Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

OBJECTIVE: For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. METHOD: Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. RESULTS: Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. DISCUSSION: Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. PUBLIC SIGNIFICANCE: Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

No relationship between male pubertal timing and depression - new insights from epidemiology and Mendelian randomization.

BACKGROUND: In males, the relationship between pubertal timing and depression is understudied and less consistent than in females, likely for reasons of unmeasured confounding. To clarify this relationship, a combined epidemiological and genetic approach was chosen to exploit the methodological advantages of both approaches. METHODS: Data from 2026 males from a nationwide, representative study were used to investigate the non-/linear relationship between pubertal timing defined by the age at voice break and depression, considering a multitude of potential confounders and their interactions with pubertal timing. This analysis was complemented by Mendelian randomization (MR), which is robust to inferential problems inherent to epidemiological studies. We used 71 single nucleotide polymorphisms related to pubertal timing in males as instrumental variable to clarify its causal relationship with depression based on data from 807 553 individuals (246 363 cases and 561 190 controls) by univariable and multivariable MR, including BMI as pleiotropic phenotype. RESULTS: Univariable MR indicated a causal effect of pubertal timing on depression risk (inverse-variance weighted: OR 0.93, 95%-CI [0.87-0.99)], p = 0.03). However, this was not confirmed by multivariable MR (inverse-variance weighted: OR 0.95, 95%-CI [0.88-1.02)], p = 0.13), consistent with the epidemiological approach (OR 1.01, 95%-CI [0.81-1.26], p = 0.93). Instead, the multivariable MR study indicated a causal relationship of BMI with depression by two of three methods. CONCLUSIONS: Pubertal timing is not related to MDD risk in males.

Differentiating anorexia nervosa and atypical anorexia nervosa with absolute weight cut-offs results in a skewed distribution for premorbid weight among youth.

OBJECTIVE: Anorexia nervosa (AN) and atypical AN are conceptualized as distinct illnesses, despite similar characteristics and sequelae. Whereas DSM-5 differentiates youth with AN and atypical AN by the presence of clinical 'underweight' (i.e., 5th BMI percentile for age-and-sex (BMI%)), we hypothesized that using this weight cut-off to discern diagnoses creates a skewed distribution for premorbid weight. METHOD: Participants included hospitalized youth with AN (n = 165, 43.1%) and atypical AN (n = 218, 56.9%). Frequency analyses and chi-square tests assessed the distribution of premorbid BMI z-scores (BMIz) for diagnosis. Non-parametric Spearman correlations and Stepwise Linear regressions examined relationships between premorbid BMIz, admission BMIz, and weight loss in kg. RESULTS: Premorbid BMIz distributions differed significantly for diagnosis (p < .001), with an underrepresentation of 'overweight/obesity' (i.e., BMI% ≥ 85th) in AN. Despite commensurate weight loss in AN and atypical AN, patients with premorbid 'overweight/obesity' were 8.31 times more likely to have atypical AN than patients with premorbid BMI% < 85th. Premorbid BMIz explained 57% and 39% of the variance in admission BMIz and weight loss, respectively. DISCUSSION: Findings support a homogenous model of AN and atypical AN, with weight loss predicted by premorbid BMI in both illnesses. Accordingly, premorbid BMI and weight loss (versus presenting BMI) may better denote the presence of an AN-like phenotype across the weight spectrum. Findings also suggest that differentiating diagnoses with BMI% < 5th requires that youth with higher BMIs lose disproportionately more weight for an AN diagnosis. This is problematic given unique treatment barriers experienced in atypical AN. PUBLIC SIGNIFICANCE: Anorexia nervosa (AN) and atypical AN are considered distinct conditions in youth, with differential diagnosis hinging upon a presenting weight status of 'underweight' (i.e., BMI percentile for age-and-sex (BMI%) < 5th). In our study, youth with premorbid 'overweight/obesity' (BMI% ≥ 85th) disproportionately remained above this threshold, despite similar weight loss. Coupled with prior evidence for commensurate characteristics and sequelae in both diagnoses, we propose that DSM-5 differentiation of AN and atypical AN inadvertently reinforces weight stigma and may contribute to treatment disparities in atypical AN.

