Lisa Dinkler

Between 2014 and 2024, a multidisciplinary team of investigators at the Centre for Eating Disorders Innovation (CEDI) at Karolinska Institutet collected extensive clinical and self-report data and biological samples for genomic and other -omic studies from over 24,000 individuals with eating disorders (anorexia nervosa, bulimia nervosa, binge-eating disorder, atypical anorexia nervosa, and avoidant restrictive food intake disorder) and appropriately matched controls. CEDI studies were funded by Swedish (e.g., Swedish Research Council, FORTE, Hjärnfonden, ALF)

Danish (Lundbeckfonden)

American (National Institute of Mental Health)

industry (Shire/Takeda)

and philanthropic sources (e.g., Klarman Family Foundation, Actum Foundation)—an unprecedented investment in eating disorders science.CEDI data and samples represent a global resource that is poised to answer future questions about the biology, psychology, and environmental factors that influence risk, maintenance, and recovery from eating disorders and co-occurring conditions such as depression, anxiety, and obsessive-compulsive disorder. Moreover, our discovery of a metabolic genetic component to anorexia nervosa lends our data and samples to investigations of conditions of global public health relevance such as obesity and type 2 diabetes. No eating disorders collection in the world rivals the depth and completeness of our resource. To ensure its longevity, utility, and accessibility in accord with FAIR principles, we propose the development of CEDIX—a comprehensive, harmonized, searchable database comprising data and metadata from all CEDI studies linked with a searchable and accessible biobank of DNA, saliva, microbiome, plasma, and other study-specific biological samples housed in the KI Biobank. We will develop and systematize a self-supporting scheme for requesting data and sample access

for verifying ethical approval and GDPR compliance

and a mechanism for growing CEDIX by requiring deposit of created variables and novel findings back into the database. FORTE support would provide the personnel and infrastructure to refine, thoroughly test, and publicize availability of the resource. CEDIX and its biorepository will be an invaluable resource for current researchers as well as future global investigators who develop novel hypotheses and apply emerging methodology to address etiology, treatment, recovery, and relapse of these life-impairing and too frequently fatal conditions.

PROJECT SUMMARY We propose the Eating Disorders Genetics Initiative 2 (EDGI2), a new collaborative R01 in response to PAR- 23-050 Clinical Studies of Mental Illness. Its single-site predecessors, EDGI1 (R01 MH120170) and ARFID-GEN (R56 MH129437) have been resoundingly successful. We now unite the four original EDGI1 sites with exceptionally productive global new sites to advance genomic discovery across all major eating disorders (EDs) to identify biologically, clinically, culturally, and therapeutically meaningful and actionable insights. Aim 1: EDGI2 extends our core business by increasing sample size, diversity, and ED phenotypes. Using our comprehensive harmonized online assessment battery, we will phenotype 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. EDGI2 emphasizes co-production—with representatives from minoritized and marginalized communities, we will ascertain 30% of samples from underrepresented groups. We will also over- sample individuals with severe and enduring AN (SE-AN), whose DNA may be enriched for causative alleles. Aim 2: We will apply statistical genetic analyses to explicate heterogeneity and biology of EDs by: conducting standard GWAS analyses on diagnoses, trans-diagnostic behaviors, and continuous phenotypes including polygenic risk score (PRS), and rare variant CNV analyses

identifying clinically meaningfully patient subsets

and intensively evaluating our proposal that AN is a metabo-psychiatric disorders using LDSC, PRSet, pheWAS, and Mendelian randomization to clarify direction of causation. Aim 3: We will evaluate the relative roles of genetic and environmental risk and resilience factors to inform risk prediction by phenotypically characterizing cases and controls with high and low PRS for EDs 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 strongly implicated by the genomics of each ED

expand to relevant non-brain cell types (e.g., adipose, muscle, liver, salivary)

and use dynamic GREx to model gene expression in ED-relevant contexts (e.g., sex, BMI, stress) enabling precise and personalized modelling of gene expression. Aim 5: EDGI2 will culminate in a Translational Summit uniting forward-thinking stakeholders from multiple sectors to develop a translational 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.

Undvikande/restriktiv ätstörning (avoidant restrictive food intake disorder, ARFID) är en allvarlig, nydefinierad diagnos med en uppskattad prevalens på 1-5 %. ARFID kännetecknas av ett kraftigt begränsat matintag som leder till att den drabbade inte uppfyller sina närings- och/eller energibehov, med stor negativ hälsoinverkan. Heterogeniteten i gruppen av ARFID-patienter och bristen på kunskap om ARFID:s uppkomst försvårar utvecklingen av behandlingsåtgärder. För att kunna utveckla evidensbaserade ARFID-behandlingar är det viktigt att kunna identifiera och karakterisera subgrupper med olika behov. Detta projekt kommer att studera 33 902 svenska tvillingar, varav 682 barn med ARFID. Med hjälp av tvilling- och molekylärgenetisk metodik kommer jag att identifiera subgrupper inom ARFID genom att utforska orsaksfaktorer som ARFID delar med andra tillstånd såsom ångest, autism, ADHD, och somatiska sjukdomar. Jag kommer även att testa huruvida generna som är associerade med dessa tillstånd kan förklara uppkomsten av ARFID. Därefter kommer jag att testa och förfina subgrupperna i ytterligare en grupp bestående av 3 000 barn och vuxna med ARFID i USA. Resultaten kommer att ge unika insikter om orsakerna bakom ARFID, som i sin tur kommer att bidra till utvecklingen av åtgärder för upptäckt, förebyggande och behandling. Med detta hoppas jag kunna bidra till att vården för personer med ARFID förbättras avsevärt, då denna i dagsläget är otillräcklig.

The aim is to add ARFID, as the most under-researched major eating disorder, to the global effort of elucidating the genomics of eating disorders. We collect online surveys and DNA via saliva from 1,500 Swedish adolescents with ARFID and 500 controls. Data will be combined with genotypes of people with ARFID or other eating disorders worldwide. We will provide the most detailed phenotypic information about ARFID in adolescence to date, conduct comprehensive genomic analyses to identify the genetic factors contributing to ARFID, and clarify ARFID’s relationships with other eating disorders.

Research problem and specific questions. Avoidant/restrictive food intake disorder is a serious, taxing, and potentially life-threatening condition that affects 1-5% of the population. First recognized in 2013, we know little about causes, course, maintenance factors, and outcome

however, nutritional, medical, and psychosocial consequences are severe. We propose establishing a re-contactable, longitudinal cohort (ARFID InitiativE Sweden: ARIES) to study genetic and environmental contributors to ARFID through a developmental lens. ARIES will include rich phenotyping, DNA samples, and stool samples in a national data- and biorepository linkable to Swedish population health and quality registers to answer fundamental questions about this pernicious, life-impairing, and understudied condition. Data and method. We will first form a community-based Parent Advisory Committee (PAC) to guide our assessment domains and then recruit 500 children ages 4-9 with ARFID and 500 age and gender matched controls

collect parental report via online questionnaires on development, feeding history, food preferences, behavior, mood, feeding-related adverse events, and other domains suggested by the PAC

and create a biobank of saliva (for DNA) and stool (for intestinal microbiota and microbiome). Plan for project realisation. We will launch a national recruitment campaign using our country-wide collaborations with eating disorders clinicians and pediatricians and our social media channels to reach parents of children with ARFID. After an online eligibility screen, parents will complete questionnaires

submit saliva samples for their children

and provide a stool sample. Families will enroll in ARIES, agreeing to regular follow-ups. In addition to baseline research aims, ARIES will enable identification of predictors of transient versus enduring illness course, impact of puberty on ARFID symptoms, and impact of ARFID on educational achievement. Linking ARIES with population registers will allow research questions about ARFID comorbidity and healthcare utilization. Relevance. No evidence-based treatment for ARFID and no national guidelines exist. Parents desperately seek guidance on managing ARFID and fear for their child’s long-term well-being. ARIES will be the foundation for understanding ARFID, identifying factors related to onset, maintenance, and outcome, and be a national and international resource for essential research.