[R01] 1/3 Eating Disorders Genetics Initiative 2 (EDGI2)
Ente: National Institute of Mental Health
Scadenza: 2029-02-28
Importo max: 1.832.091 EUR
Paese: US
Descrizione
We propose the Eating Disorders Genetics Initiative 2 (EDGI2), a new collaborative R01 in response to PAR-23-050. Its predecessor, EDGI1 (R01 MH120170) was highly successful. We now include global sites to advance discovery across all major eating disorders (EDs) to identify biologically, clinically, and therapeutically actionable insights. Including foreign sites is essential scientifically: sample sizes required to detect genetic variants of small effect, that can have major health implications for Americans, can only be achieved through global collaboration. Findings will accelerate genetic insights that benefit US patients with EDs. Aim 1: Using our comprehensive online platform, EDGI2 will enroll and bio-sample 20,000 new participants with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), avoidant/restrictive food intake disorder (ARFID), and controls, over-sampling people with severe and enduring AN (SE-AN), whose DNA may be enriched for causative alleles. Aim 2: Statistical genetic analyses will explicate ED heterogeneity and biology. We will conduct standard GWAS analyses on diagnoses, cross-diagnostic behaviors, and continuous traits including polygenic risk score (PRS), and rare variant CNV analyses; identify clinically meaningfully patient subsets; and further evaluate our proposal that AN is a metabo-psychiatric disorder using LDSC, PRSet, pheWAS, and Mendelian randomization to clarify direction of causation. Aim 3: We will evaluate genetic and environmental risk and resilience factors to inform risk prediction by phenotypically characterizing cases and controls with high and low ED PRS and then by genotypically characterizing those with severe ED phenotypes. We will characterize distinct genetic or molecular groupings/patterns across cases and controls and phenotypically characterize identified molecular subtypes. Aim 4: To determine where in the body EDs “live”, we will identify brain cell types and anatomical regions implicated by genomic studies of EDs; predict genetically regulated gene expression (GREx) in brain, gut, adipose, and other ED-relevant tissues; use snRNAseq atlases to sharpen preliminary GTEx and TWAS analyses to identify brain cell types implicated by the genomics of each ED; expand to relevant non-brain cell types (e.g., adipose, muscle, liver); and use dynamic GREx to model gene expression in ED-relevant contexts (e.g., sex, BMI, stress) enabling precise modelling of gene expression. Aim 5: A Translational Summit will unite prominent individuals from multiple sectors to develop a roadmap for evidence-based ED prevention and treatment. EDGI2 will yield critical knowledge about genetic and environmental risk for EDs, reveal mechanisms that potentiate or protect against genetic risk, and transition ED genetics from discovery to clinical translation.
Istituzione: UNIV OF NORTH CAROLINA CHAPEL HILL
PI: CYNTHIA M BULIK, Laura Marianne Huckins
Progetto: 5R01MH136149-03
Settori: National Institute of Mental Health
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