Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index.
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ABSTRACT:
SUBMITTER: Hinney A
PROVIDER: S-EPMC8477229 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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 nine SNP alleles at three 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 with 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.
| S-EPMC5114162 | biostudies-literature
Project description:BackgroundStudies show that adult patients with anorexia nervosa display cognitive impairments. These impairments may be caused by illness-related circumstances such as low weight. However, the question is whether there is a cognitive adaptation to enduring undernutrition in anorexia nervosa. To our knowledge, cognitive performance has not been assessed previously in a patient with anorexia nervosa with a body mass index as low as 7.7 kg/m2.Case presentationWe present the cognitive profile of a 35-year-old woman with severe and enduring anorexia nervosa who was diagnosed at the age of 10 years. She was assessed with a broad neuropsychological test battery three times during a year. Her body mass index was 8.4, 9.3, and 7.7 kg/m2, respectively. Her general memory performance was above the normal range and she performed well on verbal and design fluency tasks. Her working memory and processing speed were within the normal range. However, her results on cognitive flexibility tasks (set-shifting) were below the normal range.ConclusionsThe case study suggests that it is possible to perform normally cognitively despite extreme and chronic malnutrition though set-shifting ability may be affected. This opens for discussion whether patients with anorexia nervosa can maintain neuropsychological performance in spite of extreme underweight and starvation.Trial registrationClinicalTrials.gov, NCT02502617. Registered 20 July 2015.
| S-EPMC7275539 | biostudies-literature
Project description:Proposed treatments for severe and enduring anorexia nervosa (SE-AN) focus on quality of life, and psychological and social functioning. By de-emphasizing weight restoration as a priority, however, premature diagnosis of SE-AN may reduce potential for recovery. The present study assessed the effect of weight restoration, illness duration, and severity on treatment outcome 6 months after discharge from an intensive, meal-based behavioral treatment program. Participants included hospitalized adult women (N = 191) with AN or underweight other specified feeding and eating disorder (OSFED). Participants were characterized as short-term (ill <7 years; n = 74) or long-term ill (ill ≥ 7 years; n = 117). Compared with short-term ill, long-term ill patients were older, had lower lifetime body mass index (BMI), more prior admissions, and exhibited greater depression and neuroticism. Long-term vs. short-term ill patients gained weight at the same rate (~2 kg/wk) and were equally likely to be weight restored by discharge (>75% reached BMI ≥ 19 kg/m2 in both groups). At 6-month follow-up (n = 99), both groups had equivalent self-reported BMI, and depression, drive for thinness, body dissatisfaction, and bulimia scores. The only predictor of BMI ≥ 19 kg/m2 at follow-up was discharge BMI. The likelihood of a BMI ≥ 19 kg/m2 at follow-up was 5-fold higher for those with discharge BMI ≥ 19 kg/m2. Few studies of long-term ill inpatients with AN have examined the impact of full weight restoration on short-term outcomes. This study supports the therapeutically optimistic stance that, regardless of illness duration, hospitalized patients with AN benefit from gaining weight to a BMI ≥ 19 kg/m2.
| S-EPMC7946839 | biostudies-literature
Project description:Genetic factors are relevant for both eating disorders and body weight regulation. A recent genome-wide association study (GWAS) for anorexia nervosa (AN) detected eight genome-wide significant chromosomal loci. One of these loci, rs10747478, was also genome-wide and significantly associated with body mass index (BMI). The nearest coding gene is the Polypyrimidine Tract Binding Protein 2 gene (PTBP2). To detect mutations in PTBP2, Sanger sequencing of the coding region was performed in 192 female patients with AN (acute or recovered) and 191 children or adolescents with (extreme) obesity. Twenty-five variants were identified. Twenty-three of these were predicted to be pathogenic or functionally relevant in at least one in silico tool. Two novel synonymous variants (p.Ala77Ala and p.Asp195Asp), one intronic SNP (rs188987764), and the intronic deletion (rs561340981) located in the highly conserved region of PTBP2 may have functional consequences. Ten of 20 genes interacting with PTBP2 were studied for their impact on body weight regulation based on either previous functional studies or GWAS hits for body weight or BMI. In a GWAS for BMI (Pulit et al. 2018), the number of genome-wide significant associations at the PTBP2 locus was different between males (60 variants) and females (two variants, one of these also significant in males). More than 65% of these 61 variants showed differences in the effect size pertaining to BMI between sexes (absolute value of Z-score >2, two-sided p < 0.05). One LD block overlapping 5'UTR and all coding regions of PTBP2 comprises 56 significant variants in males. The analysis based on sex-stratified BMI GWAS summary statistics implies that PTBP2 may have a more pronounced effect on body weight regulation in males than in females.
| S-EPMC9184595 | biostudies-literature
Project description:BackgroundAnorexia nervosa (AN) is a severe eating disorder, recognized by a relentless pursuit for thinness and extreme low body weight. The disorder is often accompanied by comorbid disorders such as anxiety and depression, and altered neuropsychological function in terms of poor set-shifting and reduced central coherence. The aim of this review was to evaluate whether neuropsychological impairments in AN are influenced by body mass index, anxiety or depression.MethodA systematic review approach was used, following the PRISMA guidelines for systematic reviews. Literature was identified via searches in PubMed, PsychInfo and Embase database, by using the search words [anorexia nervosa] AND [central coherence], and [anorexia nervosa] AND [set-shifting]. Studies were included if they were written in English, peer-reviewed, included individuals with AN, included tests measuring set-shifting and/or central coherence, investigated associations between set-shifting/central coherence with anxiety and/or depression and/or BMI. Risk of bias was assessed by using a critical appraisal checklist from the Joanna Briggs Institute. Results were summarized in a narrative synthesis.ResultsAlthough results are heterogeneous, the majority of studies report that neither body mass index (BMI), anxiety or depression is associated with altered central coherence and set-shifting in individuals with AN.ConclusionsFindings indicate that BMI, depression and anxiety does not influence neuropsychological function in AN, suggesting that it could be a characteristic of the disorder. A complete understanding of predisposing, precipitating and maintaining factors in AN needs to be addressed in future research. This could contribute to the development of better and more targeted treatment strategies.
| S-EPMC7938561 | biostudies-literature
Project description:BackgroundPatients with anorexia nervosa often report a conscious alteration of body image representation, with both body overestimation and body dissatisfaction. Cognitive and behavioural therapy is effective for treating many psychiatric disorders but often fails to treat anorexia nervosa and body image distortions. Although patients are aware of their weight loss, they continue to feel overweight - as if there were a conflict between a previous (maybe already false) body representation and the new one. These distortions are linked to negative emotions focused on the body but which can extend to the self (e.g. disgust and sadness).Case presentationThe present case report is the first in which the Appraisal Tendency Framework has been applied to decrease body image distortions in a patient with anorexia nervosa. The Appraisal Tendency Framework is usually used to understand how emotions influence decision making. Here, we report on a 24-year-old woman who suffered from anorexia nervosa and body image distortions, and was treated as an inpatient with conventional cognitive and behavioural therapy for an eating disorder. Body image distortions were assessed before and after the patient completed an adaptation of the Iowa Gambling Task, coupled with the induction of a heuristic processing emotion. We hypothesized that allowing the patient to focus on the emotional cues in the modified Iowa Gambling Task would improve her decisions about her true body shape.ConclusionAll body image measures were improved after the protocol. Consequently, we suggest that the Appraisal Tendency Framework might be a valuable means of investigating body image issues in eating disorders and anorexia nervosa. Further studies are required to expand and detail these findings.
