Dataset Information

Common Genetic Variation and Age of Onset of Anorexia Nervosa.

ABSTRACT:

Background

Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.

Methods

A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (<13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.

Results

Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h ²) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN.

Conclusions

Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.

SUBMITTER: Watson HJ

PROVIDER: S-EPMC9616394 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Watson Hunna J HJ Thornton Laura M LM Yilmaz Zeynep Z Baker Jessica H JH Coleman Jonathan R I JRI Adan Roger A H RAH Alfredsson Lars L Andreassen Ole A OA Ask Helga H Berrettini Wade H WH Boehnke Michael M Boehm Ilka I Boni Claudette C Buehren Katharina K Bulant Josef J Burghardt Roland R Chang Xiao X Cichon Sven S Cone Roger D RD Courtet Philippe P Crow Scott S Crowley James J JJ Danner Unna N UN de Zwaan Martina M Dedoussis George G DeSocio Janiece E JE Dick Danielle M DM Dikeos Dimitris D Dina Christian C Djurovic Srdjan S Dmitrzak-Weglarz Monika M Docampo-Martinez Elisa E Duriez Philibert P Egberts Karin K Ehrlich Stefan S Eriksson Johan G JG Escaramís Geòrgia G Esko Tõnu T Estivill Xavier X Farmer Anne A Fernández-Aranda Fernando F Fichter Manfred M MM Föcker Manuel M Foretova Lenka L Forstner Andreas J AJ Frei Oleksandr O Gallinger Steven S Giegling Ina I Giuranna Johanna J Gonidakis Fragiskos F Gorwood Philip P Gratacòs Mònica M Guillaume Sébastien S Guo Yiran Y Hakonarson Hakon H Hauser Joanna J Havdahl Alexandra A Hebebrand Johannes J Helder Sietske G SG Herms Stefan S Herpertz-Dahlmann Beate B Herzog Wolfgang W Hinney Anke A Hübel Christopher C Hudson James I JI Imgart Hartmut H Jamain Stephanie S Janout Vladimir V Jiménez-Murcia Susana S Jones Ian R IR Julià Antonio A Kalsi Gursharan G Kaminská Deborah D Kaprio Jaakko J Karhunen Leila L Kas Martien J H MJH Keel Pamela K PK Kennedy James L JL Keski-Rahkonen Anna A Kiezebrink Kirsty K Klareskog Lars L Klump Kelly L KL Knudsen Gun Peggy S GPS La Via Maria C MC Le Hellard Stephanie S Leboyer Marion M Li Dong D Lilenfeld Lisa L Lin Bochao B Lissowska Jolanta J Luykx Jurjen J Magistretti Pierre P Maj Mario M Marsal Sara S Marshall Christian R CR Mattingsdal Morten M Meulenbelt Ingrid I Micali Nadia N Mitchell Karen S KS Monteleone Alessio Maria AM Monteleone Palmiero P Myers Richard R Navratilova Marie M Ntalla Ionna I O'Toole Julie K JK Ophoff Roel A RA Padyukov Leonid L Pantel Jacques J Papežová Hana H Pinto Dalila D Raevuori Anu A Ramoz Nicolas N Reichborn-Kjennerud Ted T Ricca Valdo V Ripatti Samuli S Ripke Stephan S Ritschel Franziska F Roberts Marion M Rotondo Alessandro A Rujescu Dan D Rybakowski Filip F Scherag André A Scherer Stephen W SW Schmidt Ulrike U Scott Laura J LJ Seitz Jochen J Silén Yasmina Y Šlachtová Lenka L Slagboom P Eline PE Slof-Op 't Landt Margarita C T MCT Slopien Agnieszka A Sorbi Sandro S Świątkowska Beata B Tortorella Alfonso A Tozzi Federica F Treasure Janet J Tsitsika Artemis A Tyszkiewicz-Nwafor Marta M Tziouvas Konstantinos K van Elburg Annemarie A AA van Furth Eric F EF Walton Esther E Widen Elisabeth E Zerwas Stephanie S Zipfel Stephan S Bergen Andrew W AW Boden Joseph M JM Brandt Harry H Crawford Steven S Halmi Katherine A KA Horwood L John LJ Johnson Craig C Kaplan Allan S AS Kaye Walter H WH Mitchell James E JE Olsen Catherine M CM Pearson John F JF Pedersen Nancy L NL Strober Michael M Werge Thomas T Whiteman David C DC Woodside D Blake DB Gordon Scott S Maguire Sarah S Larsen Janne T JT Parker Richard R Petersen Liselotte V LV Jordan Jennifer J Kennedy Martin M Wade Tracey D TD Birgegård Andreas A Lichtenstein Paul P Landén Mikael M Martin Nicholas G NG Mortensen Preben Bo PB Breen Gerome G Bulik Cynthia M CM

