities in experimental studies could generate novel insights into how olfactory and visual cues differentially contribute to anticipatory and consummatory food reward processing, in healthy and disordered eating.

Disordered eating and cardiometabolic risk factors in Chinese women: evidence from the China Health and Nutrition Survey.

Disordered eating (DE) is associated with elevated cardiometabolic risk (CMR) factors, yet little is known about this association in non-Western countries. We examined the association between DE characteristics and CMR and tested the potential mediating role of BMI. This cross-sectional study included 2005 Chinese women (aged 18-50 years) from the 2015 China Health and Nutrition Survey. Loss of control, restraint, shape concern and weight concern were assessed using selected questions from the SCOFF questionnaire and the Eating Disorder Examination-Questionnaire. Eight CMR were measured by trained staff. Generalised linear models examined associations between DE characteristics with CMR accounting for dependencies between individuals in the same household. We tested whether BMI potentially mediated significant associations using structural equation modelling. Shape concern was associated with systolic blood pressure (ß (95 % CI) 0·06 (0·01, 0·10)), diastolic blood pressure (DBP) (0·07 (95 % CI 0·03, 0·11)) and high-density lipoprotein (HDL)-cholesterol (-0·08 (95 % CI -0·12, -0·04)). Weight concern was associated with DBP (0·06 (95 % CI 0·02, 0·10)), triglyceride (0·06 (95 % CI 0·02, 0·10)) and HDL-cholesterol (-0·10 (95 % CI -0·14, -0·07)). Higher scores on DE characteristics were associated with higher BMI, and higher BMI was further associated with lower HDL-cholesterol and higher other CMR. In summary, we observed significant associations between shape and weight concerns with some CMR in Chinese women, and these associations were potentially partially mediated by BMI. Our findings suggest that prevention and intervention strategies focusing on addressing DE could potentially help reduce the burden of CMR in China, possibly through controlling BMI.

Descriptives and genetic correlates of eating disorder diagnostic transitions and presumed remission in the Danish registry.

Objective: Eating disorders (EDs) are serious psychiatric disorders with an estimated 3.3 million healthy life-years lost worldwide yearly. Understanding the course of illness, diagnostic transitions and remission, and their associated genetic correlates could inform both ED etiology and treatment. The authors investigated occurrences of ED transitions and presumed remission and their genetic correlates as captured by polygenic scores (PGSs) in a large Danish register-based cohort. Methods: The sample compromised of 10,565 individuals with a diagnosis of anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) with at least two registered hospital contacts between 1995 and 2018. Based on medical records, occurrence of diagnostic transitions and periods of presumed remission were identified. Associations between 422 PGS and diagnostic transitions and presumed remission were evaluated using Cox proportional hazard models. Results: A minority of ED cases (14.1%-23.1%) experienced a diagnostic transition. Presumed remission ranged between 86.9%-89.8%. Higher (one SD increase) PGS for major depressive disorder and multisite chronic pain were positively associated with transitioning from AN to either BN or EDNOS. Higher PGS on a measure of body fat percentage and financial difficulties were positively associated with presumed remission from AN. Higher PGS for mood swings was positively associated with presumed remission from EDNOS whereas higher PGS for health rating showed the opposite. Conclusions: The authors found that most ED patients did not experience diagnostic transitions but were more likely to experience a period of presumed remission. Both diagnostic transitions and presumed remission have significant polygenic component.

Assessing Avoidant/Restrictive Food Intake Disorder (ARFID) Symptoms Using the Nine Item ARFID Screen in >9000 Swedish Adults With and Without Eating Disorders.

OBJECTIVE: The Nine Item ARFID Scale (NIAS) is a widely used measure assessing symptoms of avoidant/restrictive food intake disorder (ARFID). Previous studies suggest that individuals with eating disorders driven by shape/weight concerns also have elevated scores on the NIAS. To further describe NIAS scores among individuals with diverse current and previous eating disorders, we characterized NIAS scores in a large sample of individuals with eating disorders and evaluated overlap in symptoms measured by the NIAS and the Eating Disorder Examination-Questionnaire (EDE-Q) version 6.0. METHOD: Our sample comprised 9148 participants from the Eating Disorders Genetics Initiative Sweden (EDGI-SE), who completed surveys including NIAS and EDE-Q. NIAS scores were calculated and compared by eating disorder diagnostic group using descriptive statistics and linear models. RESULTS: Participants with current anorexia nervosa demonstrated the highest mean NIAS scores and had the greatest proportion (57.0%) of individuals scoring above a clinical cutoff on at least one of the NIAS subscales. Individuals with bulimia nervosa, binge-eating disorder, and other specified feeding or eating disorder also demonstrated elevated NIAS scores compared to individuals with no lifetime history of an eating disorder (ps < 0.05). All subscales of the NIAS showed small to moderate correlations with all subscales of the EDE-Q (rs = 0.26-0.40). DISCUSSION: Our results substantiate that individuals with eating disorders other than ARFID demonstrate elevated scores on the NIAS, suggesting that this tool is inadequate on its own for differentiating ARFID from shape/weight-motivated eating disorders. Further research is needed to inform clinical interventions addressing the co-occurrence of ARFID-related drivers and shape/weight-related motivation for dietary restriction.

