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Objective As a key player in modulating both human physiological and behavioural functions including anxiety, perception and in particular appetite, serotonin (5-hydroxytryptamine, 5-HT) is likely to be involved in the aetiology of eating disorders. Studies showing serotonin receptor type 3 (5-HT 3) receptors to mediate food intake depression (anorexic response) have triggered our interest in investigating the putative role of variants in the 5-HT 3 receptor genes, HTR3A and HTR3B, in the susceptibility to anorexia nervosa (AN) and bulimia nervosa (BN). Methods Two hundred and sixty-five patients with AN and 91 patients with BN as well as 191 healthy controls served as a pilot study group for mutational analysis by direct sequencing. Variants showing a significant association were subsequently genotyped in an independent Spanish cohort of 78 patients with AN and 119 patients with BN as well as 331 healthy controls for replication purposes. Results In the pilot study, we found the coding HTR3B variant, p.Y129S, (rs1176744, P= 0.004, odds ratio = 2.06) to be associated with the restrictive subtype of AN. The association was confirmed in the Spanish study group (P=0.034 , odds ratio=2.26). Conclusion Our study provides first evidence for an involvement of 5-HT 3 variants in the aetiopathology of eating disorders in humans.

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder among children and adolescents with high heritability. Molecular genetic findings support the thesis that dopaminergic, serotonergic, and noradrenergic neurotransmission pathways account for the etiology of this complex disease. Genetic research comprises formal genetic studies, candidate gene studies, linkage analyses, and recently large-scale genome wide association studies, gene-environement interaction studies, and pharmacogenetics. This article comprehensively reviews the latest findings on the genetics of ADHD.

Studies in rodent models demonstrated that the central cannabinoid receptor (Cnr1) mediates the orexigenic effects of cannabinoids. To analyze whether genetic variation in the cannabinoid receptor gene (CNR1) is implicated in human obesity, we initially genotyped 8 single nucleotide polymorphisms (SNPs) located in the 5' region (rs9353527, rs754387, rs6454676), intron 2 (rs806379, rs1535255), exon 3 (rs2023239), intron 3 (rs806370) and the coding region (rs1049353) in up to 364 German obesity trios (extremely obese child or adolescent and both parents). The transmission disequilibrium test (TDT) was negative for these SNPs (p>0.05). However, there was a slight trend towards preferential transmission of the A-allele of rs1049353 (p=0.12). We therefore genotyped this SNP in 235 independent German obesity families (at least two obese sibs and both parents) and in parallel screened the CNR1 coding region for sequence variations in 120 German extremely obese children and adolescents who mainly contributed to the initial trend observed for rs1049353. The trend for preferential transmission of the A-allele could not be substantiated (pedigree disequilibrium test, PDT p=0.15; A-allele less frequently transmitted). In the mutation screen we detected two rare variations, one novel non-conservative mutation (c.1256C>A; A419E) and the known variant 1419+1G>C. In addition, we confirmed the presence of rs1049353. As these variants could not explain the initial TDT, we conclude that there is no evidence for an association of CNR1 alleles with obesity in our study groups.

Zusammenfassung: Die Aufmerksamkeitsdefizit- und Hyperaktivitätsstörung (ADHS) ist mit einer Prävalenz von 3-7% eine häufige kinder- und jugendpsychiatrische Störung. Auf der Basis formalgenetischer Studien ergibt sich eine Heritabilitätsschätzung von 60-80% für ADHS mit einem ca. 5-fach erhöhten Risiko für 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 für Hyperaktivität 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-Varianten mit jeweils moderatem bis hin zu kleinem Effekt den Phänotyp ADHS bedingen (Oligo-/ Polygenie) und bei verschiedenen Betroffenen unterschiedliche Kombinationen von prädisponierenden Gen-Polymorphismen zu ADHS führen können. Entsprechend sind für molekulargenetische Studien große Fallzahlen notwendig und die bisherigen Befunde als vorläufig zu interpretieren. Zukunftsweisend für die molekulargenetische Aufklärung von ADHS sind SNP-basierte Genomscans, mit denen 10 000-1 000 000 einzelne Polymorphismen (SNPs) gleichzeitig untersucht werden können. Tiermodelle liefern Hinweise auf die Funktion relevanter Kandidatengene und tragen zur Erweiterung der bislang teilweise widersprüchlichen Kenntnisse zur Neurobiologie des ADHS bei.

