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Growth deviating from the norm during childhood has been associated with anorexia nervosa (AN) and obesity later in life. In this study, we examined whether polygenic scores (PGSs) for AN and BMI are associated with growth trajectories spanning the first two decades of life. AN PGSs and BMI PGSs were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 8,654). Using generalized (mixed) linear models, we associated PGSs with trajectories of weight, height, body mass index (BMI), fat mass index (FMI), lean mass index (LMI), and bone mineral density (BMD). Female participants with AN PGSs one standard deviation (SD) higher had, on average, 0.004% slower growth in BMI between the ages 6.5 and 24 years and a 0.4% slower gain in BMD between the ages 10 and 24 years. Higher BMI PGSs were associated with faster growth for BMI, FMI, LMI, BMD, and weight trajectories in both sexes throughout childhood. Female participants with both a high AN PGS and a low BMI PGS showed slower growth compared to those with both a low AN PGS and a low BMI PGS. We conclude that AN PGSs and BMI PGSs have detectable sex-specific effects on growth trajectories. Female participants with a high AN PGS and low BMI PGS likely constitute a high-risk group for AN, as their growth was slower compared to their peers with high PGSs on both traits. Further research is needed to better understand how the AN PGS and the BMI PGS co-influence growth during childhood and whether a high BMI PGS can mitigate the effects of a high AN PGS.
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Anorexia Nerviosa , Adolescente , Adulto , Anorexia Nerviosa/genética , Índice de Masa Corporal , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Herencia Multifactorial/genética , Obesidad , Adulto JovenRESUMEN
BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.
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Angioedema , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Estudio de Asociación del Genoma Completo , Angioedema/inducido químicamente , Angioedema/genética , BradiquininaRESUMEN
The accuracy of polygenic risk scores (PRSs) to predict complex diseases increases with the training sample size. PRSs are generally derived based on summary statistics from large meta-analyses of multiple genome-wide association studies (GWASs). However, it is now common for researchers to have access to large individual-level data as well, such as the UK Biobank data. To the best of our knowledge, it has not yet been explored how best to combine both types of data (summary statistics and individual-level data) to optimize polygenic prediction. The most widely used approach to combine data is the meta-analysis of GWAS summary statistics (meta-GWAS), but we show that it does not always provide the most accurate PRS. Through simulations and using 12 real case-control and quantitative traits from both iPSYCH and UK Biobank along with external GWAS summary statistics, we compare meta-GWAS with two alternative data-combining approaches, stacked clumping and thresholding (SCT) and meta-PRS. We find that, when large individual-level data are available, the linear combination of PRSs (meta-PRS) is both a simple alternative to meta-GWAS and often more accurate.
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Enfermedad/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Modelos Estadísticos , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Humanos , FenotipoRESUMEN
BACKGROUND: Epidemiological data offer conflicting views of the natural course of binge-eating disorder (BED), with large retrospective studies suggesting a protracted course and small prospective studies suggesting a briefer duration. We thus examined changes in BED diagnostic status in a prospective, community-based study that was larger and more representative with respect to sex, age of onset, and body mass index (BMI) than prior multi-year prospective studies. METHODS: Probands and relatives with current DSM-IV BED (n = 156) from a family study of BED ('baseline') were selected for follow-up at 2.5 and 5 years. Probands were required to have BMI > 25 (women) or >27 (men). Diagnostic interviews and questionnaires were administered at all timepoints. RESULTS: Of participants with follow-up data (n = 137), 78.1% were female, and 11.7% and 88.3% reported identifying as Black and White, respectively. At baseline, their mean age was 47.2 years, and mean BMI was 36.1. At 2.5 (and 5) years, 61.3% (45.7%), 23.4% (32.6%), and 15.3% (21.7%) of assessed participants exhibited full, sub-threshold, and no BED, respectively. No participants displayed anorexia or bulimia nervosa at follow-up timepoints. Median time to remission (i.e. no BED) exceeded 60 months, and median time to relapse (i.e. sub-threshold or full BED) after remission was 30 months. Two classes of machine learning methods did not consistently outperform random guessing at predicting time to remission from baseline demographic and clinical variables. CONCLUSIONS: Among community-based adults with higher BMI, BED improves with time, but full remission often takes many years, and relapse is common.