Building Confidence in Discussing Genetics With Patients With Eating Disorders and Their Families.

Many individuals with eating disorders and their family members are well-informed about advances in science that could affect the treatment and outcome of these illnesses. They appropriately apply this knowledge to evaluate available treatments and advocate for the best possible evidence-based care. They ask hard questions that many clinicians are often ill-prepared to answer. Genetics has advanced our understanding of eating disorders and provides a novel lens through which to understand these pernicious illnesses. Clinicians can now update their understanding of the etiology of eating disorders and abandon outdated etiological theories, some of which have done harm to patients and their families. Without becoming expert in psychiatric genetics, psychiatrists and other mental health care professionals can develop a general overview of the science, understand what it can and cannot offer, incorporate genetic factors into their case conceptualizations, and boost their confidence in discussing these topics with patients and families.

A naturalistic study of plasma lipid alterations in female patients with anorexia nervosa before and after weight restoration treatment.

BACKGROUND: Plasma lipid concentrations in patients with anorexia nervosa (AN) seem to be altered. METHODS: We conducted a naturalistic study with 75 adult female patients with AN and 26 healthy female controls (HC). We measured plasma lipid profile, sex hormones and used self-report questionnaires at admission and discharge. RESULTS: Total cholesterol (median (IQR): 4.9 (1.2)) and triglycerides (TG) (1.2 (0.8)) were elevated in AN at admission (BMI 15.3 (3.4)) compared with HC (4.3 (0.7), p = 0.003 and 0.9 (0.3), p = 0.006) and remained elevated at discharge (BMI 18.9 (2.9)) after weight restoration treatment. Estradiol (0.05 (0.1)) and testosterone (0.5 (0.7)) were lower in AN compared with HC (0.3 (0.3), p = < 0.001 and 0.8 (0.5), p = 0.03) and remained low at discharge. There was no change in eating disorder symptoms. Depression symptoms decreased (33 (17) to 30.5 (19), (p = 0.007)). Regression analyses showed that illness duration was a predictor of TG, age was a predictor of total cholesterol and LDL, while educational attainment predicted LDL and TG. CONCLUSION: Lipid concentrations remained elevated following weight restoration treatment, suggesting an underlying, premorbid dysregulation in the lipid metabolism in AN that persists following weight restoration. Elevated lipid concentrations may be present prior to illness onset in AN. LEVEL OF EVIDENCE: III: Evidence obtained from well-designed cohort or case-control analytic studies.

Fat is essential for the human body. Too much fat in the blood can be a sign of underlying illness including heart disease. This study investigated how plasma lipids (fats) are affected in individuals with anorexia nervosa (AN). We included 75 adult female individuals with AN and 26 healthy female controls, and measured lipids, sex hormones, and used questionnaires upon admission and discharge from treatment. We found that low-weight individuals with AN had higher lipids than the healthy controls, and these lipids remained elevated after weight restoration treatment. Additionally, individuals with AN had lower levels of sex hormones (estradiol and testosterone) at their low weight, and they stayed low even after weight restoration treatment. Eating disorder symptoms remained unchanged, but depression symptoms decreased during treatment. In conclusion, the study suggests that individuals with AN have changes in their lipid metabolism, which persists even after weight restoration treatment. We don't know the reason behind these elevated lipids, and therefore, this should be investigated further in future study.

What Next for Eating Disorder Genetics? Replacing Myths With Facts to Sharpen Our Understanding.

