Alessandro Rotondo

Significant Linkage on Chromosome 10p in Families with Bulimia Nervosa

Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to contribute substantially to the observed familiality. In turn, behavioral components of BN, such as self-induced vomiting, are reliably measured and heritable. To identify regions of the genome harboring genetic variants conferring susceptibility to BN, we conducted a linkage analysis of multiplex families with eating disorders that were identified through a proband with BN. Linkage analysis of the entire sample of 308 families yielded a double peak, with the highest nonparametric multipoint maximum LOD score (MLS), of 2.92, on chromosome 10. Given the high heritability of self-induced vomiting and the reliability with which it can be measured, we performed linkage analysis in a subset (n=133) of families in which at least two affected relatives reported a symptom pattern that included self-induced vomiting. The highest MLS (3.39) observed was on chromosome 10, between markers D10S1430 and D10S1423. These results provide evidence of the presence of a susceptibility locus for BN on chromosome 10p. Using simulations, we demonstrate that both of these scores, 2.92 and 3.39, meet the widely accepted criterion for genomewide significance. Another region on 14q meets the criterion for genomewide suggestive linkage, with MLSs of 1.97 (full sample) and 1.75 (subset) at 62 centimorgans from p-ter.

Impulse control disorders in women with eating disorders.

We compared symptom patterns, severity of illness, and comorbidity in individuals with eating disorders with and without impulse control disorders (ICD), and documented the temporal pattern of illness onset. Lifetime ICD were present in 16.6% of 709 women with a history of eating disorders. The most common syndromes were compulsive buying disorder and kleptomania. ICD occurred more in individuals with binge eating subtypes, and were associated with significantly greater use of laxatives, diuretics, appetite suppressants and fasting, and with greater body image disturbance, higher harm avoidance, neuroticism, cognitive impulsivity, and lower self-directedness. In addition, individuals with ICD were more likely to have obsessive-compulsive disorder, any anxiety disorder, specific phobia, depression, cluster B personality disorder, avoidant personality disorder, and to use psychoactive substances. Among those with ICD, 62% reported the ICD predated the eating disorder and 45% reported the onset of both disorders within the same 3-year window. The presence of a lifetime ICD appears to be limited to eating disorders marked by binge eating and to be associated with worse eating-related psychopathology, more pathological personality traits, and more frequent comorbid Axis I and II conditions. Untreated ICD may complicate recovery from eating disorders.

Optimism and Its Impact on Mental and Physical Well-Being

Many studies have been carried out about the effectiveness of optimism as a psychological phenomenon, leading to various theoretical formulations of the same concept, conceptualized as “disposition”, “attributional style”, “cognitive bias”, or “shared illusion”. This overview is an attempt to explore the “optimism” concept and its relations with mental health, physical health, coping, quality of life and adaptation of purpose, health lifestyle and risk perception. Positive and negative expectations regarding the future are important for understanding the vulnerability to mental disorders, in particular mood and anxiety disorders, as well as to physical illness. A significant positive relation emerges between optimism and coping strategies focused on social support and emphasis on positive aspects of stressful situations. Through employment of specific coping strategies, optimism exerts an indirect influence also on the quality of life. There is evidence that optimistic people present a higher quality of life compared to those with low levels of optimism or even pessimists. Optimism may significantly influence mental and physical well-being by the promotion of a healthy lifestyle as well as by adaptive behaviours and cognitive responses, associated with greater flexibility, problem-solving capacity and a more efficient elaboration of negative information.

Influence of overanxious disorder of childhood on the expression of anorexia nervosa

OBJECTIVE Childhood anxiety often precedes the onset of anorexia nervosa (AN) and may mark a liability to the emergence of an eating disorder for some women. This study investigates the prevalence of overanxious disorder (OAD) among women with AN and explores how OAD impacts AN symptoms and personality traits. METHOD Participants were 637 women with AN who completed an eating disorders history, the Structured Clinical Interview for DSM-IV Axis I Disorders, and assessments for childhood anxiety, eating disorder attitudes, and associated personality traits. RESULTS Of 249 women (39.1%) reporting a history of OAD, 235 (94.4%) met criteria for OAD before meeting criteria for AN. In comparison to those without OAD, women with AN and OAD self-reported more extreme personality traits and attitudes and they engaged in more compensatory behaviors. CONCLUSION Among individuals with AN, those entering AN on a pathway via OAD present with more severe eating disorder pathology.

The Spectrum Model: A More Coherent Approach to the Complexity of Psychiatric Symptomatology

The current tools used to define and diagnose mental disorders, including the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, have added specificity to the psychiatric nomenclature. However, their stereotypic rigidity in classification has resulted in the failure to identify the full range of potentially debilitating psychiatric symptoms with which patients may present. A spectrum model of psychopathology is more adept at recognizing the subclinical or threshold symptomatology that may occur concomitantly with core psychiatric disorders. The authors discuss the development of a spectrum approach to the diagnosis of mental disorders, which offers the potential to improve treatment selection and therapeutic outcomes .

