Astrid Dempfle

Melanocortin-4 Receptor Gene Variant I103 Is Negatively Associated with Obesity

Several rare mutations in the melanocortin-4 receptor gene (MC4R) predispose to obesity. For the most common missense variant V103I (rs2229616), however, the previously reported similar carrier frequencies in obese and nonobese individuals are in line with in vitro studies, which have not shown a functional implication of this variant. In the present study, we initially performed a transmission/disequilibrium test on 520 trios with obesity, and we observed a lower transmission rate of the I103 allele (P=.017), which was an unexpected finding. Therefore, we initiated two large case-control studies (N=2,334 and N=661) and combined the data with those from 12 published studies, for a total of 7,713 individuals. The resulting meta-analysis provides evidence for a negative association of the I103 allele with obesity (odds ratio 0.69; 95% confidence interval 0.50-0.96; P=.03), mainly comprising samples of European origin. Additional screening of four other ethnic groups showed comparable I103 carrier frequencies well below 10%. Genomic sequencing of the MC4R gene revealed three polymorphisms in the noncoding region that displayed strong linkage disequilibrium with V103I. In our functional in vitro assays, the variant was indistinguishable from the wild-type allele, as was the result in previous studies. This report on an SNP/haplotype that is negatively associated with obesity expands the successful application of meta-analysis of modest effects in common diseases to a variant with a carrier frequency well below 10%. The respective protective effect against obesity implies that variation in the MC4R gene entails both loss and gain of function.

Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder

Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome‐wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome‐wide significant linkage (PSR = 0.00034, POR = 0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.

Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder

Panic disorder is a common anxiety disorder characterized by sudden and recurrent panic attacks. Previous studies have indicated significant genetic contributions and a susceptibility locus for panic disorder has been mapped to human chromosome 7p 15. The receptor for Neuropeptide S (NPS) is located in the same genomic region while NPS is known to produce arousal and anxiolytic-like effects in rodents. Here we report that a coding polymorphism in the Neuropeptide S receptor (NPSR) is associated with panic disorder in male patients of Japanese ancestry. The polymorphism (Asn(107)Ile) results in a gain-of-function of the receptor protein by increasing the agonist sensitivity about tenfold. The allele representing the less active isoform (NPSR Asn(107)) was found under-represented in male panic disorder patients, indicating a potential protective function of the protein. Two unrelated groups of patients diagnosed with schizophrenia or attention-deficit/hyperactivity disorder (ADHD) showed no association of particular NPSR alleles with the disorders. These results provide evidence for a gender-specific effect of NPSR in the pathogenesis of panic disorder.

Day-patient treatment after short inpatient care versus continued inpatient treatment in adolescents with anorexia nervosa (ANDI): a multicentre, randomised, open-label, non-inferiority trial

BACKGROUND In-patient treatment (IP) is the treatment setting of choice for moderately-to-severely ill adolescents with anorexia nervosa, but it is costly, and the risks of relapse and readmissions are high. Day patient treatment (DP) is less expensive and might avoid problems of relapse and readmission by easing the transition from hospital to home. We investigated the safety and efficacy of DP after short inpatient care compared with continued IP. METHODS For this multicentre, randomised, open-label, non-inferiority trial, we enrolled female patients (aged 11-18 years) with anorexia nervosa from six centres in Germany. Patients were eligible if they had a body-mass index (BMI) below the tenth percentile and it was their first admission to hospital for anorexia nervosa. We used a computer-generated randomisation sequence to randomly assign patients to continued IP or DP after 3 weeks of inpatient care (1:1; stratified for age and BMI at admission). The treatment programme and treatment intensity in both study groups were identical. The primary outcome was the increase in BMI between the time of admission and a 12-month follow-up adjusted for age and duration of illness (non-inferiority margin of 0·75 kg/m(2)). Analysis was done by modified intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number Register, number ISRCTN67783402, and the Deutsches Register Klinischer Studien, number DRKS00000101. FINDINGS Between Feb 2, 2007, to April 27, 2010, we screened 660 patients for eligibility, 172 of whom we randomly allocated to treatment: 85 to IP and 87 to DP. DP was non-inferior to IP with respect to the primary outcome, BMI at the 12-month follow-up (mean difference 0·46 kg/m(2) in favour of DP (95% CI, -0·11 to 1·02; pnon-inferiority<0·0001). The number of treatment-related serious adverse events was similar in both study groups (eight in the IP group, seven in the DP group). Three serious adverse events in the IP group and two in the DP group were related to suicidal ideation; one patient in the DP attempted suicide 3 months after she was discharged. INTERPRETATION DP after short inpatient care in adolescent patients with non-chronic anorexia nervosa seems no less effective than IP for weight restoration and maintenance during the first year after admission. Thus, DP might be a safe and less costly alternative to IP. Our results justify the broad implementation of this approach. FUNDING German Ministry for Education and Research.