Substantial progress has been made in the understanding of anorexia nervosa (AN) and eating disorder (ED) genetics through the efforts of large-scale collaborative consortia, yielding the first genome-wide significant loci, AN-associated genes, and insights into metabo-psychiatric underpinnings of the disorders. However, the translatability, generalizability, and reach of these insights are hampered by an overly narrow focus in our research. In particular, stereotypes, myths, assumptions and misconceptions have resulted in incomplete or incorrect understandings of ED presentations and trajectories, and exclusion of certain patient groups from our studies. In this review, we aim to counteract these historical imbalances. Taking as our starting point the Academy for Eating Disorders (AED) Truth #5 "Eating disorders affect people of all genders, ages, races, ethnicities, body shapes and weights, sexual orientations, and socioeconomic statuses", we discuss what we do and do not know about the genetic underpinnings of EDs among people in each of these groups, and suggest strategies to design more inclusive studies. In the second half of our review, we outline broad strategic goals whereby ED researchers can expand the diversity, insights, and clinical translatability of their studies. Appeared originally in Mol Psychiatry 2022; 27:3929-3938.

Identification of State Markers in Anorexia Nervosa: Replication and Extension of Inflammation-Associated Biomarkers Using Multiplex Profiling.

Background: Proteomics offers potential for detecting and monitoring anorexia nervosa (AN) and its variant, atypical AN (atyp-AN). However, research has been limited by small protein panels, a focus on adult AN, and lack of replication. Methods: In this study, we performed Olink multiplex profiling of 92 inflammation-related proteins in females with AN/atyp-AN (n = 64), all of whom were ≤90% of expected body weight, and age-matched healthy control individuals (n = 44). Results: Five proteins differed significantly between the primary AN/atyp-AN group and the healthy control group (lower levels: HGF, IL-18R1, TRANCE; higher levels: CCL23, LIF-R). The expression levels of 3 proteins (lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in participants with AN in our primary model. No unique expression levels emerged for atyp-AN. In the total sample, 12 proteins (ADA, CD5, CD6, CXCL1, FGF-21, HGF, IL-12B, IL18, IL-18R1, SIRT2, TNFSF14, TRANCE) were positively correlated with body mass index and 5 proteins (CCL11, FGF-19, IL8, LIF-R, OPG) were negatively correlated with body mass index in our primary models. Conclusions: Our results replicate the results of a previous study that demonstrated a dysregulated inflammatory status in AN and extend those results to atyp-AN. Of the 17 proteins correlated with body mass index, 11 were replicated from a previous study that used similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of AN disease monitoring. Our findings underscore the complexity of AN and atyp-AN by highlighting the inability of the identified proteins to differentiate between these 2 subtypes, thereby emphasizing the heterogeneous nature of these disorders.

We examined 73 inflammation proteins in adolescent girls with anorexia nervosa (AN) and atypical AN and compared them with age-matched healthy control girls. Significant differences were found, driven by 5 key proteins (lower: HGF, IL-18R1, TRANCE; higher: CCL23, LIF-R). Three proteins (TRANCE, LIF-R, IL-18R1) uniquely distinguished low-weight participants with AN from control participants. Our study reveals distinct inflammation patterns in AN and atypical AN and sheds light on potential state-specific factors that underlie these disorders.

The role of co-occurring conditions and genetics in the associations of eating disorders with attention-deficit/hyperactivity disorder and autism spectrum disorder.

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.

Interpersonal dynamics of vocal fundamental frequency in couples: Depressive symptoms, anxiety symptoms, and relationship distress.

Given the bidirectional association between psychopathology and relationship distress, an in-depth understanding of couples' interaction processes that contribute to psychopathology is needed. This study examined the interpersonal dynamics of vocally-encoded emotional arousal (fundamental frequency, f0) during couple conversations and their associations with depressive symptoms, anxiety symptoms, and relationship distress. Data from eight samples were pooled (N = 404 couples) to examine (a) overall trajectories of f0 across the interaction and (b) moment-by-moment intraindividual changes in and interpersonal reactivity to partners' f0. Multilevel growth models and repeated-measures actor-partner interdependence models demonstrated that individuals with more severe depression showed more synchronizing reactivity to their partners' f0 on a moment-by-moment basis, and their overall baseline level of f0 was lower. More severe relationship distress was associated with more steeply increasing trajectories of f0 and with greater synchronizing reactivity to partners' f0. Relative differences in depressive symptoms between the two members of a couple were associated with interpersonal dynamics of f0 as well. There were no associations with anxiety symptoms. Thus, depressive symptoms were associated with characteristic interpersonal dynamics of vocally-encoded emotional arousal; yet, most consistent associations emerged for relationship distress, which future studies on individual psychopathology should take into account.