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BACKGROUND: Although several types of risk factors for anorexia nervosa (AN) have been identified, including birth-related factors, somatic, and psychosocial risk factors, their interplay with genetic susceptibility remains unclear. Genetic and epidemiological interplay in AN risk were examined using data from Danish nationwide registers. AN polygenic risk score (PRS) and risk factor associations, confounding from AN PRS and/or parental psychiatric history on the association between the risk factors and AN risk, and interactions between AN PRS and each level of target risk factor on AN risk were estimated. METHODS: Participants were individuals born in Denmark between 1981 and 2008 including nationwide-representative data from the iPSYCH2015, and Danish AN cases from the Anorexia Nervosa Genetics Initiative and Eating Disorder Genetics Initiative cohorts. A total of 7003 individuals with AN and 45 229 individuals without a registered AN diagnosis were included. We included 22 AN risk factors from Danish registers. RESULTS: Risk factors showing association with PRS for AN included urbanicity, parental ages, genitourinary tract infection, and parental socioeconomic factors. Risk factors showed the expected association to AN risk, and this association was only slightly attenuated when adjusted for parental history of psychiatric disorders or/and for the AN PRS. The interaction analyses revealed a differential effect of AN PRS according to the level of the following risk factors: sex, maternal age, genitourinary tract infection, C-section, parental socioeconomic factors and psychiatric history. CONCLUSIONS: Our findings provide evidence for interactions between AN PRS and certain risk-factors, illustrating potential diverse risk pathways to AN diagnosis.
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BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.
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Genome-wide association studies (GWAS) provide biological insights into disease onset and progression and have potential to produce clinically useful biomarkers. A growing body of GWAS focuses on quantitative and transdiagnostic phenotypic targets, such as symptom severity or biological markers, to enhance gene discovery and the translational utility of genetic findings. The current review discusses such phenotypic approaches in GWAS across major psychiatric disorders. We identify themes and recommendations that emerge from the literature to date, including issues of sample size, reliability, convergent validity, sources of phenotypic information, phenotypes based on biological and behavioral markers such as neuroimaging and chronotype, and longitudinal phenotypes. We also discuss insights from multi-trait methods such as genomic structural equation modelling. These provide insight into how hierarchical 'splitting' and 'lumping' approaches can be applied to both diagnostic and dimensional phenotypes to model clinical heterogeneity and comorbidity. Overall, dimensional and transdiagnostic phenotypes have enhanced gene discovery in many psychiatric conditions and promises to yield fruitful GWAS targets in the years to come.
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OBJECTIVE: The present study examined prevalence and correlates of pica behaviors during childhood using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) study. METHOD: Data on 10,109 caregivers from the ALSPAC study who reported pica behavior at 36, 54, 65, 77, and 115 months on their child were included. Autism was obtained through clinical and education records, while DD was derived from the Denver Developmental Screening Test. RESULTS: A total of 312 parents (3.08%) reported pica behaviors in their child. Of these, 19.55% reported pica at least at two waves (n = 61). Pica was most common at 36 months (N = 226; 2.29%) and decreased as children aged. A significant association was found between pica and autism at all five waves (p < .001). There was a significant relationship between pica and DD, with individuals with DD more likely to experience pica than those without DD at 36 (p = .01), and 54 (p < .001), 65 (p = .04), 77 (p < .001), and 115 months (p = .006). Exploratory analyses examined pica behaviors with broader eating difficulties and child body mass index. DISCUSSION: This study enhances understanding of childhood pica behaviors, addressing a significant gap in knowledge. Pica occurrence in the general population is poorly understood due to few epidemiological studies. Findings from the present study indicate pica is an uncommon behavior in childhood; however, children with DD or autism may benefit from pica screening and diagnosis between ages 36 and 115 months. Children who exhibit undereating, overeating, and food fussiness may also engage in pica behaviors.