No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies.

The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.

Does hypoleptinemia trigger entrapment in anorexia nervosa? Etiological and clinical considerations.

Based on the recent observation that human recombinant leptin (r-Met-hu-leptin; metreleptin) may induce a profound alleviation of the complex symptomatology of patients with anorexia nervosa (AN), we examine the implications for our conceptualisation of this eating disorder. Hypoleptinemia as a core endocrine feature of AN serves as a central and peripheral trigger of tissue-specific adaptations to starvation. In this narrative review, we argue that leptin deficiency may explain many of the puzzling features of this eating disorder. Weight loss can be viewed as a two-step process, with only the second step entailing hypoleptinemia and thereby the entrapment characteristic of AN. We discuss the central and peripheral distribution of leptin receptors and consider possible functional implications of hypoleptinemia. We contrast the slow psychological recovery of patients with AN and of people who experienced starvation upon weight recovery with the rapid onset of improvements upon off-label metreleptin treatment. Characteristics of the sex and age dependent secretion of leptin may contribute to the elevated vulnerability of young females to develop AN.

The Diagnosis and Treatment of Anorexia Nervosa in Childhood and Adolescence.

BACKGROUND: Anorexia nervosa (AN) is a serious disease with a lifetime prevalence of up to 3.6% in women and 0.3% in men. Abnormally low weight and the associated starvation partly account for its somatic and mental manifestations. METHODS: This review is based on publications retrieved by a selective search concerning AN in childhood and adolescence. RESULTS: The peak age of onset of AN is 15.5 years. The frequency of inpatient treatment for AN rose by 40% during the COVID pandemic, indicating the importance of environmental factors; the heritability of AN is estimated at 0.5. The ICD-11 sets the threshold for AN-associated underweight at the fifth percentile for age of the body mass index, as long as the remaining diagnostic criteria are met. The main goal of the multiprofessional treatment of AN is the return to normal body weight, which is a central prerequisite for regaining somatic and mental health. The mean duration of AN is 3.4 years, and approximately twothirds of patients recover from the disease over the long term. CONCLUSION: Marked weight loss in childhood and adolescence can trigger AN in the presence of a predisposition to this disease. Patients and their families should receive psychoeducation regarding the symptoms of starvation and their overlap with those of AN. Important objectives are to shorten the duration of the illness, minimize mortality and the risk of chronic illness, and to identify pharmacological approaches to treatment.

Case report: clinical improvements observed in first off-label metreleptin treatment of a patient with atypical anorexia nervosa.

Off-label metreleptin treatment resulted in cognitive, emotional and behavioral improvements of patients with anorexia nervosa, who presented with hypoleptinemia. We now report a case study of a 16-year-old female patient with atypical anorexia nervosa who was treated off-label with metreleptin for 11 days. She had lost 21 kg over 6 months. Her body mass index at referral for inpatient treatment was 20 kg/m2, her serum leptin level was just within the normal range (2.4 ng/ml). Dosing resulted in prominent improvements of mood and weight phobia entailing a comparatively brief inpatient treatment. The observed improvements are similar to those observed in patients with AN, suggesting overlapping mechanisms with respect to clinical effects induced by elevations of absolute or relative hypoleptinemia. Randomized controlled trials are warranted for both eating disorders.

Evaluation of the MC3R gene pertaining to body weight and height regulation and puberty development.

Recent studies reported an impact of the melanocortin 3 receptor (MC3R) on the regulation of body weight, linear growth and puberty timing. Previously, allele p.44Ile of a frequent non-synonymous variant (NSV) p.Val44Ile was reported to be associated with decreased lean body mass (LBM) and later puberty in both sexes. We Sanger sequenced the coding region of MC3R in 185 children or adolescents with short normal stature (SNS) or 258 individuals with severe obesity, and 192 healthy-lean individuals. Eleven variants (six NSVs) were identified. In-silico analyses ensued. Three rare loss-of-function (LoF) variants (p.Phe45Ser, p.Arg220Ser and p.Ile298Ser) were only found in severely obese individuals. One novel highly conserved NSV (p.Ala214Val), predicted to increase protein stability, was detected in a single lean female. In the individuals with SNS, we observed deviation from Hardy-Weinberg Equilibrium (HWE) (p = 0.012) for p.Val44Ile (MAF = 11.62%). Homozygous p.44Ile carriers with SNS had an increased BMI, but this effect did not remain significant after Bonferroni correction. In line with previous findings, the detected LoF NSVs may suggest that dysfunction in MC3R is associated with decreased body height, obesity and delayed puberty.