Shared Genetic Architecture Between Schizophrenia and Anorexia Nervosa: A Cross-trait Genome-Wide Analysis.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SCZ) and anorexia nervosa (AN) are 2 severe and highly heterogeneous disorders showing substantial familial co-aggregation. Genetic factors play a significant role in both disorders, but the shared genetic etiology between them is yet to be investigated. STUDY DESIGN: Using summary statistics from recent large genome-wide association studies on SCZ (Ncases = 53 386) and AN (Ncases = 16 992), a 2-sample Mendelian randomization analysis was conducted to explore the causal relationship between SCZ and AN. MiXeR was employed to quantify their polygenic overlap. A conditional/conjunctional false discovery rate (condFDR/conjFDR) framework was adopted to identify loci jointly associated with both disorders. Functional annotation and enrichment analyses were performed on the shared loci. STUDY RESULTS: We observed a cross-trait genetic enrichment, a suggestive bidirectional causal relationship, and a considerable polygenic overlap (Dice coefficient = 62.2%) between SCZ and AN. The proportion of variants with concordant effect directions among all shared variants was 69.9%. Leveraging overlapping genetic associations, we identified 6 novel loci for AN and 33 novel loci for SCZ at condFDR <0.01. At conjFDR <0.05, we identified 10 loci jointly associated with both disorders, implicating multiple genes highly expressed in the cerebellum and pituitary and involved in synapse organization. Particularly, high expression of the shared genes was observed in the hippocampus in adolescence and orbitofrontal cortex during infancy. CONCLUSIONS: This study provides novel insights into the relationship between SCZ and AN by revealing a shared genetic component and offers a window into their complex etiology.

Maladaptive exercise in eating disorders: lifetime and current impact on mental health and treatment seeking.

BACKGROUND: Many patients with eating disorders report exercise as a central symptom of their illness-as a way to compensate for food intake, prevent weight-gain, and/or reduce negative affect. Previous findings show associations between maladaptive exercise and more severe eating disorder pathology, higher risk for relapse, other co-morbid symptoms, and worse treatment outcome. METHODS: In this study, we included 8252 participants with eating disorders and investigated associations between maladaptive exercise (both lifetime and current) and ED pathology, illness duration, depression, anxiety, self-harm and suicidal ideation, and treatment seeking patterns in individuals with lifetime maladaptive exercise. Participants were included via the Swedish site of the large global study The Eating Disorders Genetics Initiative (EDGI) and completed measures of both lifetime and current symptomatology. RESULTS: Results indicate that lifetime maladaptive exercise is associated with higher prevalence of lifetime depression and anxiety and with patients more often receiving treatment, although these results need to be investigated in future studies. Current maladaptive exercise was associated with more severe ED symptoms, and higher levels of depression, anxiety, obsessive-compulsive traits, and suicidal ideation. CONCLUSIONS: Our findings point to the complexities of exercise as an eating disorder symptom and the need for clearly assessing and acknowledging this, as well as tailoring interventions to treat this symptom to achieve sustainable recovery.

Many individuals with eating disorders view exercise as a crucial aspect of their illness, often using it to control weight and emotions. Research suggests that maladaptive exercise correlates with more severe eating disorder symptoms, increased risk of relapse, and poorer treatment outcomes. Analyzing data from 8252 participants with eating disorders, this study from the Swedish site of The Eating Disorders Genetics Initiative (EDGI) found that lifetime maladaptive exercise is linked to higher rates of depression and anxiety and increased treatment seeking behaviors. Current maladaptive exercise was associated with heightened eating disorder severity, depression, anxiety, obsessive-compulsive traits, and suicidal thoughts. These findings underscore the importance of recognizing exercise as a symptom of eating disorders and tailoring interventions accordingly for sustainable recovery.

The natural course of binge-eating disorder: findings from a prospective, community-based study of adults.