Biological psychiatry global open science 20210920 4

<h4>Background</h4>Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.<h4>Methods</h4>A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from Europ ...[more]

PMID: 36324647

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Project description:BackgroundAnorexia nervosa (AN) is a serious multifactorial eating disorder characterized by insufficient nutritional intake to maintain a minimum normal weight for one's age and height, a fear of gaining weight and a distorted body image. It affects mainly adolescents, but a decreased age at diagnosis has been reported, leading to the definition of a rare form of AN called early-onset or prepubertal anorexia nervosa (EOAN; ORPHA 525738), with reported epidemiological and clinical specificity. Current knowledge and specific treatments for this particular condition remain scarce. We aim to summarize the literature review and synthesize actual knowledge on EOAN for preliminary guidelines to harmonize the diagnosis, treatment and follow-up.MethodsA scoping literature review was performed from 2010-2021 using PubMed, Web of Science, PsycInfo and Cochrane via the following search terms: (anorexia nervosa) AND (early-onset OR premenarchal OR prepubertal OR childhood). International guidelines were screened for additional hits. Data extraction was limited to findings relevant to the key topic questions: epidemiology and clinical specificities section, diagnosis and initial evaluation section, treatment section, and follow-up and prognosis section.ResultsA total of 1257 titles were retrieved via the initial search strategy. Finally, 42 records were included in the present article (30 articles and 11 international guidelines and 1 literature review). We identified 15 articles relevant for the epidemiology and clinical specificities section, 11 for the diagnosis and initial evaluation section, 3 for the treatment section, and 1 for the follow-up and prognosis section. Despite the growing literature on the epidemiological and clinical features of EOAN, knowledge of specific treatments and prognoses remains scarce in the absence of extensive standardized data collection and few age-specific clinical research protocols. Current international guidelines generally extrapolate strategies proposed for adolescents and young adults to children with a low level of evidence.ConclusionsContinuing research efforts in this specific younger population is needed to validate child-specific care strategies, enabling the establishment of age-appropriate recommendations with a higher level of evidence targeting specific determinants and clinical specificities of EOAN.