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals.

Context: The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. Objective: We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Methods: Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. Results: Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). Conclusion: Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

Genetic variants in genes involved in creatine biosynthesis in patients with severe obesity or anorexia nervosa.

Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (CKB, CKMT1B, and GATM) revealed one sex-dimorphic BMI-associated SNP in CKB (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, CKB and GATM, and nine variants in the coding sequence of CKMT1B. Non-synonymous variants identified in CKB and CKMT1B were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). In silico tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in CKMT1B. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of CKB with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future in vitro analyses are needed to assess the functional implications of these findings.

Age at menarche relates to depression in adolescent girls: Comparing a clinical sample to the general pediatric population.

CONTEXT: The timing of puberty, physical features of pubertal development, and hormones are closely intertwined but may also individually contribute to the risk for depression and depression severity. Additionally, their effects on mood may depend on depression severity, but previously this has only been studied in mostly subclinical depression. METHODS: In 184 girls from a single psychiatric hospital with significant depressive symptoms (Beck Depression Inventory-II score > 13), the relationship between depression severity and age at menarche (AAM), pubertal status, and gonadal/adrenal hormones (estradiol, progesterone, DHEA-S, androstenedione, testosterone, dihydrotestosterone) was investigated. Moreover, AAM in depressed girls was compared to that from a representative sample of German adolescents without a psychiatric disorder (N = 1674). Androgen levels were compared to those of age- and sex-matched controls (N = 59). RESULTS: AAM but not pubertal stage or biochemical parameters related to depression. Girls with AAM at the lower normative range of pubertal development were 61 % more likely to develop depression and scored 4.9 points higher on the depression scale than girls experiencing menarche at the population average. Androstenedione levels were increased in the psychiatric sample, but neither androgen nor gonadal hormone levels were associated with depression severity. LIMITATIONS: The study is cross-sectional. CONCLUSIONS: These observations confirm previous studies in mostly subclinical depression and highlight the importance of AAM for adolescent depression. Thus, AAM could be considered a prognostic factor for a clinical risk score assessing the probability of adolescent depression. Moreover, these findings suggest fostering efforts that address risk factors that contribute to an earlier AAM.

Suggestive Evidence for an Antidepressant Effect of Metreleptin Treatment in Patients with Lipodystrophy.

INTRODUCTION: Lipodystrophy (LD) syndromes are rare heterogeneous disorders characterized by reduction or absence of subcutaneous fat, low or nondetectable leptin concentrations in blood and impaired hunger/satiety regulation. Metreleptin treatment reverses metabolic complications and improves eating behavior in LD. Because depression in anorexia nervosa (AN), which is also characterized by hypoleptinemia, improves substantially upon treatment with metreleptin, we hypothesized that metreleptin substitution may be associated with an antidepressant effect in patients with LD, too. METHODS: In this ancillary study, 10 adult patients with LD were treated with metreleptin. To assess depressive symptoms, the self-rating questionnaire Beck's Depression Inventory (BDI) was filled in at preestablished time points prior (T1) and after initiation of metreleptin (T2: 1 week; T3: 4 weeks; T4: 12 weeks) dosing. The differences between time points were tested with nonparametric Friedman's analysis of variance. Sensitivity analyses were performed upon exclusion of the BDI items addressing appetite and weight changes. RESULTS: According to their BDI scores, 4 patients had mild depression and 2 had moderate depression at baseline. Friedman's test revealed significant differences in BDI scores between the four time points. Post hoc analyses revealed that the difference between T1 and T3 was significant upon Bonferroni correction (p = 0.034, effect size r = 0.88). The sensitivity analyses upon exclusion of the appetite and weight change items again revealed a significant Friedman's test and significant Bonferroni corrected differences in the revised BDI scores between T1 versus T2 (p = 0.002, r = 0.99) and T1 versus T3 (p = 0.007, r = 0.79). DISCUSSION/CONCLUSION: Our study for the first time revealed suggestive evidence for an antidepressant effect of metreleptin in patients with LD. Metreleptin caused a rapid drop in depression scores within 1 week of treatment. A reduction of the depression score was also observed in 2 of the 3 LD patients whose BDI scores were in the normal range before start of the treatment. The reduction in total scores of BDI was still apparent after 3 months (T4) of dosing. This observation matches findings obtained in clinical case studies of AN patients, in whom depression scores also dropped during the first week of metreleptin treatment. It needs to be noted that by the nature of this observational study without a placebo group, nonspecific treatment expectation affecting mood cannot fully be ruled out.