Association Study of 182 Candidate Genes in Anorexia Nervosa

We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case–control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome‐Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing‐based rare variant discovery assays, and pathway‐based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.

Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates

To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR), and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum body mass index (BMI), concern over mistakes (CM), and food‐related obsessions (OBF) for covariate‐based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate‐based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate‐based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.

Symptom profile of major depressive disorder in women with eating disorders

Objective: Based on the well-documented association between eating disorders (EDs) and affective disorders, the patterns of comorbidity of EDs and major depressive disorder (MDD) were investigated. The temporal relation between EDs and MDD onset was analyzed to determine differences in the course and nature of MDD when experienced prior to versus after the onset of the ED. Method: Lifetime MDD and depressive symptoms were assessed in 1371 women with a history of ED. The prevalence of MDD was first explored across ED subtypes, and ages of onset of MDD and EDs were compared. Depressive symptoms were examined in individuals who developed MDD before and after ED onset. Results: The lifetime prevalence of MDD was 72.9%. Among those with lifetime MDD (n =963), 34.5% reported MDD onset before the onset of ED. Those who experienced MDD first reported greater psychomotor agitation (OR =1.53; 95%CI =1.14–2.06), and thoughts of own death (but not suicide attempts or ideation; OR =1.73; 95%CI =1.31–2.30). Among individuals who had MDD before ED, 26.5% had the MDD onset during the year before the onset of ED; 67% of individuals had the onset of both disorders within the same 3 year window. Conclusion: Clinicians treating individuals with new-onset ED or MDD should remain vigilant for the emergence of additional psychopathology, especially during the initial 3 year window following the onset of the first disorder.

Substance use disorders in women with anorexia nervosa.

OBJECTIVE We examined prevalence of substance use disorders (SUD) in women with: (1) anorexia nervosa (AN) restricting type (RAN); (2) AN with purging only (PAN); (3) AN with binge eating only (BAN); and (4) lifetime AN and bulimia nervosa (ANBN). Secondary analyses examined SUD related to lifetime purging behavior and lifetime binge eating. METHOD Participants (N = 731) were drawn from the International Price Foundation Genetic Studies. RESULTS The prevalence of SUD differed across AN subtypes, with more in the ANBN group reporting SUD than those in the RAN and PAN groups. Individuals who purged were more likely to report substance use than those who did not purge. Prevalence of SUD differed across lifetime binge eating status. DISCUSSION SUD are common in AN and are associated with bulimic symptomatology. Results underscore the heterogeneity in AN, highlighting the importance of screening for SUD across AN subtypes.

Investigation of the serotonin transporter regulatory region polymorphism in bulimia nervosa: relationships to harm avoidance, nutritional parameters, and psychiatric comorbidity.

Objective: Genes involved in 5HT transmission have been supposed to contribute to the biologic vulnerability for bulimia nervosa (BN). Because a long (L) and a short (S) variant of the promoter region of the 5HT transporter gene have been identified, we tested whether the 5HTT gene-linked polymorphic region (5HTTLPR) could represent a susceptibility factor for BN and/or could be related to nutritional parameters, harm avoidance personality dimension, and psychiatric comorbidity. Methods: A total of 219 white women (125 bulimics and 94 healthy control subjects) underwent a blood sample collection for 5HTTLPR genotyping and a clinical evaluation assessing comorbidity for axis I and II psychiatric disorders, harm avoidance personality dimension, and body composition (only patients). Results: The distribution of the 5HTTLPR genotypes did not significantly differ between patients and control subjects, although the L allele was significantly more frequent in the former. Bulimic individuals carrying at least one copy of the S allele had significantly lower mean body mass index and body fat mass values and significantly higher mean harm avoidance score than patients with the LL genotype. No significant association was found between the 5HTTLPR genotype and comorbid axis I and II psychiatric disorders. Conclusions: These findings support the view that polymorphic variants of the 5HTT promoter region do not play a part in predisposing to BN, whereas they seem to predispose bulimic individuals to nutritional impairment and increased harm avoidance. ANOVA = analysis of variance; BMI = body mass index; BW = body weight; BN = bulimia nervosa; MINI = Mini International Neuropsychiatric Interview; NS = not significant; 5HT = serotonin; 5HTT = serotonin transporter; 5HTTLPR = serotonin transporter length polymorphic region; SCID-IP = Structured Clinical Interview for DSM IV Axis I disorders–Patient Edition; SCID-II = Structured Clinical Interview for DSM IV Axis II personality disorders; TCI-R = Temperament and Character Inventory Revised.