Polygenicity at the pathway level for anorexia nervosa

Abstract Genome-wide association studies of common disorders reveal polygenic architectures. While these variants may converge into biologically relevant pathways, how polygenicity aggregates across pathways remains unknown. We studied polygenicity at the pathway level in anorexia nervosa (AN)—a psychiatric disorder with multi-systemic clinical manifestations. We constructed pathway-based polygenic risk scores (pathway PRS) to model genetic risk at the pathway level for 3,687 individuals with AN and 11,257 controls. We identified 497 AN- associated pathways after Bonferroni correction, including pathways involved in the brain, metabolism, immunity/stress, and reproduction/development. A strong positive correlation was observed between number of pathways ranking at top 10% and AN case proportion (r = 0.74, P = 7.98×10−21). The positive correlation between pathway count and AN risk was also observed when restricted to individuals with low overall genetic risk of AN. Pathways ranking at top 10% among cases were more diverse than those in controls. Higher AN risk was observed for pathway aggregation within function (e.g., brain or metabolism) and across functions (e.g., brain + metabolism). Individuals at top 10% risk of brain-brain and brain-metabolism pathway pairs had the highest average AN risk compared to other pathway pairs (e.g., brain-immune, metabolism- metabolism). Further, pathway PRS provided higher prediction power of AN than overall genome-wide PRS and contributed to the genetic liability of AN among AN cases with low overall genetic risk. Together, our results demonstrate that polygenicity exists at the pathway level, opening new avenues for disease prediction and identification of actionable targets. Competing Interest Statement C.M.B. reports Pearson Education Inc. (author, royalty recipient) and Orbimed (consultant). The rest of authors declare no competing interests. Funding Statement J.X. and L.M.H. are both supported by the National Institute of Mental Health (NIMH) grants R01MH124839 and R01MH136149. CMB is supported by NIMH (R01MH136149, R01MH134039, R56MH129437, R01MH120170, R01MH124871, R01MH124871), Swedish Research Council (Vetenskapsrådet, award: 538-2013-8864), and Swedish Research Council 2024 (2024-02450). J.G.G. is supported by a grant from the National Human Genome Research Institute (NHGRI, 1K99HG013547-01). P.F.O. is supported by funding from NIMH (R01MH122866) and NHGRI (R01HG012773). K.J.B. is supported by funding from NIMH (R01MH109897, R56MH101454, R01MH123155, R01MH106056) and from the National Institute of Environmental Health Sciences (R01ES033630). The funding body is not involved in the study design, data collection, data analysis, result interpretation, and writing of the manuscript. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Because only deidentified data were used, our study was not considered as human research under the US Department of Health and Human Services regulations and was thus exempt from the Yale ethics committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵# These are co-first authors. Data availability Datasets from the Psychiatric Genomics Consortium Eating Disorders Working Group are available by requesting data access through the PGC data access portal (https://pgc.unc.edu/for-researchers/data-access-committee/data-access-portal/).