Genetische Befunde bei der Aufmerksamkeitsdefizit- und Hyperaktivitätsstörung (ADHS)

Zusammenfassung: Die Aufmerksamkeitsdefizit- und Hyperaktivitatsstorung (ADHS) ist mit einer Pravalenz von 3-7% eine haufige kinder- und jugendpsychiatrische Storung. Auf der Basis formalgenetischer Studien ergibt sich eine Heritabilitatsschatzung von 60-80% fur ADHS mit einem ca. 5-fach erhohten Risiko fur erstgradige Verwandte von Betroffenen. Bislang vier Genomscans lieferten potentiell relevante chromosomale Regionen, insbesondere den einheitlichen Kopplungsbefund auf 5p13. Aus einer Vielzahl von Assoziationsstudien zu Kandidatengenen deuten aktuelle Metaanalysen auf die Relevanz der Gene der dopaminergen Rezeptoren DRD4 und DRD5 sowie des serotonergen Rezeptors HTR1B und des Synaptosomal Assoziierten Proteins (SNAP-25). In Tiermodellen liegen vorwiegend Paradigmen fur Hyperaktivitat vor; diese sind in knockout- und Quantitative Trait Loci (QTL) Designs mit viel versprechenden Ergebnissen zum dopaminergen System untersucht worden. Es ist davon auszugehen, dass erst das Zusammenwirken verschiedener Gen...

Weighting schemes in pooled linkage analysis.

To identify susceptibility gene regions for complex diseases a combined linkage analysis of several genome scans might give additional insights to individual studies. In this article we consider different weighting schemes to combine the score statistics of individual studies to an overall statistic within multipoint nonparametric linkage analysis by GENEHUNTER/ALLEGRO. With the Genetic Analysis Workshop (GAW) 12 asthma data sets the weights are dominated by the large differences in the relevant sample sizes.

Elevated growth differentiation factor 15 levels predict outcome in patients undergoing transcatheter aortic valve implantation

Transcatheter aortic valve implantation (TAVI) has emerged as a treatment of aortic stenosis in patients at high surgical risk. However, risk stratification in this elderly population is challenging, as patients at extreme risk might not benefit from TAVI. While several clinical criteria have been proposed for estimating the outcome, prediction of individual risk remains difficult. Therefore, our aim was to assess the prognostic value of the biomarker growth differentiation factor 15 (GDF15).

Confidence Intervals for Genotype Relative Risks and Allele Frequencies from the Case Parent Trio Design for Candidate-Gene Studies

Objectives: Confidence intervals for genotype relative risks, for allele frequencies and for the attributable risk in the case parent trio design for candidate-gene studiesare proposed which can be easily calculated from the observed familial genotype frequencies. Methods: Likelihood theory and the delta method were used to derive point estimates and confidence internals. We used Monte Carlo simulations to show the validity of the formulae for a variety of given modes of inheritance and allele frequencies and illustrated their usefulness by applying them to real data. Results: Generally these formulae were found to be valid for ‘sufficiently large’ sample sizes. For smaller sample sizes the estimators for genotype relative risks tended to be conservative whereas the estimator for attributable risk was found to be anti-conservative for moderate to high allele frequencies. Conclusions: Since the proposed formulae provide quantitative information on the individual and epidemiological relevance of a genetic variant they might be a useful addition to the traditional statistical significance level of TDT results.

Hypothalamic Inflammation in Human Obesity is Mediated by Environmental and Genetic Factors

Obesity is associated with hypothalamic inflammation (HI) in animal models. In the current study, we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched nonobese control subjects by MRI and analyzed the T2 hyperintensity as a measure of HI. Obese subjects exhibited T2 hyperintensity in the left but not the right MBH, which was strongly associated with systemic low-grade inflammation. MRS revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects, suggesting functional but not structural impairment due to the inflammatory process. To gain mechanistic insights, we performed nutritional analysis and 16S rDNA microbiome sequencing, which showed that high-fat diet induces reduction of Parasutterella sp. in the gut, which is significantly correlated with MBH T2 hyperintensity. In addition to these environmental factors, we found subjects carrying common polymorphisms in the JNK or the MC4R gene to be more susceptible to HI. Finally, in a subgroup analysis, bariatric surgery had no effect on MBH T2 hyperintensity despite inducing significant weight loss and improvement of peripheral insulin sensitivity. In conclusion, obesity in humans is associated with HI and disturbances in the gut-brain axis, which are influenced by both environmental and genetic factors.

Sex- and Subtype-Related Differences in the Comorbidity of Adult ADHDs

Objective: Comorbidity in adult ADHD (aADHD) has been investigated in a large number of studies using varying research approaches with divergent results. In contrast, there is limited information about sex- or subtype-related differences from studies with small sample size. Method: A large sample of 910 individuals (458 males, 452 females) affected with aADHD was recruited at a tertiary referral center. All probands underwent a four-step procedure for diagnosing aADHD, including the Structured Clinical Interview of Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) Axis I disorders to assess comorbidity. This study will provide additional information regarding the co-morbidity of Axis I disorders in the currently largest clinical referral sample. However, the main objective of this study is to gain information about sex- or subtype-related differences. Results: Affected females show higher rates of mood (61% vs. 49%), anxiety (32% vs. 22%), and eating disorders (16% vs. 1%) than affected males, while substance use disorders were more frequent in affected males (45% vs. 29%), which mirrors sex differences in prevalence in the general population. There were hardly any relevant differences in comorbidities between subtypes, with the exception of the inattentive subtype having an especially low prevalence of panic disorder. Comorbidity in general and substance use disorders in particular, but not sex or subtype, were highly predictive of lower psychosocial status. Conclusion: Sex-related differences in the comorbidity of aADHD are more pronounced than subtype-related differences.