Genetic correlation analysis identifies TMEM106B, ACE, and ERC2 as genetic loci shared between Alzheimer’s disease and primary psychiatric disorders

Background Neuropsychiatric symptoms (NPS) occur in up to 85% of Alzheimer’s disease (AD) cases. Current treatments—repurposed from psychiatric disorders despite limited understanding of etiologic overlap—are often ineffective.

To characterize the genetic overlap between AD and major psychiatric disorders and identify shared molecular pathways we conducted genetic correlation analyses between AD and depression, schizophrenia, bipolar disorder and anxiety using MiXeR and LAVA using GWAS summary statistics (AD: n=487,511; bipolar disorder: n=413,466; depression: n=1,154,267; schizophrenia: n=130,644; anxiety: n=1,096,458).

Genetic correlation analyses followed by fine mapping and functional analyses identified a missense variant in TMEM106B (rs3173615) shared between AD and depression and anxiety, a regulatory region variant in ACE (rs4292) shared between AD/schizophrenia, and two NMD transcript variants in ERC2 (rs17288728; rs815460) shared between AD/anxiety.

The specific molecular pathways associated with these variants provide critical information on shared etiologic components underlying these traits, and inform development of improved therapeutic targets. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the National Institutes of Health (NIH) under awards P30AG066462, U01AG079850, and R01AG064614. The funders had no role in study design; data collection, analysis, or interpretation; manuscript preparation; or the decision to submit this work for publication. Except for the support listed above, the authors and their institutions did not receive payment or services from any third party for any aspect of the submitted work. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 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: This study analyzed third party GWAS summary statistics. A portion of the data is controlled access (dbGaP) and the remainder is openly available at public repositories. No individual level data were used. Controlled access: Million Veteran Program (MVP) GWAS summary statistics obtained under an approved data access request from dbGaP (accession: phs001672.v1.p1). Access requires application/approval and a data use agreement. Openly available: 1. Alzheimer disease: Bellenguez C. et al. Nat Genet (2022) DOI: 10.1038/s41588-022-01024-z; GWAS summary statistics in EBI GWAS Catalog, accession GCST90027158. 2. Bipolar disorder: Mullins N. et al. Nat Genet (2021) DOI: 10.1038/s41588-021-00857-4; summary statistics publicly available via the PGC Results & Downloads portal (https://www.med.unc.edu/pgc/results-and-downloads ). 3. Schizophrenia: Trubetskoy V. et al. Nature (2022) DOI: 10.1038/s41586-022-04434-5; summary statistics available via the PGC schizophrenia downloads page (https://www.med.unc.edu/pgc/download-results/scz/ ). 4. Anxiety disorders: Friligkou E. et al. Nat Genet (2024) DOI: 10.1038/s41588-024-01908-2; summary statistics on Zenodo, DOI 10.5281/zenodo.13135834. 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 Data Availability This study analyzed third-party GWAS summary statistics. A portion of the data is controlled-access and the remainder is openly available. No individual-level data were used, and this work did not generate new human datasets. Controlled-access: Million Veteran Program (MVP) GWAS summary statistics obtained via dbGaP (accession phs001672.v1.p). Access is controlled and requires an approved data-access request and data-use agreement. Openly available: 1. Alzheimer disease: Bellenguez et al. (2022), EBI GWAS Catalog accession GCST90027158 (DOI: 10.1038/s41588-022-01024-z). 2. Bipolar disorder: Mullins et al. (2021), publicly available via the PGC Results & Downloads portal (DOI: 10.1038/s41588-021-00857-4). 3. Schizophrenia: Trubetskoy et al. (2022), publicly available via the PGC schizophrenia downloads page (DOI: 10.1038/s41586-022-04434-5). 4. Anxiety disorders: Friligkou et al. (2024), Zenodo DOI 10.5281/zenodo.13135834.