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.
- MeSH
- alkoholismus genetika MeSH
- celogenomová asociační studie MeSH
- depresivní porucha unipolární genetika MeSH
- fenotyp MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- poruchy příjmu potravy genetika MeSH
- poruchy spojené s užíváním psychoaktivních látek genetika MeSH
- poruchy vyvolané užíváním tabáku genetika MeSH
- rizikové faktory MeSH
- schizofrenie genetika MeSH
- vazebná nerovnováha MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, N.I.H., Extramural MeSH
Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
- MeSH
- celogenomová asociační studie * MeSH
- dospělí MeSH
- duševní poruchy komplikace genetika MeSH
- fenotyp MeSH
- genetická predispozice k nemoci * MeSH
- genomika metody MeSH
- index tělesné hmotnosti MeSH
- lidé MeSH
- lokus kvantitativního znaku * MeSH
- mentální anorexie etiologie genetika patologie MeSH
- metabolické nemoci komplikace genetika MeSH
- prognóza MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
1 svazek : ilustrace, tabulky ; 30 cm
Genetické studie poruch příjmu potravy (AN, BN a BED), které mají multifaktoriální příčinu vzniku, vyžadují upřesnění fenotypizace jednotlivých subtypů onemocnění a studie vztahů mezi nimi a vlivy enviromentu. Současná fenotypizace neodpovídá klinicky používané klasifikaci. Proto autoři navrhují přidat k sledování a upřesnění charakteristik endofenotypů (neurofyziologické koreláty, měření bolesti, hyperaktivity a kognitivních faktorů v patologickém vnímání vlastního těla) ještě koreláty genetické. V genetické části projektu budou studovány varianty baterie genů, související se vznikem AN a BN a/nebo modifikují jejich průběh a vyústění. Zaměříme se na geny ovlivňující centrální mechanismus regulace příjmu potravy, související se stresovými faktory: receptory serotoninu, dopaminu, stresové proteiny, neurotrofní faktor; insulin-like growth factor-2; COMT a poprvé u PPP i geny pro tvorbu plynných molekul, jejichž polymorfizmy podle některých studií ovlivňují chování.; Genetic studies of eating disorders (AN, BN and BED), which have a multifactorial etiology, require a more precise phenotyping of various subtypes. Therefore, the authors propose to add refinement of characteristic endophenotypes (neurophysiological correlates, measurement of pain, overactive and cognitive factors in pathological perception of own body). The genetic part of the project will address a battery of genes related to the development of AN and BN and/or modify their course and outcome. We will focus on genes influencing the central regulation of food intake and on stress, personality and autoaggressive factors: serotonin, dopamine and cannabinoid receptors, stress proteins (Hsp 70 and 32), neurotrophic factors, insulin-like growth factor-2; arginine vasopressin 1a receptor, COMT and polymorphisms within nNOS. In families with multiple disease precipitation, new method of exome sequencing will be used to search for novel genetic determinants responsible for fenotypic expression the disease.
- MeSH
- bulimia nervosa genetika MeSH
- endofenotypy analýza MeSH
- exom MeSH
- genetická predispozice k nemoci MeSH
- mentální anorexie genetika MeSH
- metaanalýza jako téma MeSH
- nemoc vyvolaná prostředím MeSH
- poruchy příjmu potravy genetika MeSH
- záchvatovité přejídání genetika MeSH
- Konspekt
- Psychiatrie
- NLK Obory
- psychiatrie
- genetika, lékařská genetika
- environmentální vědy
- biologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
Dual hereditary jaundice, a combination of Dubin-Johnson and Gilbert's syndromes, is a rare clinical entity resulting from the compound defects of bilirubin conjugation and transport. We aimed to study the hereditary jaundice in 56 members from seven seemingly unrelated Roma families, to find the causal genetic defect and to estimate its origin in Roma population. On the basis of biochemical results of total and conjugated serum bilirubin and clinical observations, ABCC2 gene, TATA box and phenobarbital enhancer (PBREM) of UGT1A1 gene were analyzed by sequencing, RFLP and fragment analysis. We found a novel variant c.1013_1014delTG in the eighth exon of ABCC2 gene in 17 individuals in homozygous state. Dual defect NG_011798.1:c.[1013_1014delTG]; NG_002601.2:g.[175492_175493insTA] in homozygous state was found in four subjects. Biochemical analyses of porphyrins and coproporphyrin isomers in urine performed by HPLC showed inverted ratio of excreted coproporphyrin, with the predominance of coproporphyrin I (up to 100%), typical for patients with Dubin-Johnson syndrome. Pursuant cultural and social specifics of the population led us to suspect a founder effect; therefore, we performed a haplotype study using genotyping data from Affymetrix Genome-Wide Human SNP Array 6.0. As a result, we detected a common 86 kbp haplotype encompassing promoter and part of the ABCC2 coding region among all families, and estimated the age of the ancestral variant to 178-185 years. In this study, we found a novel deletion in ABCC2 gene, described genetic and biochemical features of dual hereditary jaundice and confirmed the existence of founder effect and common haplotype among seven Roma families.
