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Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by the absence of paternally expressed and maternally imprinted genes on chromosome 15q 11.2–13. It is associated with a certain behavioural phenotype, especially temper outbursts with verbal and physical aggression towards others. Recent studies show a promising therapeutic effect of serotonin reuptake inhibitors like sertraline on frequency and intensity of outbursts. Monoamine oxidase A (MAOA) (X p11.23) plays a crucial role in the metabolism of monoamines. Dysregulation in methylation of the CpG island spanning the promoter region and exon 1 of MAOA is implicated in impulsive and aggressive behaviour. In the present study, methylation rates of CpG dinucleotides in the MAOA promoter and exon 1 region were determined from DNA derived from whole blood samples of PWS patients (n = 32) and controls (n = 14) matched for age, sex and BMI via bisulfite sequencing. PWS patients were grouped into those showing temper outbursts, and those who do not. Overall, PWS patients show a significant lower methylation rate at the promoter/exon 1 region than healthy controls in both sexes. Furthermore, PWS patients, male as well female with temper outbursts show a significant lower methylation rate than those without temper outbursts (p < 0.001 and p = 0.006). The MAOA promoter/exon 1 region methylation seems to be dysregulated in PWS patients in sense of a hypomethylation, especially in those suffering from temper outbursts. This dysregulation probably plays a crucial role in the pathophysiology of temper outbursts in PWS. • Individuals with PWS have a significantly lower methylation rate at CpGs at exon1/promoter region of MAOA than healthy controls • Methylation rates at the investigated region in MAOA did not differ between the genetic subtypes of PWS • Individuals with PWs who show temper outbursts have a significantly lower methylation rate at the investigated region of MAOA than those without temper outbursts and healthy controls • MAOA seems to be critically involved in the disturbance of the serotonergic pathway in PWS [ABSTRACT FROM AUTHOR]

Background & Aims There are numerous coding and non-coding variants in the SCARB1 gene that encodes scavenger receptor class B member 1 (SR-BI), a key receptor for both high density lipoproteins and hepatitis C virus (HCV). Many have been linked to clinical phenotypes, yet their impact on the HCV replication cycle is incompletely understood. The aim of this study was to analyze the impact of these variants on the molecular biology and clinical course of HCV. Methods We analyzed key coding non-synonymous as well as non-coding SCARB1 variants using virological in vitro and human genetics approaches. Results Non-synonymous variants: S112F and T175A have greatly reduced HCV receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load. Haplotype analysis confirmed these findings and identified haplotype rs3782287 A/rs5888 C as a risk allele associated with increased viral load. We also detected a trend towards lower hepatic SR-BI expression in individuals with the rs3782287 GG genotype associated with low viral load suggesting a potential underlying mechanism. Conclusion Coding and non-coding genetic SCARB1 variants modulate the HCV replication cycle and possibly clinical features of hepatitis C. These findings underscore the relevance of SR-BI as an HCV receptor and contribute to our understanding of inter-individual variation in HCV infection. Lay summary The cell surface receptor SR-BI (scavenger receptor class B member 1), is essential for hepatitis C virus (HCV) entry into hepatocytes. Variations in the gene coding this receptor influence infectivity and viral load. We analyzed these variations to gain a better understanding of inter-individual differences over the course of HCV infection. [ABSTRACT FROM AUTHOR]

Prader-Willi syndrome (PWS), a neurodevelopmental disorder based on the loss of paternally derived but maternally imprinted genes on chromosome 15q11–13, is typically associated with hyperphagia-related behavior leading to massive obesity. Recently, there has been increasing evidence for dysregulated expression patterns of genes outside the PWS locus that influence the behavioral phenotype and for alterations in the dopaminergic system associated with weight regulation in PWS. In this study, we investigated the epigenetic regulation of the promoter regions of the dopamine transporter (DAT) and dopamine receptor D2 (DRD2) genes and their association with hyperphagia-related behavior in PWS. Methylation of the DAT and DRD2 promoter regions was examined by DNA bisulfite sequencing in 32 individuals with PWS and compared with a control group matched for sex, age, and body mass index (BMI). Hyperphagia-related behavior was assessed using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Analysis by linear mixed models revealed a significant effect of factor group on mean DAT promoter methylation rate with decreased mean methylation in PWS (7.3 ± 0.4%) compared to controls (18.8 ± 0.6%), p < 0.001. In the PWS group, we further identified effects of HQ-CT score and BMI on DAT promoter methylation. Although also statistically significantly different (8.4 ± 0.2 in PWS, 10.5 ± 0.3 in controls, p < 0.001), DRD2 promoter methylation visually appeared to be evenly distributed between groups, raising concerns regarding a biological effect. Here, we provide evidence for altered epigenetic regulation of the DAT gene in PWS, which is associated with PWS-typical hyperphagia-related behaviors. • Dopamine transporter and dopamine receptor D2 gene promoters are hypomethylated in Prader-Willi syndrome. • Methylation of dopamine transporter gene is associated with hyperphagia-related behavior in Prader-Willi syndrome. • Dopaminergic reward system appears to be a modulator of PWS-typical food-seeking behavior. [ABSTRACT FROM AUTHOR]

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11–13. PWS individuals typically show insatiable appetite with subsequent obesity representing the major mortality factor unless food intake is inhibited. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, a region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and DNA methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter DNA methylation was assessed by bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated significantly with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to sex-, age- and BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror those seen in non-syndromic obesity. [ABSTRACT FROM AUTHOR]

Both atrial natriuretic peptide (ANP) and vasopressin (VP) influence alcohol intake and withdrawal as well as craving and are also regulated by epigenetic factors. Disturbances in expression and promoter methylation status have been described in patients suffering from alcohol use disorder and alcohol withdrawal therapy. In this study, we wanted to map the progression of cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoter of ANP and VP immediately after starting alcohol withdrawal therapy when compared with healthy controls We recruited 34 males suffering from alcohol addiction or harmful use alongside 43 healthy male controls. Blood samples for methylation analyses were drawn on days 1, 2, 3, 4, and 7–10. There was no difference in mean methylation for both VP and ANP during withdrawal. There was no difference at the ANP CpG-sites after correction for multiple testing. Regarding VP, methylation was significantly higher at CpG 033, CpG 064, CpG 103, CpG 118, and CpG 194 and significantly lower at CpG 053, CpG 060, and CpG 214 when compared to healthy controls. Via in silico analysis, we identified transcription factor binding sites that could potentially influence methylation-dependent gene transcription. While there was no change in methylation status during withdrawal, significant differences in average methylation of specific CpG sites were observed for VP. We also identified the role of transcription factors in the context of promoter methylation as one potential mechanism that could explain the differences in VP levels between alcohol-dependent patients and healthy controls. • ANP and VP methylation did not change during alcohol withdrawal over the course of 1–10 days. • Mean methylation at specific CpG sites of the VP promoter was different in alcohol-dependent patients compared to controls. • Transcription factor analysis revealed that specific transcription factors could potentially influence promoter methylation. [ABSTRACT FROM AUTHOR]