Anke Hinney

Genetic variants may affect the body mass index (BMI) and the effectiveness of obesity treatments. However, it remains largely unclear whether these effects differ between men and women. Thus, this study investigates genetic variants in incretin-related genes ( GIP , GIP-R , GCG , GCG-R and GLP-1R ) using sex-stratified genetic and functional approaches. First, sex-specific genome-wide association study data were analysed to identify variants with a sex-specific effect on BMI. Identified variants were then examined in an independent cohort of adults undergoing bariatric surgery and functionally assessed in a cellular model. Finally, all genes were screened for rare variants in children and adolescents with severe obesity. Nine highly linked variants within GLP-1R showed stronger effects on BMI in men than in women. Among these, only rs1042044 (p.Leu260Phe) is located in the coding region. In a cohort of 807 bariatric surgery patients, rs1042044 showed a nominal association with achieving a weight loss of more than 10%, particularly in women. However, no differences in receptor internalisation were observed between wildtype and mutant GLP-1R in vitro . Additionally, 26 variants were identified across the genes in a paediatric cohort. Future studies should incorporate sex-stratified analyses to uncover putative sex-dependent genetic modifiers of BMI and weight loss outcomes.

Eating disorders and obesity are severe health conditions arising from an impaired body weight regulation. Both are strongly influenced by genetic factors. Accordingly, obesity can be broadly classified as either monogenic, caused by mutations in a single gene, or polygenic, resulting from the cumulative effects of numerous variants, each exerting modest effects on body weight. Although the genetic architecture of obesity is relatively well characterized, novel mutations underlying monogenic obesity are still being uncovered, and the mechanisms linking polygenic variants to the phenotype are not fully elucidated. In contrast, the genetic basis of eating disorders is considerably less well understood. Among these, anorexia nervosa has been the most intensively studied, with several genomic regions already associated with disease susceptibility. The present review summarizes the current knowledge about the genetics of obesity and anorexia nervosa, highlighting shared and distinct mechanisms and discusses emerging research directions.

Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuroaxonal and astrocytic damage but remain understudied in adolescent psychiatric populations. This study investigated sNfL and GFAP levels in 412 adolescents diagnosed with anorexia nervosa (AN) ( n = 52), depression ( n = 237), and other psychiatric disorders ( n = 123). We assessed their diagnostic utility, correlation with disease severity, and longitudinal changes during AN treatment. Biomarkers were measured using Single Molecule Array technology, with Z-scores derived from reference datasets. Compared to population norms, both biomarkers were elevated in AN (sNfL: 1.15 ± 1.17; GFAP: 1.50 ± 0.84) and in depression (sNfL: 0.34 ± 1.10; GFAP: 0.58 ± 1.00). Patients with AN showed significantly higher biomarker levels than those with depression or other psychiatric disorders; importantly, this distinction remained evident in sensitivity analyses restricted to underweight individuals with depression. In AN, sNfL levels correlated with baseline weight loss (β = −0.45, R² = 0.20) and declined significantly during treatment, while GFAP changes were less pronounced. Neither marker correlated with depressive symptom severity. Bootstrapped ROC analyses showed moderate-to-good discriminatory power (AUCs 0.70–0.84) for distinguishing AN from depression. These findings suggest that neuroaxonal and astrocytic stress is a component of adolescent psychopathology, particularly in AN. sNfL appears sensitive to starvation-related neurobiological changes, with levels normalizing alongside weight restoration. GFAP showed similar but less robust trends. Accordingly, the observed biomarker changes reflect more than underweight alone, supporting a potential role in differential diagnosis and treatment monitoring.

Eating disorders—including anorexia nervosa (AN), bulimia nervosa and binge-eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. Here we conducted a genomic meta-analysis of case–control studies of binge-eating behavior (BE; 39,279 cases, 1,227,436 controls), alongside analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six BE-associated loci, including loci associated with a higher body mass index and impulse-control behaviors. AN genome-wide association studies yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry studies. BE and AN exhibited similar positive genetic correlations with psychiatric disorders but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with body mass index. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

Adolescence is a vulnerable period for the emergence of mental health problems. Adrenarche, an early stage of pubertal development marked by rising adrenal androgens, particularly dehydroepiandrosterone (DHEA), may influence emotional and behavioral development. However, longitudinal evidence linking early-adolescent endocrine influences to adolescent psychopathology remains limited. Using data from the Adolescent Brain Cognitive Development (ABCD) Study (up to N = 11 696), we analyzed whether salivary DHEA during early adolescence predicted later externalizing and internalizing symptoms during adolescence. Early-adolescent hormone levels were averaged across baseline and 1-year follow-up (age range = 8.9–12.4 years). Outcomes were measured via the Child Behavior Checklist (CBCL) at the 2-, 3-, and 4-year follow-ups (up to = 14.08 ± 0.68 years). Sex-stratified linear mixed models adjusted for age, race/ethnicity, BMI and physical activity. In males, higher DHEA levels were linked to fewer externalizing symptoms across follow-ups (e.g., β = –0.07 SD change of CBCL per SD-change of log-transformed DHEA levels (95% CI [–0.10, –0.04] at 3-year) and fewer internalizing symptoms at 3-year and 4-year follow-ups. Higher early-adolescent DHEA in males also reduced the probability of externalizing symptoms to reach clinical thresholds across follow-ups (e.g., adjusted Risk Ratio = 0.81 to reach clinical threshold for CBCL externalizing per SD increase in log-transformed DHEA; 95% CI [0.70, 0.93] at 3-year). In females, no hormone–symptom associations emerged. Sex-by-DHEA interaction effects tended to increase across follow-up years for both symptom domains. These findings suggest that early-adolescent adrenal endocrine influences may contribute to the development of sex-specific vulnerability during adolescence. Future studies should consider adrenarche as a sensitive period for hormonal effects on mental health.

Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits but differ between diagnostic categories in context and directionality.

Eating disorders—including anorexia nervosa (AN), bulimia nervosa, and binge eating disorder—are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. We conducted the first genomic meta-analysis of binge-eating behaviour (BE; 39,279 cases, 1,227,436 controls), alongside new analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries). We identified six loci associated with BE, including loci associated with higher body mass index (BMI) and impulse-control behaviours. AN GWAS yielded eight loci, validating six loci. Subsequent polygenic risk score analysis demonstrated an association with AN in two East Asian ancestry cohorts. BE and AN exhibited similar positive genetic correlations with psychiatric disorders, but opposing genetic correlations with anthropometric traits. Most of the genetic signal in BE and AN was not shared with BMI. We have extended eating disorder genomics beyond AN; future work will incorporate multiple diagnoses and global ancestries.

The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lep ^ob/ob mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation.