Epigenetic alterations in patients with anorexia nervosa-a systematic review.

Anorexia nervosa (AN) is a complex metabolic and psychological disorder that is influenced by both heritable genetic components and environmental factors. Exposure to various environmental influences can lead to epigenetically induced changes in gene expression. Epigenetic research in AN is still in its infancy, and studies to date are limited in determining clear, valid links to disease onset and progression are limited. Therefore, the aim of this systematic review was to compile and critically evaluate the available results of epigenetic studies specifically in AN and to provide recommendations for future studies. In accordance with the PRISMA guidelines, a systematic literature search was performed in three different databases (PubMed, Embase, and Web of Science) through May 2023. Twenty-three original papers or conference abstracts on epigenetic studies in AN were collected. Epigenome-wide association studies (EWASs), which analyze DNA methylation across the genome in patients with AN and identify potential disease-relevant changes in promoter/regulatory regions of genes, are the most promising for future research. To date, five EWASs on AN have been published, suggesting a potential reversibility of malnutrition-induced epigenetic changes once patients recover. Hence, determining differential DNA methylation levels could serve as a biomarker for disease status or early diagnosis and might be involved in disease progression or chronification. For future research, EWASs with a larger sample size, longitudinal study design and uniform methods should be performed to contribute to the understanding of the pathophysiology of AN, the development of individual interventions and a better prognosis for affected patients.

Detailed stratified GWAS analysis for severe COVID-19 in four European populations.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

No relationship between male pubertal timing and depression - new insights from epidemiology and Mendelian randomization.

BACKGROUND: In males, the relationship between pubertal timing and depression is understudied and less consistent than in females, likely for reasons of unmeasured confounding. To clarify this relationship, a combined epidemiological and genetic approach was chosen to exploit the methodological advantages of both approaches. METHODS: Data from 2026 males from a nationwide, representative study were used to investigate the non-/linear relationship between pubertal timing defined by the age at voice break and depression, considering a multitude of potential confounders and their interactions with pubertal timing. This analysis was complemented by Mendelian randomization (MR), which is robust to inferential problems inherent to epidemiological studies. We used 71 single nucleotide polymorphisms related to pubertal timing in males as instrumental variable to clarify its causal relationship with depression based on data from 807 553 individuals (246 363 cases and 561 190 controls) by univariable and multivariable MR, including BMI as pleiotropic phenotype. RESULTS: Univariable MR indicated a causal effect of pubertal timing on depression risk (inverse-variance weighted: OR 0.93, 95%-CI [0.87-0.99)], p = 0.03). However, this was not confirmed by multivariable MR (inverse-variance weighted: OR 0.95, 95%-CI [0.88-1.02)], p = 0.13), consistent with the epidemiological approach (OR 1.01, 95%-CI [0.81-1.26], p = 0.93). Instead, the multivariable MR study indicated a causal relationship of BMI with depression by two of three methods. CONCLUSIONS: Pubertal timing is not related to MDD risk in males.

What Amount of Weight Loss Can Entail Anorexia Nervosa or Atypical Anorexia Nervosa After Bariatric Surgery?

OBJECTIVE: Post-operative development of restrictive eating disorders can occur in patients after bariatric surgery. In children and adolescents with anorexia nervosa (AN) or atypical AN, premorbid body mass index (BMI) has recently been shown to predict total weight loss. We hypothesized that pre-operative BMI similarly predicts weight loss and the development of a restrictive eating disorder in adult bariatric patients. METHOD: A PubMed search identified case studies/series of 29 adult females who developed AN or atypical AN/eating disorder not otherwise specified following bariatric surgery. Non-parametric Spearman's correlation (rs) between pre-operative BMI and total weight loss was calculated; a scatterplot was used to illustrate the relationship between pre-operative/premorbid BMI and weight loss in kg for 29 bariatric patients and 460 children and adolescents with AN or atypical AN as published previously. RESULTS: The correlation between pre-operative BMI and weight loss among bariatric patients was rs = 0.65 (p = 0.0001). Scatterplot data of this relationship fit the previously identified pattern in children and adolescents with AN or atypical AN. DISCUSSION: The prediction of weight loss by pre-operative/premorbid BMI appears applicable across the weight spectrum, from underweight to severe obesity, thus strengthening our hypothesis of underlying regulatory mechanisms for the development of AN and atypical AN. Such data may guide the determination of critical weight loss thresholds that trigger eating disorder development in predisposed individuals.