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Cohorte de Nacimiento , Pica , Niño , Humanos , Preescolar , Pica/epidemiología , Prevalencia , Estudios Longitudinales , Conducta InfantilRESUMEN
OBJECTIVE: The Nine Item ARFID Scale (NIAS) is a widely used measure assessing symptoms of avoidant/restrictive food intake disorder (ARFID). Previous studies suggest that individuals with eating disorders driven by shape/weight concerns also have elevated scores on the NIAS. To further describe NIAS scores among individuals with diverse current and previous eating disorders, we characterized NIAS scores in a large sample of individuals with eating disorders and evaluated overlap in symptoms measured by the NIAS and the Eating Disorder Examination-Questionnaire (EDE-Q) version 6.0. METHOD: Our sample comprised 9148 participants from the Eating Disorders Genetics Initiative Sweden (EDGI-SE), who completed surveys including NIAS and EDE-Q. NIAS scores were calculated and compared by eating disorder diagnostic group using descriptive statistics and linear models. RESULTS: Participants with current anorexia nervosa demonstrated the highest mean NIAS scores and had the greatest proportion (57.0%) of individuals scoring above a clinical cutoff on at least one of the NIAS subscales. Individuals with bulimia nervosa, binge-eating disorder, and other specified feeding or eating disorder also demonstrated elevated NIAS scores compared to individuals with no lifetime history of an eating disorder (ps < 0.05). All subscales of the NIAS showed small to moderate correlations with all subscales of the EDE-Q (rs = 0.26-0.40). DISCUSSION: Our results substantiate that individuals with eating disorders other than ARFID demonstrate elevated scores on the NIAS, suggesting that this tool is inadequate on its own for differentiating ARFID from shape/weight-motivated eating disorders. Further research is needed to inform clinical interventions addressing the co-occurrence of ARFID-related drivers and shape/weight-related motivation for dietary restriction.
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OBJECTIVE: This study assessed the associations of binge eating, compensatory behaviors, and dietary restraint with the composition and diversity of the intestinal microbiota among participants with binge-eating disorder or bulimia nervosa. METHODS: We analyzed data from 265 participants aged 18 to 45 years with current binge-eating disorder or bulimia nervosa enrolled in the Binge Eating Genetics Initiative study. We evaluated the associations of binge-eating frequency; presence/absence and frequency of vomiting, laxative use, and compulsive exercise; and dietary restraint with abundances of gut microbial genera, species, and diversity (Shannon diversity, Faith phylogenetic diversity, and Peilou's evenness) from 16S rRNA gene sequencing. General linear regression models adjusted for potential confounders, including age and current body mass index, were used to test associations; p values were corrected for the false discovery rate. RESULTS: The normalized abundance of four genus- and species-level gut microbes and three diversity indices were lower among Binge Eating Genetics Initiative participants who reported any laxative use compared with those who reported no laxative use. Vomiting frequency was positively associated with the normalized abundance of the genus Escherichia-Shigella , a potential pathobiont, although the association was attenuated to nonsignificance after adjustment for age, body mass index, and binge-eating episodes. CONCLUSIONS: Laxative use was highly and uniformly predictive of a reduced gut microbial diversity including potential commensals and pathobionts, and should be assessed and accounted for in all future studies of eating disorders and the gut microbiota. Future studies should collect data on specific medications-particularly laxatives-and dietary intake to obtain unbiased estimates of the effect of eating disorders on the gut microbiota and identify potential downstream clinical implications.Trial Registration:ClinicalTrials.gov identifier: NCT04162574 .