| S-EPMC6172742 | biostudies-literature
Project description:A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
| S-EPMC4854022 | biostudies-literature
Project description:ObjectiveTo compare bone mineral density (BMD) and body composition among adolescents: (a) with atypical anorexia nervosa (AAN) versus anorexia nervosa (AN) and (b) those with and without a prior history of overweight.MethodElectronic medical records of patients 9-20 years with AN or AAN who underwent dual-energy x-ray absorptiometry scans were retrospectively reviewed and analyzed.ResultsA total of 286 adolescents with AN or AAN were included. In linear regression models, AAN was associated with greater Z-scores in whole body bone mineral content (BMC, B = 0.88, p < 0.001), lumbar spine BMD (B = 0.79, p = 0.002), femoral neck BMD (B = 0.670, p = 0.009); fat mass index (B = 1.33, p = 0.003), and lean body mass index (LBMI, B = 1.10, p < 0.001) compared to AN, adjusting for age, sex, and duration of illness. A prior overweight history was associated with greater Z-scores in whole body BMC; lumbar spine BMD, total hip BMD, femoral neck BMD, and LBMI.DiscussionAdolescents with AAN had higher BMD Z-scores than adolescents with AN; adolescents with a prior overweight history had greater BMD Z-scores than adolescents without a prior overweight history. These findings may inform clinical guidelines for the medical management of AAN.
| S-EPMC6613651 | biostudies-literature
Project description:Increased physical activity (PA) affects outcomes in patients with anorexia nervosa (AN). To objectively assess PA patterns of hospitalized AN patients in comparison with healthy, outpatient controls (HC), and to analyze the effect of PA on Body Mass Index (BMI) change in patients with AN, we measured PA in 50 female patients with AN (median age = 25 years, range = 18?52 years; mean BMI = 14.4 ± 2.0 kg/m²) at the initiation of inpatient treatment and in 30 female healthy controls (median age = 26 years, range = 19?53 years; mean BMI = 21.3 ± 1.7 kg/m²) using the SenseWear™ armband. Duration of inpatient stay and weight at discharge were abstracted from medical records. Compared with controls, AN patients spent more time in very light-intensity physical activity (VLPA) (median VLPA = 647 vs. 566 min/day, p = 0.004) and light-intensity physical activity (LPA) (median LPA = 126 vs. 84 min/day, p < 0.001) and less time in moderate-intensity physical activity (MPA) (median MPA = 82 vs. 114 min/day, p = 0.022) and vigorous physical activity (VPA) (median VPA = 0 vs. 16 min/day, p < 0.001). PA and BMI increase were not associated in a linear model, and BMI increase was mostly explained by lower admission BMI and longer inpatient stay. In a non-linear model, an influence of PA on BMI increase seemed probable (jack knife validation, r² = 0.203; p < 0.001). No direct association was observed between physical inactivity and BMI increase in AN. An altered PA pattern exists in AN patients compared to controls, yet the origin and consequences thereof deserve further investigation.
| S-EPMC6162412 | biostudies-literature
Project description:Individuals with anorexia nervosa (AN) typically display anxious traits prior to the onset of food avoidance and weight loss that characterize the disorder. Meal associated anxiety is an especially common clinical feature in these patients, and heightened sensitivity to sympathetically mediated interoceptive sensations has also been observed. However, it remains unclear how heightened interoceptive sensitivity relates to experiences of anxiety before and after meals. To investigate this relationship, we experimentally induced anxiety and panic symptoms with isoproterenol, a peripheral sympathetic agonist similar to adrenaline, across several different conditions: during panic provocation, during anticipation of a 1,000 Calorie meal, and after meal consumption. Fifteen AN and 15 age- and sex-matched healthy comparisons received bolus infusions of isoproterenol and saline in a double-blinded, randomized design. Participants rated anxiety symptoms after each infusion, completed panic rating scales, and traced the location of perceived palpitations on a manikin to index interoceptive "body map" representation. The AN group reported significantly elevated anxiety relative to healthy comparisons during infusions before and after the meal, but surprisingly, not during panic provocation. These symptoms were accompanied by geographical differences in patterns of perceived heartbeat sensations across each condition. In particular, the AN group localized heartbeat sensations disproportionately to the chest during meal related saline infusions, when no cardiorespiratory modulation actually occurred. The AN group also showed a trend toward higher panic attack rates during the meal anticipation period. Correcting for anxiety levels reported during saline infusions abolished group differences in anxiety change across all conditions, suggesting a significant contribution of anxious traits in AN. The observation of meal related "visceral illusions" provides further evidence that AN is associated with abnormal interoceptive representation of the heartbeat and suggests that meal consumption, particularly when anticipated, preferentially alters the processing of interoception related signals in AN.
| S-EPMC6160545 | biostudies-literature