Project description:ImportanceThe COVID-19 pandemic has had considerable mental health consequences for children and adolescents, including the exacerbation of previously diagnosed eating disorders. Whether the pandemic is a factor associated with the concomitant increase in new-onset anorexia nervosa or atypical anorexia nervosa remains unknown.ObjectiveTo assess the incidence and severity of newly diagnosed anorexia nervosa or atypical anorexia nervosa in a national sample of youth before and during the first wave of the COVID-19 pandemic.Design, setting, and participantsThis repeated cross-sectional study analyzed new eating disorder assessments that were conducted at 6 pediatric tertiary-care hospitals in Canada between January 1, 2015, and November 30, 2020. Patients aged 9 to 18 years with a new anorexia nervosa or atypical anorexia nervosa diagnosis at the index assessment were included.ExposuresCOVID-19-associated public health confinement measures during the first wave of the pandemic (March 1 to November 30, 2020).Main outcomes and measuresPrimary outcomes were the incidence and hospitalization rates within 7 days of de novo anorexia nervosa or atypical anorexia nervosa diagnosis. Event rate trends during the first wave were compared with trends in the 5-year prepandemic period (January 1, 2015, to February 28, 2020) using an interrupted time series with linear regression models. Demographic and clinical variables were compared using a χ2 test for categorical data and t tests for continuous data.ResultsOverall, 1883 children and adolescents with newly diagnosed anorexia nervosa or atypical anorexia nervosa (median [IQR] age, 15.9 [13.8-16.9] years; 1713 female patients [91.0%]) were included. Prepandemic anorexia nervosa or atypical anorexia nervosa diagnoses were stable over time (mean [SD], 24.5 [1.6] cases per month; β coefficient, 0.043; P = .33). New diagnoses increased during the first wave of the pandemic to a mean (SD) of 40.6 (20.1) cases per month with a steep upward trend (β coefficient, 5.97; P < .001). Similarly, hospitalizations for newly diagnosed patients increased from a mean (SD) of 7.5 (2.8) to 20.0 (9.8) cases per month, with a significant increase in linear trend (β coefficient, -0.008 vs 3.23; P < .001). These trends were more pronounced in Canadian provinces with higher rates of COVID-19 infections. Markers of disease severity were worse among patients who were diagnosed during the first wave rather than before the pandemic, including more rapid progression (mean [SD], 7.0 [4.2] months vs 9.8 [7.4] months; P < .001), greater mean (SD) weight loss (19.2% [9.4%] vs 17.5% [9.6%]; P = .01), and more profound bradycardia (mean [SD] heart rate, 57 [15.8] beats per minute vs 63 [15.9] beats per minute; P < .001).Conclusions and relevanceThis cross-sectional study found a higher number of new diagnoses of and hospitalizations for anorexia nervosa or atypical anorexia nervosa in children and adolescents during the first wave of the COVID-19 pandemic in Canada. Research is needed to better understand the drivers and prognosis for these patients and to prepare for their mental health needs in the event of future pandemics or prolonged social isolation.

Project description:The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

Project description:ObjectiveRecent preliminary studies indicated a seasonal association of BMI at admission to inpatient treatment for anorexia nervosa (AN), indicating lower BMI in the cold season for restrictive AN. An impaired thermoregulation was proposed as the causal factor, based on findings in animal models of AN. However, findings regarding seasonality of BMI and physical activity levels in the general population indicate lower BMI and higher physical activity in summer than in winter. Therefore, we aimed to thoroughly replicate the findings regarding seasonality of BMI at admission in patients with AN in this study.MethodAN subtype, age- and gender-standardized BMI scores (BMI-SDS) at admission, mean daily sunshine duration and ambient temperature at the residency of 304 adolescent inpatients with AN of the multi-center German AN registry were analyzed.ResultsA main effect of DSM-5 AN subtype was found (F(2,298) = 6.630, p = .002), indicating differences in BMI-SDS at admission between restrictive, binge/purge and subclinical AN. No main effect of season on BMI-SDS at admission was found (F(1,298) = 4.723, p = .025), but an interaction effect of DSM-5 subtype and season was obtained (F(2,298) = 6.625, p = .001). Post-hoc group analyses revealed a lower BMI-SDS in the warm season for restrictive AN with a non-significant small effect size (t(203.16) = 2.140, p = .033; Hedges'g = 0.28). Small correlations of mean ambient temperature (r = -.16) and daily sunshine duration (r = -.22) with BMI-SDS in restrictive AN were found. However, the data were widely scattered.ConclusionsOur findings are contrary to previous studies and question the thermoregulatory hypothesis, indicating that seasonality in AN is more complex and might be subject to other biological or psychological factors, for example physical activity or body dissatisfaction. Our results indicate only a small clinical relevance of seasonal associations of BMI-SDS merely at admission. Longitudinal studies investigating within-subject seasonal changes might be more promising to assess seasonality in AN and of higher clinical relevance.

Dataset Information

Common Genetic Variation and Age of Onset of Anorexia Nervosa.

Background

Methods

Results

Conclusions

Publications

Common Genetic Variation and Age of Onset of Anorexia Nervosa.

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