BACKGROUND: Epidemiological data offer conflicting views of the natural course of binge-eating disorder (BED), with large retrospective studies suggesting a protracted course and small prospective studies suggesting a briefer duration. We thus examined changes in BED diagnostic status in a prospective, community-based study that was larger and more representative with respect to sex, age of onset, and body mass index (BMI) than prior multi-year prospective studies. METHODS: Probands and relatives with current DSM-IV BED (n = 156) from a family study of BED ('baseline') were selected for follow-up at 2.5 and 5 years. Probands were required to have BMI > 25 (women) or >27 (men). Diagnostic interviews and questionnaires were administered at all timepoints. RESULTS: Of participants with follow-up data (n = 137), 78.1% were female, and 11.7% and 88.3% reported identifying as Black and White, respectively. At baseline, their mean age was 47.2 years, and mean BMI was 36.1. At 2.5 (and 5) years, 61.3% (45.7%), 23.4% (32.6%), and 15.3% (21.7%) of assessed participants exhibited full, sub-threshold, and no BED, respectively. No participants displayed anorexia or bulimia nervosa at follow-up timepoints. Median time to remission (i.e. no BED) exceeded 60 months, and median time to relapse (i.e. sub-threshold or full BED) after remission was 30 months. Two classes of machine learning methods did not consistently outperform random guessing at predicting time to remission from baseline demographic and clinical variables. CONCLUSIONS: Among community-based adults with higher BMI, BED improves with time, but full remission often takes many years, and relapse is common.

Diagnosed eating disorders in Danish registers - incidence, prevalence, mortality, and polygenic risk.

Eating disorders are a group of severe and potentially enduring psychiatric disorders associated with increased mortality. Compared to other severe mental illnesses, they have received relatively limited research attention. Epidemiological studies often only report relative measures despite these being difficult to interpret having limited practical use. The aims of this study were to evaluate the incidence and prevalence of diagnosed anorexia nervosa (AN), bulimia nervosa, and eating disorder not otherwise specified recorded in Danish hospital registers and estimate both relative and absolute measures of subsequent mortality - both all-cause and cause-specific in a general nationwide population of 1,667,374 individuals. In a smaller, genetically informed case-cohort sample, the prediction of polygenic scores for AN, body fat percentage, and body mass index on AN prevalence and severity was estimated. Despite males being less likely to be diagnosed with an eating disorder, those that do have significantly increased rates of mortality. AN prevalence was highest for individuals with high AN and low body fat percentage/body mass index polygenic scores.

Neurodevelopmental and psychiatric conditions in 600 Swedish Children with the ARFID phenotype.

Objective: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder characterized by extremely restricted dietary variety and/or quantity resulting in serious consequences for physical health and psychosocial functioning. ARFID often co-occurs with neurodevelopmental conditions (NDCs) and psychiatric conditions, but previous data are mostly limited to small clinical samples examining a narrow range of conditions. Here, we examined NDCs and psychiatric conditions in a large, population-based group of children with ARFID. Method: In a sample of 30,795 children born 1992-2008 in Sweden, ARFID was assessed using parent reports and clinical diagnoses from national health registers. Parents further reported symptoms of NDCs and psychiatric conditions at child age 9 or 12 years. We conducted regressions for symptom scores and screening diagnoses (identified using validated cut offs) on ARFID and examined interactions with sex. Results: Children with ARFID had significantly increased odds of all 17 screening diagnoses with odds ratios ranging from 3.3 for visual hallucinations to 13.7 for autism (all p<.0001). The most common NDCs were oppositional defiant disorder (19.4%), ADHD (16.9%), tic disorders (14.8%), and autism (12.1%). Among psychiatric conditions, separation anxiety disorder (29.0%) and sleep problems (20.0%) had the highest prevalence. We did not find any sex-specific differences in co-occurring conditions. Conclusion: This study highlights the co-occurrence of a broad range of NDCs and psychiatric conditions with ARFID in a large, non-clinical cohort. Our findings underscore that children with ARFID face significant burden from multiple co-existing conditions which should be considered during assessment and treatment.

Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study.

BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

Energy expenditure during nutritional rehabilitation: a scoping review to investigate hypermetabolism in individuals with anorexia nervosa.