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Trastorno por Atracón , Bulimia Nerviosa , Bulimia , Trastornos de Alimentación y de la Ingestión de Alimentos , Microbiota , Masculino , Femenino , Humanos , Laxativos , Filogenia , ARN Ribosómico 16S , VómitosRESUMEN
BACKGROUND: Diet, a key component of type 1 diabetes (T1D) management, modulates the intestinal microbiota and its metabolically active byproducts-including SCFA-through fermentation of dietary carbohydrates such as fiber. However, the diet-microbiome relationship remains largely unexplored in longstanding T1D. OBJECTIVES: We evaluated whether increased carbohydrate intake, including fiber, is associated with increased SCFA-producing gut microbes, SCFA, and intestinal microbial diversity among young adults with longstanding T1D and overweight or obesity. METHODS: Young adult men and women with T1D for ≥1 y, aged 19-30 y, and BMI of 27.0-39.9 kg/m2 at baseline provided stool samples at baseline and 3, 6, and 9 mo of a randomized dietary weight loss trial. Diet was assessed by 1-2 24-h recalls. The abundance of SCFA-producing microbes was measured using 16S rRNA gene sequencing. GC-MS measured fecal SCFA (acetate, butyrate, propionate, and total) concentrations. Adjusted and Bonferroni-corrected generalized estimating equations modeled associations of dietary fiber (total, soluble, and pectins) and carbohydrate (available carbohydrate, and fructose) with microbiome-related outcomes. Primary analyses were restricted to data collected before COVID-19 interruptions. RESULTS: Fiber (total and soluble) and carbohydrates (available and fructose) were positively associated with total SCFA and acetate concentrations (n = 40 participants, 52 visits). Each 10 g/d of total and soluble fiber intake was associated with an additional 8.8 µmol/g (95% CI: 4.5, 12.8 µmol/g; P = 0.006) and 24.0 µmol/g (95% CI: 12.9, 35.1 µmol/g; P = 0.003) of fecal acetate, respectively. Available carbohydrate intake was positively associated with SCFA producers Roseburia and Ruminococcus gnavus. All diet variables except pectin were inversely associated with normalized abundance of Bacteroides and Alistipes. Fructose was inversely associated with Akkermansia abundance. CONCLUSIONS: In young adults with longstanding T1D, fiber and carbohydrate intake were associated positively with fecal SCFA but had variable associations with SCFA-producing gut microbes. Controlled feeding studies should determine whether gut microbes and SCFA can be directly manipulated in T1D.
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COVID-19 , Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Femenino , Humanos , Masculino , Adulto Joven , Acetatos , Fibras de la Dieta/análisis , Ingestión de Alimentos , Ácidos Grasos Volátiles/análisis , Heces/química , Fructosa , Obesidad , Sobrepeso , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Familial co-aggregation studies of eating disorders (EDs) and schizophrenia reveal shared genetic and environment factors, yet their etiological and clinical relationship remains unclear. We evaluate the influence of schizophrenia family history on clinical outcomes of EDs. METHODS: We conducted a cohort evaluation of the association between family history of schizophrenia and ED clinical features, psychiatric comorbidities, and somatic and mental health burden in individuals born in Sweden 1977-2003 with anorexia nervosa (AN) or other EDs (OED: bulimia nervosa, binge-eating disorder, and ED not otherwise specified). RESULTS: Of 12 424 individuals with AN and 20 716 individuals with OED, 599 (4.8%) and 1118 (5.4%), respectively, had a family history of schizophrenia (in up to third-degree relatives). Among individuals with AN, schizophrenia in first-degree relatives was significantly associated with increased comorbid attention-deficit/hyperactivity disorder (ADHD) [HR(95% CI) 2.26 (1.27-3.99)], substance abuse disorder (SUD) [HR (95% CI) 1.93 (1.25-2.98)], and anxiety disorders [HR (95% CI) 1.47 (1.08-2.01)], but higher lowest illness-associated body mass index (BMI) [1.14 kg/m2, 95% CI (0.19-2.10)]. Schizophrenia in any relative (up to third-degree) in AN was significantly associated with higher somatic and mental health burden, but lower ED psychopathology scores [-0.29, 95% CI (-0.54 to -0.04)]. Schizophrenia in first-degree relatives in individuals with OED was significantly associated with increased comorbid ADHD, obsessive-compulsive disorder, SUD, anxiety disorders, somatic and mental health burden, and suicide attempts. CONCLUSIONS: We observed different patterns of ED-related outcomes, psychiatric comorbidity, and illness burden in individuals with EDs with and without family histories of schizophrenia and provide new insights into the diverse manifestations of EDs.
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Anorexia Nerviosa , Trastorno por Atracón , Bulimia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Esquizofrenia , Trastornos Relacionados con Sustancias , Humanos , Esquizofrenia/epidemiología , Esquizofrenia/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Anorexia Nerviosa/epidemiología , Anorexia Nerviosa/psicología , Bulimia Nerviosa/epidemiología , Bulimia Nerviosa/psicología , Trastorno por Atracón/epidemiología , Trastorno por Atracón/psicología , Comorbilidad , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
BACKGROUND: A subgroup of patients with anorexia nervosa (AN) undergoing involuntary treatment (IT) seems to account for most of the IT events. Little is known about these patients and their treatment including the temporal distribution of IT events and factors associated with subsequent utilization of IT. Hence, this study explores (1) utilization patterns of IT events, and (2) factors associated with subsequent utilization of IT in patients with AN. METHODS: In this nationwide Danish register-based retrospective exploratory cohort study patients were identified from their first (index) hospital admission with an AN diagnosis and followed up for 5 years. We explored data on IT events including estimated yearly and total 5-year rates, and factors associated with subsequent increased IT rates and restraint, using regression analyses and descriptive statistics. RESULTS: IT utilization peaked in the initial few years starting at or following the index admission. A small percentage (1.0%) of patients accounted for 67% of all IT events. The most frequent measures reported were mechanical and physical restraint. Factors associated with subsequent increased IT utilization were female sex, lower age, previous admissions with psychiatric disorders before index admission, and IT related to those admissions. Factors associated with subsequent restraint were lower age, previous admissions with psychiatric disorders, and IT related to these. CONCLUSIONS: High IT utilization in a small percentage of individuals with AN is concerning and can lead to adverse treatment experiences. Exploring alternative approaches to treatment that reduce the need for IT is an important focus for future research.
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Anorexia Nerviosa , Tratamiento Involuntario , Humanos , Femenino , Masculino , Anorexia Nerviosa/terapia , Estudios de Cohortes , Estudios Retrospectivos , HospitalizaciónRESUMEN
BACKGROUND: Clinical, epidemiological, and genetic findings support an overlap between eating disorders, obsessive-compulsive disorder (OCD), and anxiety symptoms. However, little research has examined the role of genetics in the expression of underlying phenotypes. We investigated whether the anorexia nervosa (AN), OCD, or AN/OCD transdiagnostic polygenic scores (PGS) predict eating disorder, OCD, and anxiety symptoms in a large developmental cohort in a sex-specific manner. METHODS: Using summary statistics from Psychiatric Genomics Consortium AN and OCD genome-wide association studies, we conducted an AN/OCD transdiagnostic genome-wide association meta-analysis. We then calculated AN, OCD, and AN/OCD PGS in participants from the Avon Longitudinal Study of Parents and Children to predict eating disorder, OCD, and anxiety symptoms, stratified by sex (combined N = 3212-5369 per phenotype). RESULTS: The PGS prediction of eating disorder, OCD, and anxiety phenotypes differed between sexes, although effect sizes were small. AN and AN/OCD PGS played a more prominent role in predicting eating disorder and anxiety risk than OCD PGS, especially in girls. AN/OCD PGS provided a small boost over AN PGS in the prediction of some anxiety symptoms. All three PGS predicted higher compulsive exercise across different developmental timepoints [ß = 0.03 (s.e. = 0.01) for AN and AN/OCD PGS at age 14; ß = 0.05 (s.e. = 0.02) for OCD PGS at age 16] in girls. CONCLUSIONS: Compulsive exercise may have a transdiagnostic genetic etiology, and AN genetic risk may play a role in the presence of anxiety symptoms. Converging with prior twin literature, our results also suggest that some of the contribution of genetic risk may be sex-specific.
