The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single nucleotide polymorphisms (SNPs) with the lowest p-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI related loci was performed in the AN GWAMA. We detected significant associations (p-values < 5×10−5, Bonferroni corrected p < 0.05) for 9 SNP alleles at 3 independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; poverall: 2.47 × 10−06/pfemales: 3.45 × 10−07/pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet induced obese (DIO) mice as compared to age-matched lean controls. We observed no evidence for associations for the look-up of BMI related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

Background Comorbidity between psychopathologies may be attributed to genetic and environmental differences between people as well as causal processes within individuals, where one pathology increases risk for another. Disentangling between‐person (co)variance from within‐person processes of psychopathology dimensions across childhood may shed light on developmental causes of comorbid mental health problems. Here, we aim to determine whether and to what extent directional relationships between psychopathology dimensions within‐person, and between individuals within families, play a role in comorbidity. Methods We conducted random intercepts cross‐lagged panel model (RI‐CLPM) analyses to unravel the longitudinal co‐occurrence of child psychopathology dimensions, jointly estimating between‐person and within‐person processes from childhood to early adolescence (age 7–12). We further developed an extension of the model to estimate sibling effects within‐family (wf‐RI‐CLPM). Analyses were separately conducted in two large population‐based cohorts, TEDS and NTR, including parent‐rated measures of child problem behaviours based on the SDQ and CBCL scales respectively. Results We found evidence for strong between‐person effects underlying the positive intercorrelation between problem behaviours across time. Beyond these time‐varying within‐person processes accounted for an increasing amount of trait variance, within‐ and cross‐trait, overtime in both cohorts. Lastly, by accommodating family level data, we found evidence for reciprocal directional influences within sib‐pairs longitudinally. Conclusions Our results indicate that within‐person processes partly explain the co‐occurrence of psychopathology dimensions across childhood, and within sib‐pairs. Analyses provided substantive results on developmental processes underlying comorbidity in behavioural problems. Future studies should consider different developmental timeframes to shed more light on the processes contributing to developmental comorbidity.