The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: Implications for anorexia nervosa.

This narrative review aims to pinpoint mental and behavioral effects of starvation, which may be triggered by hypoleptinemia and as such may be amenable to treatment with leptin receptor agonists. The reduced leptin secretion results from the continuous loss of fat mass, thus initiating a graded triggering of diverse starvation related adaptive functions. In light of leptin receptors located in several peripheral tissues and many brain regions adaptations may extend beyond those of the hypothalamus-pituitary-end organ-axes. We focus on gastrointestinal tract and reward system as relevant examples of peripheral and central effects of leptin. Despite its association with extreme obesity, congenital leptin deficiency with its many parallels to a state of starvation allows the elucidation of mental symptoms amenable to treatment with exogenous leptin in both ob/ob mice and humans with this autosomal recessive disorder. For starvation induced behavioral changes with an intact leptin signaling we particularly focus on rodent models for which proof of concept has been provided for the causative role of hypoleptinemia. For humans, we highlight the major cognitive, emotional and behavioral findings of the Minnesota Starvation Experiment to contrast them with results obtained upon a lesser degree of caloric restriction. Evidence for hypoleptinemia induced mental changes also stems from findings obtained in lipodystrophies. In light of the recently reported beneficial cognitive, emotional and behavioral effects of metreleptin-administration in anorexia nervosa we discuss potential implications for the treatment of this eating disorder. We postulate that leptin has profound psychopharmacological effects in the state of starvation.

Evidence for correlations between BMI-associated SNPs and circRNAs.

Circular RNAs (circRNAs) are regulators of processes like adipogenesis. Their expression can be modulated by SNPs. We analysed links between BMI-associated SNPs and circRNAs. First, we detected an enrichment of BMI-associated SNPs on circRNA genomic loci in comparison to non-significant variants. Analysis of sex-stratified GWAS data revealed that circRNA genomic loci encompassed more genome-wide significant BMI-SNPs in females than in males. To explore whether the enrichment is restricted to BMI, we investigated nine additional GWAS studies. We showed an enrichment of trait-associated SNPs in circRNAs for four analysed phenotypes (body height, chronic kidney disease, anorexia nervosa and autism spectrum disorder). To analyse the influence of BMI-affecting SNPs on circRNA levels in vitro, we examined rs4752856 located on hsa_circ_0022025. The analysis of heterozygous individuals revealed an increased level of circRNA derived from the BMI-increasing SNP allele. We conclude that genetic variation may affect the BMI partly through circRNAs.

Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian Randomization Study.