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Anorexia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Trastorno Obsesivo Compulsivo , Masculino , Femenino , Humanos , Anorexia Nerviosa/epidemiología , Estudios Longitudinales , Estudio de Asociación del Genoma Completo , Comorbilidad , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/genética , Trastorno Obsesivo Compulsivo/diagnóstico , Ansiedad/genéticaRESUMEN
BACKGROUND: Anorexia nervosa (AN) is a psychiatric disorder with complex etiology, with a significant portion of disease risk imparted by genetics. Traditional genome-wide association studies (GWAS) produce principal evidence for the association of genetic variants with disease. Transcriptomic imputation (TI) allows for the translation of those variants into regulatory mechanisms, which can then be used to assess the functional outcome of genetically regulated gene expression (GReX) in a broader setting through the use of phenome-wide association studies (pheWASs) in large and diverse clinical biobank populations with electronic health record phenotypes. METHODS: Here, we applied TI using S-PrediXcan to translate the most recent PGC-ED AN GWAS findings into AN-GReX. For significant genes, we imputed AN-GReX in the Mount Sinai BioMe™ Biobank and performed pheWASs on over 2000 outcomes to test the clinical consequences of aberrant expression of these genes. We performed a secondary analysis to assess the impact of body mass index (BMI) and sex on AN-GReX clinical associations. RESULTS: Our S-PrediXcan analysis identified 53 genes associated with AN, including what is, to our knowledge, the first-genetic association of AN with the major histocompatibility complex. AN-GReX was associated with autoimmune, metabolic, and gastrointestinal diagnoses in our biobank cohort, as well as measures of cholesterol, medications, substance use, and pain. Additionally, our analyses showed moderation of AN-GReX associations with measures of cholesterol and substance use by BMI, and moderation of AN-GReX associations with celiac disease by sex. CONCLUSIONS: Our BMI-stratified results provide potential avenues of functional mechanism for AN-genes to investigate further.
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Anorexia Nerviosa , Estudio de Asociación del Genoma Completo , Humanos , Anorexia Nerviosa/genética , Polimorfismo de Nucleótido Simple , Fenotipo , Transcriptoma , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Although bivariate associations between attention-deficit/hyperactivity disorder (ADHD) and eating disorders in adolescent girls and boys have been previously identified, the mechanistic link underlying the symptom-level associations remains unclear. We evaluated shared genetic and environmental influences on ADHD symptoms and disordered eating in 819 female and 756 male twins from the Swedish TCHAD cohort using bivariate models. Common additive genetic and unique environmental effects accounted for majority of ADHD and disordered eating associations in a differential manner. For girls, the strongest genetic correlation was observed for cognitive/inattention problems-bulimia (0.54), with genetic factors accounting for 67% of the phenotypic correlation. For boys, the strongest genetic correlations were observed for conduct problems-bulimia and hyperactivity-bulimia (~ 0.54), accounting for 83% and 95% of the phenotypic correlation, respectively. As per our findings, the risk of comorbidity and shared genetics highlights the need for preventative measures and specialized treatment for ADHD and disordered eating in both sexes.
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Trastorno por Déficit de Atención con Hiperactividad , Bulimia , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Masculino , Adolescente , Femenino , Trastorno por Déficit de Atención con Hiperactividad/genética , Bulimia/complicaciones , Bulimia/genética , Gemelos/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/complicaciones , ComorbilidadRESUMEN
Schizophrenia is a serious mental disorder with considerable somatic and psychiatric morbidity. It is unclear whether comorbid health conditions predominantly arise due to shared genetic risk or consequent to having schizophrenia. To explore the contribution of genetic risk for schizophrenia, we analysed the effect of schizophrenia polygenic risk scores (PRS) on a broad range of health problems in 406 929 individuals with no schizophrenia diagnosis from the UK Biobank. Diagnoses were derived from linked health data including primary care, hospital inpatient records, and registers with information on cancer and deaths. Schizophrenia PRS were generated and tested for associations with general health conditions, 16 ICD10 main chapters, and 603 diseases using linear and logistic regressions. Higher schizophrenia PRS was significantly associated with poorer overall health ratings, more hospital inpatient diagnoses, and more unique illnesses. It was also significantly positively associated with 4 ICD10 chapters: mental disorders; respiratory diseases; digestive diseases; and pregnancy, childbirth and the puerperium, but negatively associated with musculoskeletal disorders. Thirty-one specific phenotypes were significantly associated with schizophrenia PRS, and the 19 novel findings include several musculoskeletal diseases, respiratory diseases, digestive diseases, varicose veins, pituitary hyperfunction, and other peripheral nerve disorders. These findings extend knowledge of the pleiotropic effect of genetic risk for schizophrenia and offer insight into how some conditions often comorbid with schizophrenia arise. Additional studies incorporating the genetic basis of hormone regulation and involvement of immune mechanisms in the pathophysiology of schizophrenia may further elucidate the biological mechanisms underlying schizophrenia and its comorbid conditions.