BACKGROUND: Weight gain and nutritional rehabilitation are essential first steps to achieve medical stabilization in anorexia nervosa, and frequent resistance to weight gain requires patients to consume high kilocalorie loads. Adaptive hypometabolism is common when patients begin treatment, and rebound hypermetabolism is suspected to be a significant barrier to weight gain. The aim of this review was to summarize existing data describing metabolic changes in anorexia nervosa during weight restoration. The reported findings challenge current hypotheses of weight gain resistance and highlight key areas for future research. METHODS: Using scoping review guidelines, three databases were searched for studies investigating metabolic changes in anorexia nervosa before and after renourishment. Two reviewers systematically screened the titles and abstracts of 447 articles, and full-text versions of 106 studies were assessed for eligibility. A total of 36 studies were included for review. Data regarding the study description, sample population (including age, weight, BMI, duration of treatment, and caloric intake), and metabolic variable descriptions were extracted. RESULTS: Female patients with anorexia nervosa from studies across 13 countries were included. Across the studies, average BMI increased from 13.7 kg/m2 at admission to 17.57 kg/m2. Patients presented to treatment with clinically reduced energy expenditure levels. After varying levels of nutritional rehabilitation and weight restoration, measured energy expenditure increased significantly in 76% of the studies. Energy expenditure values at the second timepoint increased to the standard range for normal weight female teenagers and adults. Despite these increases, the studies do not indicate the presence of a hypermetabolic state during renourishment. Additionally, all studies including both measured and predicted energy expenditure reported that predicted energy expenditure overestimated measured values. CONCLUSION: This study provides a detailed evaluation of the literature investigating energy expenditure and metabolic rate in patients with anorexia nervosa before and following a period of renourishment. The findings from this review identify important gaps in the current beliefs of energy expenditure in anorexia nervosa and highlight a need for further exploration of metabolic alterations during weight restoration.

Nutritional rehabilitation and weight restoration are two primary goals of anorexia nervosa treatment that pose significant physiological and psychological challenges for patients. Patients often require high caloric loads to continue an adequate weight gain trajectory, but the underlying cause of weight gain resistance remains unknown. We completed a scoping review of research into energy expenditure and metabolic rate during treatment. Our search identified 447 relevant articles from academic databases, and 106 were deemed eligible after screening. We extracted data, including sample characteristics, kilocalorie intake, energy expenditure, and treatment information, from 36 studies. When individuals arrived for treatment, their energy expenditure was lower than that of individuals without an eating disorder due to the prolonged state of nutrient deprivation. After varying amounts of time and kilocalorie intake, most studies reported significant increases in energy expenditure. However, energy expenditure after a period of renourishment did not indicate an overactive metabolism (i.e., "hypermetabolism"). Funders should consider supporting exploration of additional factors that may be functioning as barriers to weight gain during treatment, in pursuit of making treatment more efficient and long-lasting. Additionally, future research describing metabolism in anorexia nervosa should provide more consistent methodologies, robust statical testing, and comprehensive reporting of dietary intake.

Co-existing mental and somatic conditions in Swedish children with the avoidant restrictive food intake disorder phenotype.

Background: Avoidant restrictive food intake disorder (ARFID) is a feeding and eating disorder, characterized by limited variety and/or quantity of food intake impacting physical health and psychosocial functioning. Children with ARFID often present with a range of psychiatric and somatic symptoms, and therefore consult various pediatric subspecialties; large-scale studies mapping comorbidities are however lacking. To characterize health care needs of people with ARFID, we systematically investigated ARFID-related mental and somatic conditions in 616 children with ARFID and >30,000 children without ARFID. Methods: In a Swedish twin cohort, we identified the ARFID phenotype in 6-12-year-old children based on parent-reports and register data. From >1,000 diagnostic ICD-codes, we specified mental and somatic conditions within/across ICD-chapters, number of distinct per-person diagnoses, and inpatient treatment days between birth and 18th birthday (90 outcomes). Hazard ratios (HR) and incidence rate ratios (IRR) were calculated. Findings: Relative risks of neurodevelopmental, gastrointestinal, endocrine/metabolic, respiratory, neurological, and allergic disorders were substantially increased in ARFID (e.g., autism HR[CI95%]=9.7[7.5-12.5], intellectual disability 10.3[7.6-13.9], gastroesophageal reflux disease 6.7[4.6-9.9], pituitary conditions 5.6[2.7-11.3], chronic lower respiratory diseases 4.9[2.4-10.1], epilepsy 5.8[4.1-8.2]). ARFID was not associated with elevated risks of autoimmune illnesses and obsessive-compulsive disorder. Children with ARFID had a significantly higher number of distinct mental diagnoses (IRR[CI95%]=4.7[4.0-5.4]) and longer duration of hospitalizations (IRR[CI95%]=5.5[1.7-17.6]) compared with children without ARFID. Children with ARFID were diagnosed earlier with a mental condition than children without ARFID. No sex-specific differences emerged. Interpretation: This study yields the broadest and most detailed evidence of co-existing mental and somatic conditions in the largest sample of children with ARFID to date. Findings suggest a complex pattern of health needs in youth with ARFID, underscoring the critical importance of attention to the illness across all pediatric specialties. Funding: Fredrik and Ingrid Thurings Foundation, Mental Health Foundation.

Genome-wide association study identifies new loci associated with OCD.

To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.