Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

A within-sibling pair analysis of lifestyle behaviours and BMI z-score in the multi-centre I.Family study.

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.

Risk of eating disorders in immigrant populations.

OBJECTIVE: The risk of certain psychiatric disorders is elevated among immigrants. To date, no population studies on immigrant health have addressed eating disorders. We examined whether risk of eating disorders in first- and second-generation immigrants differs from native-born Danes and Swedes. METHOD: All individuals born 1984-2002 (Danish cohort) and 1989-1999 (Swedish cohort) and residing in the respective country on their 10th birthday were included. They were followed up for the development of eating disorders based on out-patient and in-patient data. RESULTS: The risks of all eating disorder types were lower among first-generation immigrants compared to the native populations: Incidence-rate ratio (95% confidence interval) was 0.39 (0.29, 0.51) for anorexia nervosa, 0.60 (0.42, 0.83) for bulimia nervosa, and 0.62 (0.47, 0.79) for other eating disorders in Denmark and 0.27 (0.21, 0.34) for anorexia nervosa, 0.30 (0.18, 0.51) for bulimia nervosa, and 0.39 (0.32, 0.47) for other eating disorders in Sweden. Likewise, second-generation immigrants by both parents were at lower risk, whereas those with only one foreign-born parent were not. CONCLUSION: The decreased risk of eating disorders among immigrants is opposite to what has been observed for other psychiatric disorders, particularly schizophrenia. Possible explanations include buffering sociocultural factors and underdetection in health care.

A genome-wide association study of anorexia nervosa.

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.

Genetic and environmental effects on body mass index during adolescence: a prospective study among Finnish twins.

OBJECTIVE: To study genetic and environmental factors affecting body mass index (BMI) and BMI phenotypic correlations across adolescence. DESIGN: Prospective, population-based, twin cohort study. PARTICIPANTS AND METHODS: We used twin modeling in 2413 monozygotic and same-sex and opposite-sex dizygotic Finnish twin pairs born in 1983-1987 and assessed using self-report questionnaires at 11-12, 14 and 17 years of age. RESULTS: Heritability of BMI was estimated to be 0.58-0.69 among 11-12- and 14-year-old boys and girls, 0.83 among 17-year-old boys and 0.74 among 17-year-old girls. Common environmental effects shared by siblings were 0.15-0.24 among 11-12- and 14-year-old boys and girls but no longer discernible at 17 years of age. Unique environmental effects were 0.15-0.23. Additive genetic factors explained 90-96% of the BMI phenotypic correlations across adolescence, whereas unique environmental factors explained the rest. Common environment had no effect on BMI phenotypic correlations. CONCLUSIONS: The genetic contribution to BMI is strong during adolescence, and it mainly explains BMI phenotypic correlations across adolescence. Common environmental factors have an effect on BMI during early adolescence, but that effect disappears by late adolescence.

Eating styles, overweight and obesity in young adult twins.

OBJECTIVE: To explore the association of eating styles with overweight and obesity in young adults, controlling for identical genetic background in monozygotic twins. DESIGN: Prospective twin cohort study. SETTING: Finland, 1991-2002. SUBJECTS: Two-hundred and thirty-three women and 2060 men from the FinnTwin16 study, aged 16 years at baseline (T1), and ranging from 22 to 27 years at the time of the nutritional assessment (T4). METHODS: Eating styles (Restrictive/overeating, health-conscious, snacking, emotional and externally induced), self-reported at T4, were contrasted with body mass indices (BMIs) at T1 and T4. RESULTS: At T4, obesity (BMI>or=30Kg/m(2)) was significantly cross-sectionally associated with restrictive eating, frequent snacks, eating in the evening, avoiding fatty foods and failure to maintain healthy eating patterns. These associations were independent of BMI at T1. Obese women self-reported more vulnerability to external eating cues and comfort eating than normal-weight women. However, in a multivariable model, only restrictive/overeating and health-conscious eating styles were significant correlates of obesity at T4, independent of gender and BMI at T1. When we controlled for genetic background restricting the analysis to the 39 female and 45 male monozygotic twin pairs discordant for obesity or overweight (BMI>or=25Kg/m(2)), restrictive/overeating eating style was still statistically significantly associated with excess weight. CONCLUSIONS: The eating styles of obese young adults differ from their normal-weight counterparts: restrictive eating, overeating and fewer healthy food choices are associated with obesity. Different eating styles may partially explain weight differences in individuals with identical genetic background.

Comparison of manual and automated quantification methods of 123I-ADAM.