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Esquizofrenia , Bancos de Muestras Biológicas , Femenino , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Herencia Multifactorial/genética , Factores de Riesgo , Esquizofrenia/genética , Reino Unido/epidemiologíaRESUMEN
Substantial progress has been made in the understanding of anorexia nervosa (AN) and eating disorder (ED) genetics through the efforts of large-scale collaborative consortia, yielding the first genome-wide significant loci, AN-associated genes, and insights into metabo-psychiatric underpinnings of the disorders. However, the translatability, generalizability, and reach of these insights are hampered by an overly narrow focus in our research. In particular, stereotypes, myths, assumptions and misconceptions have resulted in incomplete or incorrect understandings of ED presentations and trajectories, and exclusion of certain patient groups from our studies. In this review, we aim to counteract these historical imbalances. Taking as our starting point the Academy for Eating Disorders (AED) Truth #5 "Eating disorders affect people of all genders, ages, races, ethnicities, body shapes and weights, sexual orientations, and socioeconomic statuses", we discuss what we do and do not know about the genetic underpinnings of EDs among people in each of these groups, and suggest strategies to design more inclusive studies. In the second half of our review, we outline broad strategic goals whereby ED researchers can expand the diversity, insights, and clinical translatability of their studies.
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Anorexia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Femenino , Humanos , Masculino , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Anorexia Nerviosa/genéticaRESUMEN
BACKGROUND: Exercise for weight loss and maladaptive exercise (exercise that results in negative consequences or interference with daily life) are common behaviors among youth and are associated with increased risk of disordered eating symptoms. The current study clarifies processes that influence exercise-related risk in adolescence and young adulthood, including the frequency with which young people transition between engaging in exercise for weight loss and experiencing negative consequences of this behavior. METHOD: Participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) reported on eating disorder cognitions at age 14, and exercise behavior at ages 14, 16, 18, and 24 years old. Analyses examined rates of transition between the categories of 'No Exercise for Weight Loss', 'Exercise for Weight Loss', and 'Maladaptive Exercise' over time, identified overall trends in endorsement of exercise for weight loss and maladaptive exercise, and clarified predictors of these behaviors. RESULTS: Endorsement of exercise for weight loss and maladaptive exercise increased over time in both males and females. Those in the 'Exercise for Weight Loss' category were more likely than those in the 'No Exercise for Weight Loss Category' to transition to 'Maladaptive Exercise' over time. Body mass index (Age 13) and fear of weight gain (Age 14) were consistent predictors of maladaptive exercise across sex. CONCLUSIONS: Results support re-framing motivations for exercise in youth away from weight loss at a population level and targeting reductions in fear of weight gain for high-risk individuals.
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Conducta Alimentaria , Trastornos de Alimentación y de la Ingestión de Alimentos , Masculino , Femenino , Adolescente , Niño , Humanos , Adulto Joven , Adulto , Estudios Longitudinales , Índice de Masa Corporal , Aumento de Peso , Pérdida de PesoRESUMEN
Levine and Sadeh-Sharvit (2023) open the door to a logical and evidence-based targeted prevention strategy adapted from the field of depression. Their proposal is likely to benefit parents who are dealing with their own eating disorders and disordered eating while simultaneously breaking the cycle of risk inherent in the intergenerational transmission of eating disorders. The approach honors the wishes of parents who desperately want to buffer their children from the pain they experienced with their own suffering and provides hope for reducing environmental exposures that could augment any genetic risk that children of affected parents may hold.