Genetic influences on disordered eating behaviour are largely independent of body mass index.

Objective: Prior studies suggest eating disorders and related characteristics are moderately to substantially heritable. We are interested in identifying the genes underlying disordered eating behaviour (DEB), and want to know how much of the genetic influence underlying DEB is attributable to genetic influences on body mass index (BMI). Method: Bivariate analyses were performed, in adolescent twins and siblings, to estimate the genetic and environmental contributions for DEB, BMI, and their overlap. Results: Shared genetic risk factors explained the overlap between BMI and DEB (genetic correlation was 0.43 in women, 0.51 in men). DEB was highly heritable in women (

Sex Differences in Sum Scores May Be Hard to Interpret: The Importance of Measurement Invariance

In most assessment instruments, distinct items are designed to measure a trait, and the sum score of these items serves as an approximation of an individual’s trait score. In interpreting group differences with respect to sum scores, the instrument should measure the same underlying trait across groups (e.g., male/female, young/old). Differences with respect to the sum score should accurately reflect differences in the latent trait of interest. A necessary condition for this is that the instrument is measurement invariant. In the current study, the authors illustrate a stepwise approach for testing measurement invariance with respect to sex in a four-item instrument designed to assess disordered eating behavior in a large epidemiological sample (1,195 men and 1,507 women). This approach can be applied to other phenotypes for which group differences are expected. Any analysis of such variables may be subject to measurement bias if a lack of measurement invariance between grouping variables goes undetected

Sex Differences in Sum Scores May Be Hard to Interpret: The Importance of Measurement Invariance

Abstract In most assessment instruments, distinct items are designed to measure a trait, and the sum score of these items serves as an approximation of an individual's trait score. In interpreting group differences with respect to sum scores, the instrument should measure the same underlying trait across groups (e.g., male/female, young/old). Differences with respect to the sum score should accurately reflect differences in the latent trait of interest. A necessary condition for this is that the instrument is measurement invariant. In the current study, the authors illustrate a stepwise approach for testing measurement invariance with respect to sex in a four-item instrument designed to assess disordered eating behavior in a large epidemiological sample (1,195 men and 1,507 women). This approach can be applied to other phenotypes for which group differences are expected. Any analysis of such variables may be subject to measurement bias if a lack of measurement invariance between grouping variables goes undetected

Characterization of the PLP-dependent decarboxylases GADL1 and CSAD

Pyridoxal 5’-phosphate (PLP) -dependent enzymes constitute an essential superfamily of enzymes for all living organisms. Due to the chemistry of their cofactor, PLP, these enzymes catalyze a wide variety of reactions. PLP-dependent decarboxylases (PLPDCs) play key roles in amino acid metabolism and are considered important biocatalysts for the pharmaceutical and chemical industries. In this project, we focused on the recently discovered enzyme glutamate decarboxylase-like 1 (GADL1) and its homolog, cysteine sulfinic acid (CSA) decarboxylase (CSAD). We investigated the expression pattern as well as the structural and biochemical features of both GADL1 and CSAD. Furthermore, we studied the physiological role of GADL1 by developing the first knockout mouse model for this enzyme. In addition, we reported crystal structures of mouse GADL1 (MmGADL1) and CSAD (MmCSAD). We found that GADL1 decarboxylates aspartate (Asp) to β-alanine, and consequently, it plays a role in the production of carnosine. Both carnosine and β-alanine are pH buffers, metal chelators, and have antioxidants effects. In addition to β-alanine, we observed that GADL1 decarboxylases CSA to hypotaurine, which leads to the production of taurine, one of the most abundant free amino acids in mammals. Taurine also functions as an antioxidant, membrane stabilizer, and neurotransmitter in the central nervous system (CNS). Similarly, CSAD decarboxylates CSA to hypotaurine and has a higher affinity to CSA than GADL1. The tissue distribution of the two enzymes was investigated, and it was found that in humans, both GADL1 and CSAD are expressed in the brain, whereas only CSAD is found in the liver. In mice, both enzymes are expressed in the brain, olfactory bulb (OB), and skeletal muscle (SKM). In the kidney, GADL1 has lower expression than CSAD and in the liver, only the expression of CSAD was found. To find the physiological role of GADL1 we generated Gadl1−/− mice. These mice were deficient in β-alanine, carnosine, and anserine, particularly in the OB, brain, and SKM, indicating a role for GADL1 in carnosine dipeptide production. Furthermore, Gadl1−/− mice had increased levels of oxidative stress markers, indicating the importance of carnosine as a cellular antioxidant. In addition, in different behavioral examinations, Gadl1−/−, mice showed a slightly decreased level of anxiety. Human genetic studies show a strong association of the GADL1 locus with plasma levels of carnosine, subjective well-being, kidney function, and muscle strength. In addition, investigating the GADL1 active site indicates that the enzyme may have multiple physiological substrates in vivo, including Asp and CSA. Structural studies on MmGADL1 and MmCSAD in this project showed that the overall fold and the conformation of the bound PLP are similar to other PLP-DCs. Both GADL1 and CSAD showed a more loose conformation in solution than in the crystal state, with open/close motions. In addition, in the MmCSAD structure, phenylalanine94 plays a critical role in substrate binding, and its mutation to serine changed MmCSAD affinity towards both CSA and Asp and also affected enzyme stability. The structural studies of MmGADL1 and MmCSAD provided details on substrate recognition in the PLP-DC family. These results are useful for future studies in structure-based inhibitor design and drug discovery. In conclusion, in this project, the biochemical and physiological roles of CSAD and a novel PLP-DC, GADL1, were investigated. This study also introduces Gadl1 knockout mice as a multi-aspect model to investigate carnosine biology. Using a structural approach, new information was revealed about the structure and features of both MmGADL1 and MmCSAD.Doktorgradsavhandlin

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

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\u2009860 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\u2009080 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 7 10-7) in SOX2OT and rs17030795 (P=5.84 7 10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 7 10-6) between CUL3 and FAM124B and rs1886797 (P=8.05 7 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 7 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