No evidence for a causal contribution of bioavailable testosterone to ADHD in sex-combined and sex-specific two-sample Mendelian randomization studies.

The higher prevalence of attention-deficit/hyperactivity disorder (ADHD) in males raises the question of whether testosterone is implicated in ADHD risk. However, cross-sectional studies did not identify an association between ADHD and testosterone levels. Mendelian randomization (MR) studies can overcome limitations inherent to association studies, especially of reverse causation and residual confounding. In the current study, sex-combined and sex-specific two-sample MR analyses were conducted to address whether testosterone has a causal influence on ADHD risk. Sex-combined as well as sex-specific target-genetic variants for bioavailable testosterone were derived from a large genome-wide association study (GWAS) on up to 382,988 adult white European UK Biobank study participants. In our sex-specific analyses for ADHD, including data from 14,154 males and 4,945 females with ADHD (17,948 and 16,246 controls respectively), no association between bioavailable testosterone and ADHD risk was found, neither in males (inverse-variance weighted (IVW): beta = 0.09, 95%-CI [-0.10, 0.27]) nor in females (IVW: beta=-0.01, 95%-CI [-0.20, 0.19]). However, in the sex-combined analysis, including 38,691 cases and 186,843 controls, genetically predicted bioavailable testosterone was associated with ADHD risk (IVW: beta = 0.24, 95%-CI [0.09, 0.39]). The inclusion of birth weight and/or SHBG as additional variables in multivariable MR analyses did not alter this result. However, when correcting for potential BMI-driven pleiotropy by a multivariable MR study, all effect estimates for testosterone showed non-significant results. Taken together, no robust evidence for a causal effect of bioavailable testosterone on the risk for ADHD was found.

Does hypoleptinemia trigger entrapment in anorexia nervosa? Etiological and clinical considerations.

Based on the recent observation that human recombinant leptin (r-Met-hu-leptin; metreleptin) may induce a profound alleviation of the complex symptomatology of patients with anorexia nervosa (AN), we examine the implications for our conceptualisation of this eating disorder. Hypoleptinemia as a core endocrine feature of AN serves as a central and peripheral trigger of tissue-specific adaptations to starvation. In this narrative review, we argue that leptin deficiency may explain many of the puzzling features of this eating disorder. Weight loss can be viewed as a two-step process, with only the second step entailing hypoleptinemia and thereby the entrapment characteristic of AN. We discuss the central and peripheral distribution of leptin receptors and consider possible functional implications of hypoleptinemia. We contrast the slow psychological recovery of patients with AN and of people who experienced starvation upon weight recovery with the rapid onset of improvements upon off-label metreleptin treatment. Characteristics of the sex and age dependent secretion of leptin may contribute to the elevated vulnerability of young females to develop AN.

Rapid amelioration of anorexia nervosa in a male adolescent during metreleptin treatment including recovery from hypogonadotropic hypogonadism.

With this case report we support our medical hypothesis that metreleptin treatment ameliorates starvation related emotional, cognitive and behavioral symptomatology of anorexia nervosa (AN) and show for the first time strong effects in a male patient with AN. A 15.9 year old adolescent with severe AN of eight-month duration was treated off-label with metreleptin. Hyperactivity was assessed with accelerometry. Visual analogue scales (VAS), validated self- and clinician rating scales and lab results tracked changes from baseline to end of the 24-day dosing period and a five-month follow-up. Substantial improvements of mood and eating disorder related cognitions and hyperactivity set in after two days of treatment. During dosing, sub-physiological testosterone and TT3 levels normalized; clinically libido reemerged. Weight did not increase substantially during the dosing period. During follow-up target weight was attained; mood did not deteriorate; hyperactivity ceased. The results substantiate the strong effects seen in female cases and underscore the need for a double-blind placebo-controlled trial to confirm the observed strong, multiple and rapid onset beneficial effects of metreleptin in AN.