Three groups have previously performed genome scans in attention-deficit/ hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent. © 2006 Nature Publishing Group All rights reserved.

GH secretagogue receptor (GHSR, ghrelin receptor) is involved in regulation of body weight and GH secretion. We initially analyzed two single-nucleotide polymorphisms of the GHSR in up to 184 extremely obese children and adolescents and up to 184 healthy underweight students. The frequency of the 171T allele of rs495225 was higher in our obese samples (75.0%) than in the underweight individuals (70.2%; nominal P = 0.14). This trend could not be substantiated in an additional association study in 270 obese and 145 underweight and normal weight individuals and in a transmission disequilibrium test based on 387 obesity trios (transmission rate of 171T, 51.8%; nominal P = 0.53). Additionally, the coding region of GHSR was systematically screened, and seven sequence variants were identified in 93 obese, 96 normal weight, and 94 underweight individuals and 43 children with short normal stature (SNS). Five silent single-nucleotide polymorphisms showed similar genotype frequencies in the different weight groups and SNS children (all nominal P > 0.3). Two novel missense variants were detected only in one obese carrier and one SNS child, respectively. In conclusion, we did not obtain conclusive evidence for an involvement of the ghrelin receptor gene in body weight regulation or SNS in our study groups.

Das Netzwerk “Adipositas und assoziierte Storungen”, das seit 2001 als Bestandteil des Nationalen Genomforschungsnetzes (NGFN) durch das Bundesministerium fur Bildung und Forschung gefordert wird, beschaftigt sich mit den genetischen Ursachen der Adipositas. Dabei sollen fur (extremes) Ubergewicht mitverantwortliche Gene identifiziert und klinisch, epidemiologisch und funktionell charakterisiert werden.

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood onset. Clinical and biological evidence points to shared common central nervous system (CNS) pathology of ADHD and restless legs syndrome (RLS). It was hypothesized that variants previously found to be associated with RLS in two large genome-wide association studies (GWA), will also be associated with ADHD. SNPs located in MEIS1 (rs2300478), BTBD9 (rs9296249, rs3923809, rs6923737), and MAP2K5 (rs12593813, rs4489954) as well as three SNPs tagging the identified haplotype in MEIS1 (rs6710341, rs12469063, rs4544423) were genotyped in a well characterized German sample of 224 families comprising one or more affected sibs (386 children) and both parents. We found no evidence for preferential transmission of the hypothesized variants to ADHD. Subsequent analyses elicited nominal significant association with haplotypes consisting of the three SNPs in BTBD9 (chi2 = 14.8, df = 7, nominal p = 0.039). According to exploratory post hoc analyses, the major contribution to this finding came from the A-A-A-haplotype with a haplotype-wise nominal p-value of 0.009. However, this result did not withstand correction for multiple testing. In view of our results, RLS risk alleles may have a lower effect on ADHD than on RLS or may not be involved in ADHD. The negative findings may additionally result from genetic heterogeneity of ADHD, i.e. risk alleles for RLS may only be relevant for certain subtypes of ADHD. Genes relevant to RLS remain interesting candidates for ADHD; particularly BTBD9 needs further study, as it has been related to iron storage, a potential pathophysiological link between RLS and certain subtypes of ADHD.

Background A recent genome-wide association (GWA) study of U.S. Caucasians suggested that eight single nucleotide polymorphisms (SNPs) in CTNNBL1 are associated with obesity and increased fat mass. We analysed the respective SNPs in data from our previously published GWA for early onset obesity (case-control design), in GWA data from a population-based cohort of adults, and in an independent family-based obesity study. We investigated whether variants in CTNNBL1 (including rs6013029) and in three other genes (SH3PXD2B, SLIT3 and FLJ42133,) were associated with obesity. Methods The GWA studies were carried out using Affymetrix® SNP Chips with approximately 500,000 markers each. In the families, SNP rs6013029 was genotyped using the TaqMan® allelic discrimination assay. The German case-control GWA included 487 extremely obese children and adolescents and 442 healthy lean individuals. The adult GWA included 1,644 individuals from a German population-based study (KORA). The 775 independent German families consisted of extremely obese children and adolescents and their parents. Results We found no evidence for an association of the reported variants in CTNNBL1 with early onset obesity or increased BMI. Further, in our family-based study we found no evidence for over-transmission of the rs6013029 risk-allele T to obese children. Additionally, we found no evidence for an association of SH3PXD2B, SLIT3 and FLJ42133 variants in our two GWA samples. Conclusion We detected no confirmation of the recent association of variants in CTNNBL1 with obesity in a population of Central European ancestry.

Because information on weight changes after lifestyle intervention in children with mutations in the melanocortin 4 receptor (MC4R) gene is scarce, we compared weight changes after lifestyle intervention between children with and without MC4R variations. A group of 514 overweight children (aged 5–16 years), who presented to participate in a 1-year lifestyle intervention based on exercise, behavior, and nutrition therapy were screened for MC4R mutations. For comparison, children with MC4R mutations leading to reduced receptor function (group A) were each of them randomly matched with five children of same age and gender without MC4R mutations (group B). Changes of weight status were analyzed as change of BMI standard deviation scores (BMI-SDSs). Furthermore, 16 children (3.1%) harbored MC4R mutations leading to reduced receptor function, and 17 (3.3%) children carried variations not leading to reduced receptor function. Children with and without MC4R mutations reduced their overweight at the end of intervention to a similar degree (P = 0.318 between groups based on an intention-to-treat analysis). The maintenance of weight loss after intervention among children with MC4R mutations leading to reduced receptor function failed in contrast to children without such mutations (P < 0.001 adjusted for BMI-SDS at baseline, age, and gender in an intention-to-treat analysis). In conclusion, children with MC4R mutations leading to reduced receptor function were able to lose weight in a lifestyle intervention but had much greater difficulties to maintain this weight loss supporting the impact of these mutations on weight status.

Objective: The T allele of the single-nucleotide polymorphism rs7903146 in TCF7L2 (transcription factor 7 like 2 gene) is associated with type 2 diabetes mellitus. The aim of this study was to analyze whether there is an allele-dosage effect on changes of insulin resistance and sensitivity indices in overweight children participating in a lifestyle intervention. Methods: We genotyped rs7903146 in 236 overweight children (mean age 10.7 years, mean body mass index (BMI) 28.1 kg/m²) completing a 1-year lifestyle intervention. Degree of overweight as BMI-SDS, homeostasis model assessment for insulin resistance (HOMA-IR) and the insulin sensitivity index QUICKI were measured before and after intervention. Results: Lifestyle intervention resulted in an overweight reduction of -0.29±0.02 BMI-SDS. HOMA-IR (-0.63±0.22) and QUICKI (+0.008±0.003) indices improved significantly (P

Background. Obesity is a major health problem. Although heritability is substantial, genetic mechanisms predisposing to obesity are not very well understood. We have performed a genome wide association study (GWA) for early onset (extreme) obesity. Methodology/Principal Findings. a) GWA (Genome-Wide Human SNP Array 5.0 comprising 440,794 single nucleotide polymorphisms) for early onset extreme obesity based on 487 extremely obese young German individuals and 442 healthy lean German controls; b) confirmatory analyses on 644 independent families with at least one obese offspring and both parents. We aimed to identify and subsequently confirm the 15 SNPs (minor allele frequency ≥ 10%) with the lowest p-values of the GWA by four genetic models: additive, recessive, dominant and allelic. Six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) within one linkage disequilibrium (LD) block including the GWA SNP rendering the lowest p-value (rs1121980; log-additive model: nominal p=1.13×10⁻⁷, corrected p=0.0494; odds ratio (OR)CT 1.67, 95% confidence interval (Cl) 1.22-2.27; ORTT 2.76, 95% Cl 1.88-4.03) belonged to the 15 SNPs showing the strongest evidence for association with obesity. For confirmation we genotyped 11 of these in the 644 independent families (of the six FTO SNPs we chose only two representing the LD bock). For both FTO SNPs the initial association was confirmed (both Bonferroni corrected p

Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5' region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable common neurodevelopmental disorder with onset in childhood. A coding SNP (rs6265, Val66Met) of the brain-derived neurotrophic factor gene (BDNF) has recently been associated with ADHD. More specifically, paternal over-transmission of the common Val66 allele to affected children had been observed. We aimed to confirm these findings in a large, sufficiently powered, and well characterized German ADHD family sample. The Val66Met polymorphism of BDNF was genotyped in 294 families comprising one or more affected sibs (468 children). Contrary to previous reports, we did not observe over-transmission of the common Val66 allele, from either parent to affected children. We did not find support for an involvement of the Val66 allele of the Val66Met polymorphism of BDNF in the pathogenesis of ADHD in our sample.

Attention-Deficit and Hyperactivity Disorder (ADHD) is a common child and adolescent psychiatric disorder with a prevalence rate of 3-7%. Formal genetic studies provided an estimated heritability of 0.6-0.8 and an approximately five-fold elevated risk for ADHD in first-degree relatives. Currently, four genome scans have led to the identification of chromosomal regions potentially relevant in ADHD; especially the evidence for linkage to chromosome 5p13 is convincing. Meta-analyses of a large number of candidate gene studies suggest association with gene variants of the dopaminergic receptors DRD4 and DRD5, the serotonergic receptor HTR1B, and the synaptosomal receptor protein (SNAP-25). Hyperactivity has been investigated particularly in animal models, focusing on knockout- and quantitative trait loci (QTL) designs, with promising results for the dopaminergic system. It is likely that several gene polymorphisms with moderate to small effect sizes contribute to the phenotype ADHD; different combinations of such predisposing variants presumably underlie ADHD in different individuals. Therefore, large samples for molecular genetic studies are mandatory to detect these polymorphisms. Accordingly, several of today's findings have to be regarded as preliminary. The understanding of ADHD's neurobiology may be advanced by new technologies, such as SNP-based genome scans performed with gene chips comprising 10,000-1,000,000 SNPs, as well as using more sophisticated animal model designs.

Alterations in the serotonergic pathway have been implicated in the pathogenesis of attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate seven genetic variants in three genes (serotonin transporter (5-HTT), serotonin receptor 1B (5-HTR1B) and serotonin receptor 2A (5-HTR2A)), which have previously been shown to be associated with ADHD. The polymorphisms under investigation were the 5-HTTLPR, the VNTR in intron 2 and the 3'UTR SNP in 5-HTT, the 5-HTR1B variations 861G>C and 102T>C, and the 5-HTR2A variations His452Tyr and 1438G>A. We genotyped these variants in a sample of 102 families with 229 children with ADHD according to DSM-IV criteria. Among the affected children, 69% fulfilled criteria for the combined type, 27% for the predominantly inattentive type, and 4% for the predominantly hyperactive-impulsive type. Associations were tested by the pedigree transmission disequilibrium test (PDT). All investigated polymorphisms in serotonergic candidate genes showed no association to ADHD in our sample. Earlier studies of these polymorphisms had also shown inconsistent results, with some studies reporting significant associations and others demonstrating no association. This discordance between studies may reflect variation in patient ascertainment criteria, genetic heterogeneity, too low statistical power for the expected effects or false positive results in the initial reports. We cannot rule out the possibility that other variations in the investigated genes contribute to the etiology of ADHD.

Stature is a highly heritable trait under both polygenic and major gene control. We aimed to identify genetic regions linked to idiopathic short stature (ISS) in childhood, through a whole genome scan in 92 families each with two affected children with ISS, including constitutional delay of growth and puberty and familial short stature. Linkage analysis was performed for ISS, height and bone age retardation. Chromosome 12q11 showed significant evidence of linkage to ISS and height (maximum non-parametric multipoint LOD scores 3.18 and 2.31 at 55-58 cM, between D12S1301 and D12S1048), especially in sister-sister pairs (LOD score of 1.9 for ISS in 22 pairs). These traits were also linked to chromosomes 1q12 and 2q36. The region on chromosome 12q11 had previously shown significant linkage to adult stature in several genome scans and harbors the vitamin D receptor gene, which has been associated with variation in height. A single nucleotide polymorphism (SNP) (rs10735810, FokI), which leads to a functionally relevant alteration at the protein level, showed preferential transmission of the transcriptionally more active G-allele to affected children (P=0.04) and seems to be responsible for the observed linkage (P=0.05, GIST test). Bone age retardation showed moderate linkage to chromosomes 19p11-q11 and 7p14 (LOD scores 1.69 at 57 cM and 1.42 at 50 cM), but there was no clear overlap with linkage regions for stature. In conclusion, we identified significant linkage, which might be due to a functional SNP in the vitamin D receptor (VDR) gene and could be responsible for up to 34% of ISS cases in the population.

Objective: The purpose of this study was to assess heritability of activity, attention, and impulsivity by comparing young monozygotic (MZ) twins with dizygotic (DZ) twins using objective measures. Method: The OPTAx test is an infrared motion analysis to record the movement pattern during a continuous performance test. Seventeen MZ and 12 same sexed DZ twin pairs in the range of 6 to 12 years were tested. The zygosity was determined by DNA-fingerprinting. The measures under investigation were activity (microevents and spatial scaling), impulsivity (errors of commission), and attention (accuracy and variability). For statistical analyses, the classical model of Falconer and the ACE and ADE genetic model for twin data were applied in order to estimate the proportion of the variance in activity, impulsivity and attention that is due to genetic effects. Results: The respective coefficients of intraclass correlations in MZ twins ranged between .35 and .65 whereas for DZ twins the correlations were between .12 and .88. The heritability estimates resulting from both models were about 30% for 4 of the 5 measures, but none of these was significantly different from 0. Conclusion: We found no significant influence of genetic factors for activity, attention, and impulsivity. The authors conclude that further investigation of heritability of ADHD is necessary using larger sample sizes and objective measures.

Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf+/−) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.−46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.−46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html. © 2004 Wiley-Liss, Inc.

Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder in childhood with substantial heritability. Pharmacological and molecular genetic studies as well as characterization of animal models have implicated serotonergic dysfunction in the pathophysiology of ADHD. Here, we investigated the effect of polymorphic variants in the gene of the tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in children and adolescents with ADHD. We analyzed three single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of the TPH2 gene in 103 families with 225 affected children. Allelic association in families with more than one affected child was assessed using the pedigree disequilibrium test. Preferential transmissions were detected for the two SNPs in TPH2's regulatory region (rs4570625, P = 0.049; rs11178997, P = 0.034), but not for the third SNP in intron 2 (rs4565946, P = 0.3517). Haplotype analysis revealed a strong trend of association between the regulatory region SNPs (rs4570625, rs11178997) and ADHD (P = 0.064). Our results link potentially functional TPH2 variations to the pathophysiology of ADHD, and further support the relevance of 5-HT in disorders related to altered motor activity and cognitive processes. © 2005 Nature Publishing Group All rights reserved.

Two genome wide scans, one of which was subsequently extended, have led to the identification of different chromosomal regions assumed to harbour genes underlying attention-deficit/hyperactivity disorder (ADHD). Some of these regions were also identified in patients with autism and/or dyslexia. The only region for which both studies detected a LOD score >1 was on chr 5p13 which is in the vicinity of the location of the candidate gene DAT1. The candidate gene approach has revealed the most robust and replicated findings for DRD4, DRD5, and DAT1 polymorphisms. Meanwhile interesting endophenotype studies have also been conducted suggesting a genetic basis for different diagnostic and therapeutic criteria. Animal studies for ADHD have investigated especially hyperactivity and have focused mainly on knockout and QTL designs. In knockout mice models the most promising results were obtained for genes of the dopaminergic pathway. QTL results in rodents suggest multiple loci underlying different forms of natural and induced hyperactivity. The molecular results mentioned above are presented and discussed in detail, thus providing both clinicians and geneticists with an overview of the current research status of this important child and adolescent psychiatric disorder.

Eating disorders such as anorexia nervosa and bulimia nervosa involve complex and interacting mechanisms. Formal genetic studies suggest that there is a substantial genetic influence for these disorders. Animal models of eating disorders are scarce. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Most of the studies, including meta-analysis, have yielded negative results; only a single positive finding has been replicated independently. Recently, systematic genome-wide scans based on families with two or more individuals with an eating disorder (anorexia nervosa or bulimia nervosa) revealed initial linkage regions on chromosomes 1, 3, and 4 (anorexia nervosa) and 10p (bulimia nervosa). Fine mapping of one of these regions led to the identification of genes where an association with anorexia nervosa was detected. Currently treatment of patients with eating disorders can not rely on results of molecular genetic studies.

Within the past decade the molecular basis of single forms of monogenic obesity has been elucidated. With the exception of functionally relevant mutations in the melanocortin-4 receptor gene, which occur in approximately 2-4% of extremely obese individuals, all other currently known monogenic forms are rare and additionally associated with distinct endocrinological abnormalities. A large number of association studies have been performed in 'normal' obesity. Whereas many associations have been reported, it is largely unclear which of these represent true positive findings. Over 20 genome scans pertaining to obesity and related phenotypes have been performed; specific chromosomal peak regions have been identified in different scans. We review the current status and discuss relevant issues related to phenotyping, association and linkage studies. We recommend that the procedure via which a consensus is reached as to what constitutes a true positive association finding requires formalization.

Objective. Several genome scans have been performed for adult obesity. Because single formal genetic studies suggest a higher heritability of body weight in adolescence and because genes that influence body weight in adulthood might not be the same as those that are relevant in childhood and adolescence, we performed a whole genome scan. Methods. The genome scan was based on 89 families with 2 or more obese children (sample 1). The mean age of the index patients was 13.63 ± 2.75 years. A total of 369 individuals were initially genotyped for 437 microsatellite markers. A second sample of 76 families was genotyped using microsatellite markers that localize to regions for which maximum likelihood binomial logarithm of the odd (MLB LOD) scores on use of the concordant sibling pair approach exceeded 0.7 in sample 1. Results. The regions with MLB LOD scores >0.7 were on chromosomes 1p32.3-p33, 2q37.1-q37.3, 4q21, 8p22, 9p21.3, 10p11.23, 11q11-q13.1, 14q24-ter, and 19p13-q12 in sample 1; MLB LOD scores on chromosomes 8p and 19q exceeded 1.5. In sample 2, MLB LOD scores of 0.68 and 0.71 were observed for chromosomes 10p11.23 and 11q13, respectively. Conclusion. We consider that several of the peaks identified in other scans also gave a signal in this scan as promising for ongoing pursuits to identify relevant genes. The genetic basis of childhood and adolescent obesity might not differ that much from adult obesity.

The human insulin-responsive glucose transporter 4 gene (GLUT4) has been related to non-insulin-dependent diabetes mellitus (NIDDM) in several studies. Obesity is commonly found in patients with NIDDM. Hence, genes involved in NIDDM might also be relevant for obesity. We have analyzed 212 extremely obese children and adolescents, 82 normal-weight students, and 94 underweight students for two single nucleotide polymorphisms (SNPs: promoter −30G/A; exon 4a: silent 2061T/C) in the vicinity of the GLUT4 by polymerase chain reaction with subsequent restriction fragment length polymorphism analyses (PCR-RFLP) or single-strand conformation polymorphism analyses (SSCP). Allele and genotype distributions were similar in all study groups (all p values > 0.05). Hence, we did not detect association of any of the analyzed SNP alleles in the GLUT4 to different weight extremes, so these seem not to be involved in weight regulation in our study groups.

Die Aufmerksamkeitsdefizit-Hyperaktivitatsstorung (ADHS) ist die haufigste psychiatrische Storung bei Kindern und Jugendlichen. Wissenschaftler des Nationalen Genomforschungsnetzes (NGFN) haben drei genetische Varianten identifiziert, die an der Entwicklung der ADHS beteiligt sind. Diese Veranderungen befinden sich in dem Gen, das fur den Transporter des Botenstoffs Dopamin codiert.

Studies on neural and behavioral correlates of the serotonin transporter gene polymorphism (5-HTTLPR) strongly suggested interaction effects between the 5-HTTLPR genotype and environmental conditions on infant emotionality development. However, empirical studies that involve human infants are rare. The present study thus analyzed the interaction of the 5-HTTLPR genotype with the quality of maternal parenting behavior on the development of negative emotionality and fear in infancy. In a sample of 69 healthy firstborn infants, negative emotionality and fear were assessed at 4, 8, and 12 months using a multi-method approach. The quality of previous parenting has been operationalized as the quality of the mother-infant attachment relationship measured by the strange situation procedure at 18 months. Corresponding to hypotheses, to their caregiver insecurely attached infants who were homozygous for the s-variant of the 5-HTTLPR genotype developed a high level of negative emotionality and fear. The results thus are in line with the experimental results in the non-human primate model and point to a more pronounced susceptibility of s/s carrying infants to early rearing experiences.

Background DGAT2 is a promising candidate gene for obesity because of its function as a key enzyme in fat metabolism and because of its localization on chromosome 11q13, a linkage region for extreme early onset obesity detected in our sample. We performed a mutation screen in 93 extremely obese children and adolescents and 94 healthy underweight controls. Association studies were performed in samples of up to 361 extremely obese children and adolescents and 445 healthy underweight and normal weight controls. Additionally, we tested for linkage and performed family based association studies at four common variants in the 165 families of our initial genome scan. Results The mutation screen revealed 15 DNA variants, four of which were coding non-synonymous exchanges: p.Val82Ala, p.Arg297Gln, p.Gly318Ser and p.Leu385Val. Ten variants were synonymous: c.-9447A > G, c.-584C > G, c.-140C > T, c.-30C > T, IVS2-3C > G, c.812A > G, c.920T > C, IVS7+23C > T, IVS7+73C > T and *22C > T. Additionally, the small biallelic trinucleotide repeat rs3841596 was identified. None of the case control and family based association studies showed an association of investigated variants or haplotypes in the genomic region of DGAT2. Conclusion In conclusion, our results do not support the hypothesis of an important role of common genetic variation in DGAT2 for the development of obesity in our sample. Anyhow, if there is an influence of genetic variation in DGAT2 on body weight regulation, it might either be conferred by the less common variants (MAF < 0.1) or the detected, rare non-synonymous variants.