UNLABELLED: 123I-ADAM is a novel radioligand for imaging of the brain serotonin transporters (SERTs). Traditionally, the analysis of brain receptor studies has been based on observer-dependent manual region of interest definitions and visual interpretation. Our aim was to create a template for automated image registrations and volume of interest (VOI) quantifications and to show that an automated quantification method of 123I-ADAM is more repeatable than the manual method. PATIENTS, METHODS: A template and a predefined VOI map was created from 123I-ADAM scans done for healthy volunteers (n = 15). Scans of another group of healthy persons (HS, n = 12) and patients with bulimia nervosa (BN, n = 10) were automatically fitted to the template and specific binding ratios (SBRs) were calculated by using the VOI map. Manual VOI definitions were done for the HS and BN groups by both one and two observers. The repeatability of the automated method was evaluated by using the BN group. RESULTS: For the manual method, the interobserver coefficient of repeatability was 0.61 for the HS group and 1.00 for the BN group. The introobserver coefficient of repeatability for the BN group was 0.70. For the automated method, the coefficient of repeatability was 0.13 for SBRs in midbrain. CONCLUSION: An automated quantification gives valuable information in addition to visual interpretation decreasing also the total image handling time and giving clear advantages for research work. An automated method for analysing 123I-ADAM binding to the brain SERT gives repeatable results for fitting the studies to the template and for calculating SBRs, and could therefore replace manual methods.

Breakfast skipping and health-compromising behaviors in adolescents and adults.

OBJECTIVE: To investigate which sociodemographic factors and behaviors are associated with breakfast skipping in adolescents and adults. DESIGN: Five birth cohorts of adolescent twins and their parents received an extensive behavioral and medical self-report questionnaire that also assessed breakfast-eating frequency. SETTING: Finland, 1991-1995. SUBJECTS: A population sample of 16-y-old girls and boys (n=5448) and their parents (n=4660). RESULTS: Parental breakfast eating was the statistically most significant factor associated with adolescent breakfast eating. Smoking, infrequent exercise, a low education level at 16, female sex, frequent alcohol use, behavioral disinhibition, and high body mass index (BMI) were significantly associated with adolescent breakfast skipping. In adults, smoking, infrequent exercise, low education level, male sex, higher BMI, and more frequent alcohol use were associated with breakfast skipping. In the adult sample, older individuals had breakfast more often than younger ones. Both adults and adolescents who frequently skipped breakfast were much more likely to exercise very little compared to those who skipped breakfast infrequently. Breakfast skipping was associated with low family socioeconomic status in adults and adolescent boys, but not in girls. Breakfast skipping clustered moderately with smoking, alcohol use, and sedentary lifestyle in both adults and adolescents. CONCLUSIONS: Breakfast skipping is associated with health-compromising behaviors in adults and adolescents. Individuals and families who skip breakfast may benefit from preventive efforts that also address risk behaviors other than eating patterns. SPONSORSHIP: National Institute of Alcohol Abuse and Alcoholism (AA08315), Academy of Finland (44069), European Union Fifth Framework Program (QLRT-1999-00916), Yrjö Jahnsson Foundation, and Jalmari and Rauha Ahokas Foundation.

Incidence and outcomes of bulimia nervosa: a nationwide population-based study.

BACKGROUND: Little is known about the epidemiology of bulimia nervosa outside clinical settings. We report the incidence, prevalence and outcomes of bulimia nervosa using for the first time a nationwide study design. METHOD: To assess the incidence and natural course and outcomes of DSM-IV bulimia nervosa among women from the general population, women (n=2881) from the 1975-79 birth cohorts of Finnish twins were screened for lifetime eating disorders using a two-stage procedure consisting of a questionnaire screen and the Structured Clinical Interview for DSM-IV (SCID). Clinical recovery was defined as 1-year abstinence from bingeing and purging combined with a body mass index (BMI) 19 kg/m2. RESULTS: The lifetime prevalence of DSM-IV bulimia nervosa was 2.3%; 76% of the women suffered from its purging subtype and 24% from the non-purging subtype. The incidence rate of bulimia nervosa was 300/100000 person-years at the peak age of incidence, 16-20 years, and 150/100000 at 10-24 years. The 5-year clinical recovery rate was 55.0%. Less than a third of the cases had been detected by health-care professionals; detection did not influence outcome. After clinical recovery from bulimia nervosa, the mean levels of residual psychological symptoms gradually decreased over time but many women continued to experience significantly more body image problems and psychosomatic symptoms than never-ill women. CONCLUSIONS: Few women with bulimia nervosa are recognized in health-care settings. Symptoms of bulimia are relatively long-standing, and recovery is gradual. Many clinically recovered women experience residual psychological symptoms after attaining abstinence from bingeing and purging.