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Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Abstract Background Many genes and molecular pathways are associated with obesity, but the mechanisms from genes to obesity are less well known. Eating behaviors represent a plausible pathway, but because the relationships of eating behaviors and obesity may be bi-directional, it remains challenging to resolve the underlying pathways. A longitudinal approach is needed to assess the contribution of genetic risk during the development of obesity in childhood. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood. Methods The IDEFICS/I.Family study is a school-based multicenter pan-European cohort of children observed for 6 years (mean ± SD follow-up 5.8 ± 0.4). Children examined in 2007/2008 (wave 1) (mean ± SD age: 4.4 ± 1.1, range: 2–9 years), in 2009/2010 (wave 2) and in 2013/2014 (wave 3) were included. A total of 5112 children (49% girls) participated at waves 1, 2 and 3. For 2656 children with genome-wide data we constructed a PRS based on 2.1 million single nucleotide polymorphisms. Z-score BMI and z-score waist circumference (WC) were assessed and eating behaviors and relevant confounders were reported by parents via questionnaires. Parental concern of overeating was derived from principal component analyses from an eating behavior questionnaire. Results In cross-lagged models, the prospective associations between z-score obesity indices and parental concern of overeating were bi-directional. In mediation models, the association between the PRS-BMI and parental concern of overeating at wave 3 was mediated by baseline z-BMI (β = 0.16, 95% CI: 0.10, 0.21) and baseline z-WC (β = 0.17, 95% CI: 0.11, 0.23). To a lesser extent, baseline parental concern of overeating also mediated the association between the PRS-BMI and z-BMI at wave 3 (β = 0.10, 95% CI: 0.07, 0.13) and z-WC at wave 3 (β = 0.09, 95% CI: 0.07, 0.12). Conclusions The findings suggest that the prospective associations between obesity indices and parental concern of overeating are likely bi-directional, but obesity indices have a stronger association with future parental concern of overeating than vice versa. The findings suggest parental concern of overeating as a possible mediator in the genetic susceptibility to obesity and further highlight that other pathways are also involved. A better understanding of the genetic pathways that lead to childhood obesity can help to prevent weight gain. Trial registration Registry number: ISRCTN62310987 Retrospectively registered 17 September 2018.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Objective: Childhood disadvantage is associated with a higher risk of adult obesity, but little is known about its associations with body mass index (BMI) trajectories during adulthood. This study aimed first to identify adulthood BMI trajectories, and second to investigate how childhood disadvantage is associated with trajectory group membership. Methods: Data from the Helsinki Health Study, a longitudinal cohort study of initially 40- to 60-year-old employees of the City of Helsinki in Finland, were used. The baseline survey was conducted in 2000–2002, and similar follow-up surveys in 2007, 2012, and 2017. Based on self-reported BMI, participants’ (n =5,266; 83% women) BMI trajectories, including their retrospectively reported BMI at the age of 25 years, were examined. Data on childhood disadvantage, including parental education and 7 types of childhood adversity (their own serious illness; parental divorce, death, mental disorder, or alcohol problems; economic difficulties at home; and peer group bullying) before the age of 16 years, were obtained from the baseline survey. Group-based trajectory modeling was used to identify BMI trajectories, and multinomial logistic regression to analyze the odds for trajectory group membership for the disadvantage variables. Results: Four ascending BMI trajectories in women and men were found: persistent normal weight (trajectory 1; women 35% and men 25%), normal weight to overweight (trajectory 2; women 41% and men 48%), normal weight to class I obesity (trajectory 3; women 19% and men 23%) and overweight to class II obesity (trajectory 4; women 5% and men 4%). Compared to trajectory 1, women with multiple adversities and repetitive peer bullying in childhood had greater odds of belonging to trajectories 3 and 4, whereas men with parental alcohol problems had greater odds of belonging to trajectory 4. For women and men, a low level of parental education was associated with a higher-level BMI trajectory. Conclusions: Low parental education for both genders, multiple adversities and repetitive peer bullying in childhood among women, and parental alcohol problems among men increased the odds of developing obesity during adulthood. Further studies are needed to clarify how gender differences modify the effects of childhood disadvantage on adult BMI trajectories.

Evidence remains unclear on how intergenerational social mobility is associated with body mass index (BMI) and its long-term changes. Our study identified BMI trajectories from middle to older age by intergenerational social mobility groups and stratified the analyses by gender and two birth cohorts (birth years 1940‒1947 and 1950–1962). We used questionnaire-based cohort data that consists of four survey phases: 2000–2002, 2007, 2012, and 2017. In Phase 1, participants were 40–60-year-old employees of the City of Helsinki, Finland. Our analytical sample consisted of 6,971 women and 1,752 men. Intergenerational social mobility was constructed based on self-reported parental and own education—both divided into high and low—yielding four groups: stable high socioeconomic position (SEP) (high-high), upward social mobility (low-high), downward social mobility (high-low), and stable low SEP (low-low). BMI was calculated from self-reported height and weight from all four phases. Using mixed-effects linear regression, we found increasing BMI trajectories in all four social mobility groups until the age of 65. Women and men with stable high SEP had lower BMI trajectories compared to those with stable low SEP. In the younger birth cohort, women with upward social mobility had a lower BMI trajectory than women with stable low SEP. Additionally, women and men with downward social mobility had higher BMI trajectories than those with stable high SEP. In the older birth cohort, however, the BMI trajectories of upward and downward social mobility groups were somewhat similar and settled between the BMI trajectories of stable high and stable low SEP groups. Our results indicate that the associations between intergenerational social mobility and BMI may depend on gender and birth cohort. Nevertheless, to reduce socioeconomic inequalities in unhealthy weight gain, obesity prevention actions that focus on people who are likely to remain in low SEP might be worthwhile.