- MeSH
- bilirubin metabolismus MeSH
- delece genu * MeSH
- efekt zakladatele * MeSH
- Gilbertova nemoc diagnóza genetika MeSH
- glukuronosyltransferasa genetika MeSH
- haplotypy MeSH
- homozygot MeSH
- jednonukleotidový polymorfismus MeSH
- koproporfyriny moč MeSH
- lidé MeSH
- polymorfismus délky restrikčních fragmentů MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům genetika MeSH
- TATA box MeSH
- žloutenka chronická idiopatická diagnóza genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Erythropoietic protoporphyria (EPP), a chronic erythropoietic porphyria, is characterized by excess accumulation of protoporphyrin, particularly in erythroid cells. EPP inheritance is complex, almost always associated with two molecular defects. In most EPP patients, clinical expression requires coinheritance of a private ferrochelatase (FECH) mutation trans- to a hypomorphic FECH*IVS3-48C allele. This leads to a decrease of FECH activity below the critical threshold. This is characterized by cutaneous photosensitivity in early childhood such as itching, burning, swelling and redness in sun-exposed areas. Hepatic failure occurs in some patients (about 1-10 % of EPP patients), which may necessitate liver transplantation. We investigated a Czech family with two patients with manifested EPP in four generations. We found a novel mutation, c.84G >A, in the FECH gene in four individuals including proband and his mother (G84A transition in exon 2; p.W28*). Both clinically manifested probands inherited the hypomorphic IVS3-48C allele as well, while two clinically latent individuals with FECH mutation did not. To address the question whether the relatively low incidence of EPP in the Czech Republic might be due to lower frequency of the IVS3-48C allele, we screened for the frequency of the low expression allele in a control Czech (West Slaves) Caucasian population. Such study has not been performed in any Slavic population. Among 312 control individuals, there were no IVS3-48C/C (c.68-23C-T) homozygotes; 35 IVS3-48C/T heterozygous individuals were detected. The frequency of IVS3-48C allele was thus found to be 5.5 % in the Czech population, comparable to most West Caucasian populations.
- MeSH
- biosyntetické dráhy genetika MeSH
- DNA genetika MeSH
- dospělí MeSH
- erytrocyty metabolismus MeSH
- erytropoetická protoporfyrie krev enzymologie genetika MeSH
- ferrochelatasa chemie genetika MeSH
- genetická predispozice k nemoci * MeSH
- genom lidský MeSH
- hem biosyntéza MeSH
- lidé MeSH
- mladiství MeSH
- molekulární sekvence - údaje MeSH
- mutace genetika MeSH
- mutační analýza DNA MeSH
- polymorfismus genetický * MeSH
- protoporfyriny krev MeSH
- rodina MeSH
- rodokmen MeSH
- sekvence aminokyselin MeSH
- sekvence nukleotidů MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- MeSH
- fenotyp MeSH
- genotyp MeSH
- lidé MeSH
- polymorfismus genetický MeSH
- poruchy příjmu potravy * genetika MeSH
- průzkumy a dotazníky MeSH
- výzkum MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
