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

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

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 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.

Interaction between disinhibition and restraint: Implications for body weight and eating disturbance.

An increase in obesity is usually accompanied by an increase in eating disturbances. Susceptibility to these states may arise from different combinations of underlying traits: Three Factor Eating Questionnaire (TFEQ) Restraint and Disinhibition. Two studies were conducted to examine the interaction between these traits; one on-line study (n=351) and one laboratory-based study (n=120). Participants completed a battery of questionnaires and provided self-report measures of body weight and physical activity. A combination of high Disinhibition and high Restraint was associated with a problematic eating behaviour profile (EAT-26), and a higher rate of smoking and alcohol consumption. A combination of high Disinhibition and low Restraint was associated with a higher susceptibility to weight gain and a higher sedentary behaviour. These data show that different combinations of Disinhibition and Restraint are associated with distinct weight and behaviour outcomes.

Similarities and differences between excessive exercising anorexia nervosa patients compared with DSM-IV defined anorexia nervosa subtypes.

This study describes anorexia nervosa (AN) patients who use excessive exercise for weight management and how this behaviour relates to the classical Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) sub-grouping of AN. The study compared 428 clinical AN patients with 119 age and gender-matched controls. The AN cases were initially dichotomised according to DSM-IV subtype criteria into restricting (RAN; N=198) and binge-purge (BPAN; N=230) anorexia. The psychometric instruments were chosen to reflect key features concerning the diagnosis of eating disorders and characteristics of eating and food behaviour and included the 26-item Eating Attitude Test (EAT-26), Three Factor Eating Questionnaire (TFEQ), Dutch Eating Behaviour Questionnaire (DEBQ), Eysenck Personality Inventory (EPI) and Rosenberg Self-Esteem scale (RSE). Structured clinical interviews (1) were carried out in order to identify the subgroup of patients who use excessive exercise in order to facilitate weight control (EAN). The three groups (RAN, BPAN, EAN) did not differ in measures of current age, current body mass index, age of onset of AN and measures of restrained eating. However, significant differences were observed on EAT-26, DEBQ emotional and external factors, TFEQ disinhibition and hunger factors, EPI extraversion and neuroticism, and self-esteem. The EAN were similar to the RAN on the majority of variables but showed significant differences on extraversion, neuroticism, self-esteem and disease pathology (EAT-26). Compared with BPAN, EAN had lower disease pathology (EAT-26 scores), scored higher on the EPI extraversion scale, lower on the neuroticism scale and had greater self-esteem. The EAN also displayed significantly lower emotional and external eating (DEBQ) than BPAN and significantly lower disinhibition and hunger scores (TFEQ). These data suggest that EAN group display a mixed profile of characteristics resembling both BPAN and RAN. When EAN are defined as a separate group they appear to be phenotypically more similar to RAN than BPAN on this particular profile of variables. However when DSM-IV criteria are applied they are almost exclusively classified as BPAN. This outcome suggests that EAN do constitute an identifiable group that can be distinguished from RAN and BPAN. Consequently it is likely that the behaviour of excessive exercising should be considered as clinically relevant on the outcome of treatment.