A fair number of epidemiological studies suggest that age at menarche (AAM) is associated with depression, but the reported effect sizes are small, and there is evidence of residual confounding. Moreover, previous Mendelian randomization (MR) studies to avoid inferential problems inherent to epidemiological studies have provided mixed findings. To clarify the causal relationship between age at menarche and broadly defined depression risk, we used 360 genome-wide significantly AAM-related single-nucleotide polymorphisms (SNPs) as instrumental variable and data from the latest GWAS for the broadly defined depression risk on 807,553 individuals (246,363 cases and 561,190 controls). Multiple methods to account for heterogeneity of the instrumental variable (penalized weighted median, MR Lasso, and contamination mixture method), systematic and idiosyncratic pleiotropy (MR RAPS), and horizontal pleiotropy (MR PRESSO and multivariable MR using three methods) were used. Body mass index, education attainment, and total white blood count were considered pleiotropic phenotypes in the multivariable MR analysis. In the univariable [inverse-variance weighted (IVW): OR = 0.96, 95% confidence interval = 0.94-0.98, p = 0.0003] and multivariable MR analysis (IVW: OR = 0.96, 95% confidence interval = 0.94-0.99, p = 0.007), there was a significant causal effect of AAM on depression risk. Thus, the present study supports conclusions from previous epidemiological studies implicating AAM in depression without the pitfalls of residual confounding and reverse causation. Considering the adverse consequences of an earlier AAM on mental health, this finding should foster efforts to address risk factors that promote an earlier AAM.

PTBP2 - a gene with relevance for both Anorexia nervosa and body weight regulation.

Genetic factors are relevant for both eating disorders and body weight regulation. A recent genome-wide association study (GWAS) for anorexia nervosa (AN) detected eight genome-wide significant chromosomal loci. One of these loci, rs10747478, was also genome-wide and significantly associated with body mass index (BMI). The nearest coding gene is the Polypyrimidine Tract Binding Protein 2 gene (PTBP2). To detect mutations in PTBP2, Sanger sequencing of the coding region was performed in 192 female patients with AN (acute or recovered) and 191 children or adolescents with (extreme) obesity. Twenty-five variants were identified. Twenty-three of these were predicted to be pathogenic or functionally relevant in at least one in silico tool. Two novel synonymous variants (p.Ala77Ala and p.Asp195Asp), one intronic SNP (rs188987764), and the intronic deletion (rs561340981) located in the highly conserved region of PTBP2 may have functional consequences. Ten of 20 genes interacting with PTBP2 were studied for their impact on body weight regulation based on either previous functional studies or GWAS hits for body weight or BMI. In a GWAS for BMI (Pulit et al. 2018), the number of genome-wide significant associations at the PTBP2 locus was different between males (60 variants) and females (two variants, one of these also significant in males). More than 65% of these 61 variants showed differences in the effect size pertaining to BMI between sexes (absolute value of Z-score >2, two-sided p < 0.05). One LD block overlapping 5'UTR and all coding regions of PTBP2 comprises 56 significant variants in males. The analysis based on sex-stratified BMI GWAS summary statistics implies that PTBP2 may have a more pronounced effect on body weight regulation in males than in females.

Reasons for admission and variance of body weight at referral in female inpatients with anorexia nervosa in Germany.

BACKGROUND: Body mass index (BMI) at hospital admission in patients with anorexia nervosa (AN) represents a prognostic marker for mortality, chronicity and future body weight. The current study focused on the associations between BMI standard deviation score (BMI-SDS) at admission and reasons for seeking inpatient treatment. Further interest was given to the relationship between premorbid weight and weight at admission, as well as the effect of both weight at referral and reasons for admission on treatment outcome. METHODS: Data ascertained in the German Register of Children and Adolescents with AN were analysed to assess the parental and patient overlap for 23 predefined reasons for admission, using factor analyses and regressions models. RESULTS: Complete parent-patient data sets were available for 360 patients out of 769. The highest consensus rates between parents and patients were obtained for weight and eating behavior related reasons and hyperactivity. Based on factor analysis, four factors emerged. Premorbid BMI-SDS, age and 'low body weight' as stated by patients or parents explained almost 40% of the variance of the BMI-SDS at admission. CONCLUSIONS: Results underscore the relevance of age and premorbid BMI for BMI at admission. Only single reasons for admission explained further variance, with 'low body weight' having the largest effect. Approximately 40% of the variance of BMI-SDS was explained. For the first time, the effect of premorbid BMI for BMI at admission was robustly demonstrated in a multicenter study. Of the variance in BMI-SDS at discharge, our model could explain 37%, with reasons for admission having a small effect. Further investigation of the reasons for admission would be worthwhile to improve treatment and prognosis.

