Genomic Analysis of Polygenic Traits

Posthuma, D. [Promotor]Daly, M.J. [Copromotor]Neale, B.M. [Copromotor

Can attention to the intestinal microbiota improve understanding and treatment of anorexia nervosa?

Anorexia nervosa (AN) is characterized by severe dietary restriction or other weight loss behaviors and exhibits the highest mortality rate of any psychiatric disorder. Therapeutic renourishment in AN is founded primarily on clinical opinion and guidelines, with a weak evidence base. Genetic factors do not fully account for the etiology of AN, and non-genetic factors that contribute to the onset and persistence of this disease warrant investigation. Compelling evidence that the intestinal microbiota regulates adiposity and metabolism, and more recently, anxiety behavior, provides a strong rationale for exploring the role of this complex microbial community in the onset, maintenance of, and recovery from AN. This review explores the relationship between the intestinal microbiota and AN and a potential role for this enteric microbial community as a therapy for this severe illness

Eating Disorders and the Intestinal Microbiota: Mechanisms of Energy Homeostasis and Behavioral Influence

Purpose of Review: We reviewed and evaluated recently published scientific studies that explored the role of the intestinal microbiota in eating disorders. Recent Findings: Studies have demonstrated that the intestinal microbiota is a contributing factor to both host energy homeostasis and behavior—two traits commonly disrupted in patients with eating disorders. To date, intestinal microbiota research in eating disorders has focused solely on anorexia nervosa (AN). Initial studies have reported an atypical intestinal microbial composition in patients with AN compared to healthy controls. However, the impact of these AN-associated microbial communities on host metabolism and behavior remains unknown. Summary: The intriguing pattern of findings in patients with AN encourages further investigation of the intestinal microbiota in eating disorders. Elucidating the specific role(s) of these microbial communities may yield novel ideas for augmenting current clinical therapies to promote weight gain, decrease gastrointestinal distress, and even reduce psychological symptomatology

Prioritization of Genetic Variants in the microRNA Regulome as Functional Candidates in Genome-Wide Association Studies

Comprehensive analyses of results from genome-wide association studies (GWAS) have demonstrated that complex disease/trait-associated loci are enriched in gene regulatory regions of the genome. The search for causal regulatory variation has focused primarily on transcriptional elements, such as promoters and enhancers. microRNAs (miRNAs) are now widely appreciated as critical posttranscriptional regulators of gene expression and are thought to impart stability to biological systems. Naturally occurring genetic variation in the miRNA regulome is likely an important contributor to phenotypic variation in the human population. However, the extent to which polymorphic miRNA-mediated gene regulation underlies GWAS signals remains unclear. In this study, we have developed the most comprehensive bioinformatic analysis pipeline to date for cataloging and prioritizing variants in the miRNA regulome as functional candidates in GWAS. We highlight specific findings, including a variant in the promoter of the miRNA let-7 that may contribute to human height variation. We also provide a discussion of how our approach can be expanded in the future. Overall, we believe that the results of this study will be valuable for researchers interested in determining whether GWAS signals implicate the miRNA regulome in their disease/trait of interest

Lifetime anxiety disorders in women with bulimia nervosa

We examined the prevalence and ages at onset of additional childhood and adult psychiatric disorders in women with bulimia nervosa and evaluated the differential impact of a mood or anxiety disorder on the presentation of bulimia nervosa. One hundred fourteen women participating in a clinical trial of cognitivebehavioral therapy for bulimia nervosa were assessed at pretreatment with structured diagnostic methodology. Although mood disorders were the most frequently occurring additional psychiatric disorder (75%), 64% experienced an additional anxiety disorder. Age at onset of the anxiety disorders was markedly earlier than age at onset of bulimia nervosa or other comorbid conditions. Stratification of the sample on the presence of a mood or anxiety disorder revealed no differences in the core bulimic symptoms across groups. The presence of a mood disorder was associated with greater body dissatisfaction, lower Global Assessment of Functioning Scales (GAFS) score, more externalizing disorders of childhood, and, as expected, higher Hamilton Depression Rating Scale (HDRS) scores. The presence of an anxiety disorder was related to a history of anorexia nervosa and earlier age at onset of drug or alcohol dependence. Early-onset anxiety disorders are prevalent and may represent one potential pathway to bulimia nervosa

The Gut-Brain Axis in Healthy Females: Lack of Significant Association between Microbial Composition and Diversity with Psychiatric Measures

This study examined associations between the composition and diversity of the intestinal microbiota and measures of depression, anxiety, eating disorder psychopathology, stress, and personality in a group of healthy adult females

Daily Changes in Composition and Diversity of the Intestinal Microbiota in Patients with Anorexia Nervosa: A Series of Three Cases

Anorexia nervosa, a severe psychiatric illness, is associated with an intestinal microbial dysbiosis. Individual microbial signatures dominate in healthy samples, even over time and under controlled conditions, but whether microbial markers of the disorder overcome inter-individual variation during the acute stage of illness or renourishment is unknown. We characterized daily changes in the intestinal microbiota in three acutely ill patients with anorexia nervosa over the entire course of hospital-based renourishment and found significant, patient-specific changes in microbial composition and diversity. This preliminary case series suggests that even in a state of pathology, individual microbial signatures persist in accounting for the majority of intestinal microbial variation

Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa

OBJECTIVE: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. RESULTS: Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. CONCLUSIONS: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology