Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2–18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

While observational studies show an association between 25(OH)vitamin D concentrations and depressive symptoms, intervention studies, which examine the preventive effects of vitamin D supplementation on the development of depression, are lacking. To estimate the role of lowered 25(OH)vitamin D concentrations in the etiology of depressive disorders, we conducted a two-sample Mendelian randomization (MR) study on depression, i.e., “depressive symptoms” (DS, n = 161,460) and “broad depression” (BD, n = 113,769 cases and 208,811 controls). Six single nucleotide polymorphisms (SNPs), which were genome-wide significantly associated with 25(OH)vitamin D concentrations in 79,366 subjects from the SUNLIGHT genome-wide association study (GWAS), were used as an instrumental variable. None of the six SNPs was associated with DS or BD (all p > 0.05). MR analysis revealed no causal effects of 25(OH)vitamin D concentration, either on DS (inverse variance weighted (IVW); b = 0.025, SE = 0.038, p = 0.52) or on BD (IVW; b = 0.020, SE = 0.012, p = 0.10). Sensitivity analyses confirmed that 25(OH)vitamin D concentrations were not significantly associated with DS or BD. The findings from this MR study indicate no causal relationship between vitamin D concentrations and depressive symptoms, or broad depression. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.

Depression is a significant health and economic burden worldwide affecting not only adults but also children and adolescents. Current treatment options for this group are scarce and show moderate effect sizes. There is emerging evidence that dietary patterns and specific nutritional components might play a role in the risk for developing depression. This study protocol focusses on the role of vitamin D which is for long known to be relevant for calcium and phosphorous homeostasis and bone health but might also impact on mental health. However, the assessment of the vitamin D status of depressed juvenile patients, or supplementation of vitamin D is currently not part of routine treatment. Controlled intervention studies are indispensable to prove whether a vitamin D deficiency ameliorates depressive symptoms. This double blinded, randomized controlled trial will enroll 200 inpatients from a child and adolescent psychiatric department with a vitamin D deficiency defined by a 25(OH)-vitamin D-level < 30 nmol/l (12 ng/ml) and a Beck Depressions Inventory (BDI-II) score > 13 (indicating at least: mild depression). Upon referral, all patients will be screened, checked for inclusion criteria, and those eligible will be randomized after written consent into a supplementation or placebo group. Both study-arms will receive treatment-as-usual for their psychiatric disorder according to established clinical guidelines. The participants of the vitamin D supplementation group will receive 2640 I.E. vitamin D3 q.d. for 28 days in accordance with best practice in pediatric endocrinology. We hypothesize that delaying supplementation of vitamin D in the placebo arm will affect the treatment success of the depressive symptomatology in comparison to the vitamin D supplementation group. Patients will be enrolled for a period of 28 days based on the mean length of hospitalization of juveniles with depression. Randomized controlled trials in children and adolescents with depression are needed to elucidate the role of a vitamin D deficiency for mental disorders and to investigate the relevance of a routine assessment and supplementation of vitamin D deficits. DRKS00009758, 16/06/2016 (retrospectively registered).

Anthropometric traits and mental disorders or traits are known to be associated clinically and to show genetic overlap. We aimed to identify genetic variants with relevance for mental disorders/traits and either (i) body mass index (or obesity), (ii) body composition, (and/or) (iii) body fat distribution. We performed a look-up analysis of 1,005 genome-wide significant SNPs for BMI, body composition, and body fat distribution in 15 mental disorders/traits. We identified 40 independent loci with one or more SNPs fulfilling our threshold significance criterion (P < 4.98 × 10^–5) for the mental phenotypes. The majority of loci was associated with schizophrenia, educational attainment, and/or intelligence. Fewer associations were found for bipolar disorder, neuroticism, attention deficit/hyperactivity disorder, major depressive disorder, depressive symptoms, and well-being. Unique associations with measures of body fat distribution adjusted for BMI were identified at five loci only. To investigate the potential causality between body fat distribution and schizophrenia, we performed two-sample Mendelian randomization analyses. We found no causal effect of body fat distribution on schizophrenia and vice versa. In conclusion, we identified 40 loci which may contribute to genetic overlaps between mental disorders/traits and BMI and/or shape related phenotypes. The majority of loci identified for body composition overlapped with BMI loci, thus suggesting pleiotropic effects.

Both DSM-5 and ICD-11 have provided weight cut-offs and severity specifiers for the diagnosis of anorexia nervosa (AN) in childhood, adolescence and adulthood. The aims of the current study focusing on inpatients aged < 19 years were to assess (1) the relationship between age and body mass index (BMI; kg/m²), BMI-centiles, BMI-standard deviation scores (BMI-SDS) and body height-SDS at referral, (2) the percentages of patients fulfilling the DSM-5 and ICD-11 weight criteria and severity categories for AN, and (3) the validity of the AN severity specifiers via analysis of both weight related data at discharge and inpatient treatment duration. The German Registry for Anorexia Nervosa encompassed complete data sets for 469 female patients (mean age = 15.2 years; range 8.9–18.9 years) with a diagnosis of AN (n = 404) or atypical AN (n = 65), who were ascertained at 16 German child and adolescent psychiatric hospitals. BMI at referral increased up to age 15 to subsequently plateau. Approximately one tenth of all patients with AN had a BMI above the fifth centile. The ICD-11 specifier based on a BMI-centile of 0.3 for childhood and adolescent AN entailed two equally sized groups of patients. Discharge data revealed limited validity of the specifiers. Height-SDS was not correlated with age thus stunting had no impact on our data. We corroborate the evidence to use the tenth instead of the fifth BMI-centile as the weight criterion in children and adolescents. Weight criteria should not entail major diagnostic shifts during the transition from adolescence to adulthood. The severity specifiers based on BMI or BMI-centiles do not seem to have substantial clinical validity.

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.