{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:27:05Z","timestamp":1791404825938,"version":"4.3.3"},"posted":{"date-parts":[[2026,1,5]]},"group-title":"Genetic and Genomic Medicine","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,5]]},"abstract":"<jats:p>Background: The predictive power of polygenic scores (PGSs) for lithium treatment response in bipolar disorder (BD) remains limited.\n\nAim: To enhance prediction of lithium responsiveness by developing a multi-trait PGS (mt-PGS) combining genetic information from multiple phenotypes implicated in lithium response and\/or BD aetiology.\n\nMethods: We analysed data collected from BD patients who had received lithium treatment for at least six months and participated in the International Consortium on Lithium Genetics (ConLi+Gen, N=2,367) study. The ALDA scale was used to assess lithium responsiveness, and treatment outcome was defined as continuous ALDA score (0-10) and categorical outcome (favourable \u22657 vs unfavourable response). PGSs were calculated for 59 phenotypes grouped into five clinical-biological clusters: clinical lithium exemplar (#22 phenotypes), cardiometabolic (#17), autoimmune\/inflammatory (#5), neurocognitive (#8) and renal function (#7). We applied cross-validated machine learning regression approaches in both outcomes within each cluster, and the selected features from each cluster were subsequently combined to construct the final mt-PGS models. Model performance was assessed using explained variance (R2) for the continuous outcome, and McFaddens pseudo-R2 as well as standard classification model parameters for the categorical outcomes.\n\nResults: The mt-PGS explained 5.07% (continuous outcome) to 9.02% (categorical outcome) of the interindividual variability in lithium responsiveness. Classification accuracy (AUC) for the categorical outcome was 68.13% (95% CI: 64.86, 71.77). Of the five clusters, the PGSs for clinical lithium exemplar phenotypes were most strongly associated with lithium responsiveness, accounting for 2.97%-6.20% of its variability.\n\nConclusions: By integrating polygenic scores for multiple relevant phenotypes, predictive accuracy for lithium response improved up to nine-fold compared to single-trait methods. Future research incorporating larger, more diverse populations and combining genetic scores with clinical data holds promise for further enhancing prediction and advancing clinical implementation.<\/jats:p>","DOI":"10.64898\/2026.01.01.25343187","type":"posted-content","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T22:25:18Z","timestamp":1767651918000},"source":"Crossref","is-referenced-by-count":2,"title":["Using multi-trait polygenic scores to predict lithium responsiveness in patients with bipolar disorder"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6443-6992","authenticated-orcid":false,"given":"Nigussie T.","family":"Sharew","sequence":"first","affiliation":[{"name":"Discipline of Psychiatry, School of Medicine, College of Health, Adelaide University, Adelaide, SA, Australia.;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott R.","family":"Clark","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, School of Medicine, College of Health, Adelaide University, Adelaide, SA, Australia.;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, School of Medicine, College of Health, Adelaide University, Adelaide, SA, Australia.;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergi","family":"Papiol","sequence":"additional","affiliation":[{"name":"Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig Maximilian University of Munich, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"International Consortium on Lithium Genetics Collaborators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Schulze","sequence":"additional","affiliation":[{"name":"Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig Maximilian University of Munich, Munich, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard T.","family":"Baune","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University of Munster, Munster, Germany.;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus Oliver","family":"Schubert","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, School of Medicine, College of Health, Adelaide University, Adelaide, SA, Australia.;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7940-0335","authenticated-orcid":false,"given":"Azmeraw T","family":"Amare","sequence":"additional","affiliation":[{"name":"Discipline of Psychiatry, School of Medicine, College of Health, Adelaide University, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.01.25343187","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T22:25:18Z","timestamp":1767651918000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.01.01.25343187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,5]]},"references-count":0,"URL":"https:\/\/doi.org\/10.64898\/2026.01.01.25343187","relation":{},"subject":[],"published":{"date-parts":[[2026,1,5]]},"subtype":"preprint"}}