Abstract Background Studies suggest an association between weight change and subsequent poor physical health functioning, whereas the association with mental health functioning is inconsistent. We aimed to examine whether obesity and change of body mass index among normal weight, overweight and obese women and men associate with changes in physical and mental health functioning. Methods The Helsinki Health Study cohort includes Finnish municipal employees aged 40 to 60 in 2000–02 (phase 1, response rate 67%). Phase 2 mail survey (response rate 82%) took place in 2007 and phase 3 in 2012 (response rate 76%). This study included 5668 participants (82% women). Seven weight change categories were formed based on body mass index (BMI) (phase 1) and weight change (BMI change ≥5%) (phase 1–2). The Short Form 36 Health Survey (SF-36) measured physical and mental health functioning. The change in health functioning (phase 1–3) score was examined with repeated measures analyses. Covariates were age, sociodemographic factors, health behaviours, and somatic ill-health. Results Weight gain was common among women (34%) and men (25%). Weight-gaining normal weight (−1.3 points), overweight (−1.3 points) and obese (−3.6 points) women showed a greater decline in physical component summary scores than weight-maintaining normal weight women. Among weight-maintainers, only obese (−1.8 points) women showed a greater decline than weight-maintaining normal weight women. The associations were similar, but statistically non-significant for obese men. No statistically significant differences in the change in mental health functioning occurred. Conclusion Preventing weight gain likely helps maintaining good physical health functioning and work ability.

OBJECTIVES: The aims of this study were to examine (i) the association of relative weight with subsequent disability retirement due to any diagnosis and also in two major diagnostic groups (ie, musculoskeletal diseases and mental disorders) and (ii) whether diagnosed diseases, physical and mental functioning, and working conditions explain these associations. METHODS: This prospective study comprised a cohort of 6542 middle-aged employees of the City of Helsinki, Finland. Questionnaire data were linked with register data on disability retirements, with a mean follow-up time of 7.8 years. RESULTS: Adjusting for age, body mass index (BMI) was associated with all-cause disability retirement among men and women, the highest risk being for the severely obese and the obese [hazard ratio (HR) 3.45, 95% confidence interval (95% CI) 2.53–4.69; HR 1.94, 95% CI 1.52–2.46, respectively]. Adjusting for age, relative weight was also strongly associated with the main retirement diagnoses, especially musculoskeletal diseases among the severely obese (HR 4.76, 95% CI 3.06–7.40) and obese (HR 2.35, 95% CI 1.62–3.39). The association was attenuated when adjusting for self-reported diseases and physical and mental functioning at baseline. Working conditions had negligible effects on the associations. CONCLUSIONS: Maintenance of normal weight is likely to reduce the risk of disability retirement. Among obese employees, the focus should be on the improvement of physical functioning and the effective treatment of obesity and its co-morbidities to counteract the heightened risk of disability retirement.

Background and Aims: By investigating differences in lifestyle behaviours and BMI in sibling pairs, family-level confounding is minimized and causal inference is improved, compared to cross-sectional studies of unrelated children. Thus, we aimed to investigate within-sibling pair differences in different lifestyle behaviours and differences in BMI z-scores in children and adolescents.Methods and Results: We examined three groups of sibling pairs 1) all same-sex sibling pairs with maximum 4 years age difference (n = 1209 pairs from 1072 families in 8 countries, mean age 10.7 years, standard deviation 2.4 years), 2) sibling pairs discordant for overweight (n = 262) and 3) twin pairs (n = 85). Usual dietary intake was estimated by 24-h recalls and time spent in light (LPA) and moderate-to-vigorous physical activity (MVPA) was measured by accelerometers. Screen time, sleep and dieting for weight loss were assessed by questionnaires. Within all 3 groups of sibling pairs, more time in MVPA was associated with lower BMI z-score. Higher energy intake was associated with higher BMI z-score within twin pairs and within all sibling pairs who were not currently dieting for weight loss. Regarding LPA, screen time or sleep duration, no or inconsistent associations were observed for the three groups of sibling pairs.Conclusions: MVPA and energy intake were associated with BMI differences within sibling and twin pairs growing up in the same home, thus independent of family-level confounding factors. Future studies should explore whether genetic variants regulating appetite or energy expenditure behaviours account for weight differences in sibling pairs. [ABSTRACT FROM AUTHOR]

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.