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Highlights d Three groups of highly genetically-related disorders among 8 psychiatric disorders d Identified 109 pleiotropic loci affecting more than one disorder d Pleiotropic genes show heightened expression beginning in 2 nd prenatal trimester d Pleiotropic genes play prominent roles in neurodevelopmental processes Authors Cross-Disorder Group of the Psychiatric Genomics Consortium

Objective To conduct a genome-wide association study (GWAS) of anorexia nervosa and to calculate genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method Following uniform quality control and imputation using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, we performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression (LDSC) was used to calculate genome-wide common variant heritability [ hSNP2, partitioned heritability, and genetic correlations (rg)] between anorexia nervosa and other phenotypes. Results Results were obtained for 10,641,224 single nucleotide polymorphisms (SNPs) and insertion-deletion variants with minor allele frequency > 1% and imputation quality scores > 0.6. The hSNP2 of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. We identified one genome-wide significant locus on chromosome 12 (rs4622308, p=4.3×10−9) 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 (HDL) cholesterol, and significant negative genetic correlations between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Conclusions Anorexia nervosa is a complex heritable phenotype for which we have found the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. Our results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

"Food addiction" has become a focus of interest for researchers attempting to explain certain processes and/or behaviors that may contribute to the development of obesity. Although the scientific discussion on "food addiction" is in its nascent stage, it has potentially important implications for treatment and prevention strategies. As such, it is important to critically reflect on the appropriateness of the term "food addiction", which combines the concepts of "substance-based" and behavioral addiction. The currently available evidence for a substance-based food addiction is poor, partly because systematic clinical and translational studies are still at an early stage. We do however view both animal and existing human data as consistent with the existence of addictive eating behavior. Accordingly, we stress that similar to other behaviors eating can become an addiction in thus predisposed individuals under specific environmental circumstances. Here, we introduce current diagnostic and neurobiological concepts of substance-related and non-substance-related addictive disorders, and highlight the similarities and dissimilarities between addiction and overeating. We conclude that "food addiction" is a misnomer because of the ambiguous connotation of a substance-related phenomenon. We instead propose the term "eating addiction" to underscore the behavioral addiction to eating; future research should attempt to define the diagnostic criteria for an eating addiction, for which DSM-5 now offers an umbrella via the introduction on Non-Substance-Related Disorders within the category Substance-Related and Addictive Disorders.

Surface metallization by plasma coating enhances desorption/ionization of membrane components such as lipids and sterols in imaging time-of-flight secondary ion mass spectrometry (TOF-SIMS) of tissues and cells. High-resolution images of cholesterol and other membrane components were obtained for neuroblastoma cells and revealed subcellular details (resolving power 1.5 µm). Alternatively, in matrix-enhanced SIMS, 2,5-dihydroxybenzoic acid electrosprayed on neuroblastoma cells allowed intact molecular ion imaging of phosphatidylcholine and sphingomyelin at the cellular level. Gold deposition on top of matrix-coated rat brain tissue sections strongly enhanced image quality and signal intensity in stigmatic matrixassisted laser desorption/ionization imaging mass spectrometry. High-quality total ion count images were acquired, and the neuropeptide vasopressin was localized in the rat brain tissue section at the hypothalamic area around the third ventricle. Although the mechanism of signal enhancement by gold deposition is under debate, the results we have obtained for cells and tissue sections illustrate the potential of this sample preparation technique for biomolecular surface imaging by mass spectrometry.Unraveling the spatial distribution of cellular membrane components is an important research topic in current molecular cell biology. Understanding the behavior and function of the major constituents of these membranes, i.e., lipids and sterols, has been hampered by methodological limitations, despite their relatively simple structures. Most of the current knowledge on lipid localization has been obtained using fluorescence imaging techniques.

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 2,907 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 datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 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 to 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 that 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.

We confirmed some of the findings for the newly identified obesity loci that are associated with general adiposity in a healthy Dutch female population. Our results suggest that these loci are not specifically associated with abdominal adiposity but more generally with obesity. We also found that some of the SNPs were associated with macronutrient-specific food intake.

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