A mendelian randomization study on causal effects of 25(OH)vitamin D levels on attention deficit/hyperactivity disorder.

BACKGROUND: While observational studies revealed an inverse association between serum 25(OH)vitamin D (25(OH)D) and the risk of attention deficit/hyperactivity disorder (ADHD), the causality of this relationship remains unclear. METHODS: We conducted a bidirectional two-sample Mendelian Randomization (MR) study to examine whether 25(OH)D has an effect on the risk to develop ADHD or vice versa. Information on single nucleotide polymorphisms (SNP) associated with serum 25(OH)D was obtained from a genome-wide association study (GWAS) considering phenotype data from 79,366 individuals of European ancestry. Data on risk for ADHD were derived from a GWAS analysis with 20,183 individuals diagnosed with ADHD and 35,191 controls. For our analysis, we considered effect sizes based on the European participants (19,099 cases and 34,194 controls). RESULTS: Single SNP analyses showed a causal effect of vitamin D on ADHD risk for only one SNP (rs12785878, p = 0.024). The overall MR estimates did not reveal a causal effect of 25(OH)D on risk for ADHD. In the reverse analysis, neither any single nor the multi-SNP MR analyses showed a causal effect of ADHD on 25(OH)D. CONCLUSION: Results from this two-sample MR study did not confirm a causal effect of 25(OH)D on ADHD or vice versa. Accordingly, our study does not provide evidence that improving 25(OH)D via supplementation could reduce the risk of developing ADHD.

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

[Nutrition and mental health - how findings from genetic studies can support the identification of dietary effects]. / Ernährungseffekten auf der Spur ­ Wie die Genetik helfen kann, Zusammenhänge zwischen Ernährung und seelischer Gesundheit aufzudecken.

Nutrition and mental health - how findings from genetic studies can support the identification of dietary effects Abstract. Introduction: Numerous studies indicate that dietary interventions could be an important approach to the prevention and treatment of mental disorders. However, conventional nutritional epidemiological approaches (e. g., observational studies and randomized controlled trials, RCTs) have specific limitations to consider when interpreting the results. This article examines whether genetic studies could help to establish a link between diet and the prevention of mental disorders. Furthermore, it examines whether it is possible to draw conclusions about causal relationships. Methods: This narrative review describes various approaches of genetic cross-phenotype studies and presents examples of their applications in nutritional psychiatry. In addition, it discusses specific requirements as well as the strengths and limitations of the respective approaches. Results: To date, in the context of nutritional psychiatry, genetic correlation analyses, look-up analyses, and Mendelian randomization (MR) studies have been used for genetic crossphenotype analyses. Genetic correlation and look-up analyses provide initial evidence of possible overlap between specific mental disorders and metabolic pathways or specific nutrients. MR studies are used for detailed analyses that aim to identify causal relationships. However, MR is based on specific assumptions that must be met and considered when results are interpreted. Conclusion: Genetic cross-phenotype analyses are a useful amendment to conventional nutritional epidemiological research. In particular, positive results from MR studies provide an important fundament for identifying and developing suitable dietary interventions, which in turn increases the chance of success upon testing in subsequent RCTs. Accordingly, genetic cross-phenotype analyses are important instruments for increasing the efficiency in nutritional psychiatric research.

[Genetic Analyses of Complex Phenotypes Through the Example of Anorexia Nervosa and Bodyweight Regulation]. / Ebenen der genetischen Analyse komplexer Phänotypen am Beispiel der Anorexia nervosa und der Varianz des Körpergewichts.

Genetic Analyses of Complex Phenotypes Through the Example of Anorexia Nervosa and Bodyweight Regulation Abstract. Genetics variants are important for the regulation of bodyweight and also contribute to the genetic architecture of eating disorders. For many decades, family studies, a subentity of so-called formal genetic studies, were employed to determine the genetic share of bodyweight and eating disorders and found heritability rates exceeding 50 % with both phenotypes. Because of this significant contribution of genetics, the search for those genes and their variants related to the variance in bodyweight and the etiology of eating disorders - or both - was commenced by the early 1990s. Initially, candidate genes studies were conducted targeting those genes most plausibly related to either phenotype, especially based on pathophysiological considerations. This approach, however, implicated only a few genes in the regulation of bodyweight and did not provide significant insights into the genetics of eating disorders. Driven by considerable methodological advances in genetic research, especially related to the introduction of so-called genome-wide association studies by the beginning of the 21st century, today more than 1,000 variants/loci have been detected that affect the regulation of bodyweight. Eight such loci have been identified regarding anorexia nervosa (AN). These results as well as those from cross-disorder analyses provide insights into the complex regulation of bodyweight and demonstrated unforeseen pathomechanisms for AN.

Effect of vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients: results of a randomized controlled trial.

PURPOSE: While observational studies revealed inverse associations between serum vitamin D levels [25(OH)D] and depression, randomized controlled trials (RCT) in children and adolescents are lacking. This RCT examined the effect of an untreated vitamin D deficiency compared to an immediate vitamin D3 supplementation on depression scores in children and adolescents during standard day and in-patient psychiatric treatment. METHODS: Patients with vitamin D deficiency [25(OH)D ≤ 30 nmol/l] and at least mild depression [Beck Depression Inventory II (BDI-II) > 13] (n = 113) were 1:1 randomized into verum (VG; 2640 IU vitamin D3/d) or placebo group (PG) in a double-blind manner. During the intervention period of 28 days, both groups additionally received treatment as usual. BDI-II scores were assessed as primary outcome, DISYPS-II (Diagnostic System for Mental Disorders in Childhood and Adolescence, Self- and Parent Rating) and serum total 25(OH)D were secondary outcomes. RESULTS: At admission, 49.3% of the screened patients (n = 280) had vitamin D deficiency. Although the intervention led to a higher increase of 25(OH)D levels in the VG than in the PG (treatment difference: + 14 ng/ml; 95% CI 4.86-23.77; p = 0.003), the change in BDI-II scores did not differ (+ 1.3; 95% CI - 2.22 to 4.81; p = 0.466). In contrast, DISYPS parental ratings revealed pronounced improvements of depressive symptoms in the VG (- 0.68; 95% CI - 1.23 to - 0.13; p = 0.016). CONCLUSION: Whereas this study failed to show a vitamin D supplementation effect on self-rated depression in adolescent in- or daycare patients, parents reported less depressive symptoms in VG at the end of our study. Future trials should consider clinician-rated depressive symptoms as primary outcome. TRIAL REGISTRATION: "German Clinical Trials Register" ( https://www.drks.de ), registration number: DRKS00009758.

The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis.

Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta-analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets.

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human.

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Effect of an vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients - a randomized controlled trial: study protocol.

BACKGROUND: Depression is a significant health and economic burden worldwide affecting not only adults but also children and adolescents. Current treatment options for this group are scarce and show moderate effect sizes. There is emerging evidence that dietary patterns and specific nutritional components might play a role in the risk for developing depression. This study protocol focusses on the role of vitamin D which is for long known to be relevant for calcium and phosphorous homeostasis and bone health but might also impact on mental health. However, the assessment of the vitamin D status of depressed juvenile patients, or supplementation of vitamin D is currently not part of routine treatment. Controlled intervention studies are indispensable to prove whether a vitamin D deficiency ameliorates depressive symptoms. METHODS/DESIGN: This double blinded, randomized controlled trial will enroll 200 inpatients from a child and adolescent psychiatric department with a vitamin D deficiency defined by a 25(OH)-vitamin D-level < 30 nmol/l (12 ng/ml) and a Beck Depressions Inventory (BDI-II) score > 13 (indicating at least: mild depression). Upon referral, all patients will be screened, checked for inclusion criteria, and those eligible will be randomized after written consent into a supplementation or placebo group. Both study-arms will receive treatment-as-usual for their psychiatric disorder according to established clinical guidelines. The participants of the vitamin D supplementation group will receive 2640 I.E. vitamin D3 q.d. for 28 days in accordance with best practice in pediatric endocrinology. We hypothesize that delaying supplementation of vitamin D in the placebo arm will affect the treatment success of the depressive symptomatology in comparison to the vitamin D supplementation group. Patients will be enrolled for a period of 28 days based on the mean length of hospitalization of juveniles with depression. DISCUSSION: Randomized controlled trials in children and adolescents with depression are needed to elucidate the role of a vitamin D deficiency for mental disorders and to investigate the relevance of a routine assessment and supplementation of vitamin D deficits. TRIAL REGISTRATION: DRKS00009758, 16/06/2016 (retrospectively registered).

Relevance of polymorphisms in MC4R and BDNF in short normal stature.

BACKGROUND: Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition. METHODS: We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ2-tests) population-based data sets (ExAC, EVS and KORA) were used. Cyclic AMP accumulation, cell surface expression, central expression and MAP kinase activation were assayed in vitro to determine the functional implications of identified variants. RESULTS: We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS. CONCLUSION: Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature.

The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients.

Leptin is essential for the control of energy homeostasis and eating behaviour. We investigated potential associations between serum leptin levels and food addiction in adolescent psychiatric inpatients (n = 228). The most frequent psychiatric diagnoses were mood disorders, anxiety disorders, and substance use disorders. More than three quarters of the study group suffered from more than one psychiatric disorder. Food addiction was assessed with the Yale Food Addiction Scale. Leptin was determined in serum. Analyses were conducted for the whole body weight range and for distinct weight categories to evaluate a potential impact of known nonlinearity between leptin levels and satiety due to leptin resistance in obese. A weak negative association between food addiction and leptin in normal weight patients (ß = -0.11, p = .022) was detected. In contrast, food addiction was associated with a significantly higher serum leptin (ß = 0.16. p = .038) in overweight patients. Food addiction in normal weight patients might be associated with restrained eating, previously shown to involve reduced leptin levels. The small positive association of food addiction with higher serum leptin in overweight patients might reflect leptin resistance and overeating.

Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (ß = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (ß = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

Association of common variants identified by recent genome-wide association studies with obesity in Chinese children: a case-control study.

BACKGROUND: Large-scale genome-wide association studies have identified multiple genetic variants that are associated with elevated body mass index (BMI) or the risk of obesity in Caucasian or Asian populations. We examined whether these variants are individually associated with obesity in Chinese children, and also assessed their cumulative effects and predictive value for obesity risk in Chinese children. METHODS: We genotyped 40 single nucleotide polymorphisms (SNPs) and conducted association analyses for 32/40 SNPs with an estimated minor allele frequency >1% in 2 030 unrelated Chinese children, including 607 normal-weight, 718 overweight, and 705 obese individuals from two cross-sectional study groups. Logistic regression and linear regression under the additive model were used to examine associations, and the area under the receiver operating characteristic curve (AUCROC) was reported as prediction summary. RESULTS: We identified obesity association for 6 SNPs near SEC16B, RBJ, CDKAL1, TFAP2B, MAP2K5 and FTO (odds ratios (ORs) ranged from 1.19 to 1.41, nominal two-sided P-values < 0.05). Association (Bonferroni corrected) of rs543874 near SEC16B and rs2241423 near MAP2K5 had presumably stronger effects on obesity in Chinese children than in Caucasian populations. Their risk alleles were also associated with BMI standard deviation score (BMI-SDS) variability. We demonstrated the cumulative effects of the 32 SNPs on obesity risk (per risk allele: OR = 1.06, 95 % CI: 1.03-1.11, P = 4.84 × 10(-4)) and BMI-SDS (ß = 0.04, 95% CI: 0.02-0.06, P = 3.69 × 10(-7)). The difference in AUCROC for a model with covariates (age, age square, sex and study group) and the model including covariates and all 32 SNPs was 2.8% (P = 0.0002). CONCLUSION: While six SNPs were individually associated with obesity in Chinese children, the 32 common variants identified by recent GWA studies had cumulative effects and resulted in a limited increase in the AUCROC predictive value for childhood obesity.