Suggestive Evidence for Causal Effect of Leptin Levels on Risk for Anorexia Nervosa: Results of a Mendelian Randomization Study.

Genetic correlations suggest a coexisting genetic predisposition to both low leptin levels and risk for anorexia nervosa (AN). To investigate the causality and direction of these associations, we performed bidirectional two-sample Mendelian randomization (MR) analyses using data of the most recent genome-wide association study (GWAS) for AN and both a GWAS and an exome-wide-association-study (EWAS) for leptin levels. Most MR methods with genetic instruments from GWAS showed a causal effect of lower leptin levels on higher risk of AN (e.g. IVW b = -0.923, p = 1.5 × 10-4). Because most patients with AN are female, we additionally performed analyses using leptin GWAS data of females only. Again, there was a significant effect of leptin levels on the risk of AN (e.g. IVW b = -0.826, p = 1.1 × 10-04). MR with genetic instruments from EWAS showed no overall effect of leptin levels on the risk for AN. For the opposite direction, MR revealed no causal effect of AN on leptin levels. If our results are confirmed in extended GWAS data sets, a low endogenous leptin synthesis represents a risk factor for developing AN.

Klotho KL-VS haplotype does not improve cognition in a population-based sample of adults age 55-87 years.

The heterozygous human Klotho KL-VS haplotype has been associated with improved cognitive performance but results are inconsistent. Here we assessed Klotho KL-VS haplotype and cognition using data from the third examination of the population-based Heinz Nixdorf Recall Study. We analyzed cognition tests (immediate and delayed word list, Trail-Making Test [TMT] part A and B, Maze test, interference condition of the Stroop color-word test, verbal fluency) and their associations with Klotho KL-VS haplotype. The Klotho KL-VS haplotype is classified by the V-allele at SNP rs9536314 (F352V) and the S-allele at SNP rs9527025 (C370S). Heterozygotes for the KL-VS haplotype were compared with non-carriers. Analyses were performed in 1812 subjects (55-87 years). We found consistent but only slightly lower performance in heterozygous carriers of the KL-VS haplotype in all tasks with Z-scores ranging between Z = - 0.042 (verbal fluency) and - 0.17 (TMT part A). Differences between carriers and non-carriers were similar for men and women for all tests but TMT part B (interaction contrast = 8.4 s (95% CI - 2.3; 19.1)). While cognition declined with age, we found an effect modification by age (55-65 years, 66-75 years, > 75 years). In the 66-75 years KL-VS heterozygous age group, lower performance was seen in memory, visual attention and motor speed. Contrary to our hypothesis, heterozygous carriers of the KL-VS haplotype did not show enhanced performance in cognitive tests in our study.

[Genetic Analyses of Complex Phenotypes Through the Example of Anorexia Nervosa and Bodyweight Regulation]. / Ebenen der genetischen Analyse komplexer Phänotypen am Beispiel der Anorexia nervosa und der Varianz des Körpergewichts.

Genetic Analyses of Complex Phenotypes Through the Example of Anorexia Nervosa and Bodyweight Regulation Abstract. Genetics variants are important for the regulation of bodyweight and also contribute to the genetic architecture of eating disorders. For many decades, family studies, a subentity of so-called formal genetic studies, were employed to determine the genetic share of bodyweight and eating disorders and found heritability rates exceeding 50 % with both phenotypes. Because of this significant contribution of genetics, the search for those genes and their variants related to the variance in bodyweight and the etiology of eating disorders - or both - was commenced by the early 1990s. Initially, candidate genes studies were conducted targeting those genes most plausibly related to either phenotype, especially based on pathophysiological considerations. This approach, however, implicated only a few genes in the regulation of bodyweight and did not provide significant insights into the genetics of eating disorders. Driven by considerable methodological advances in genetic research, especially related to the introduction of so-called genome-wide association studies by the beginning of the 21st century, today more than 1,000 variants/loci have been detected that affect the regulation of bodyweight. Eight such loci have been identified regarding anorexia nervosa (AN). These results as well as those from cross-disorder analyses provide insights into the complex regulation of bodyweight and demonstrated unforeseen pathomechanisms for AN.