Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Cuihua Xia^{1

2

3}, Ney Alliey-Rodriguez^{2

4}, Carol A Tamminga⁵, Matcheri S Keshavan⁶, Godfrey D Pearlson^{7

8}, Sarah K Keedy², Brett Clementz⁹, Jennifer E McDowell⁹, David Parker^{9

10}, Rebekka Lencer^{11

12}, S Kristian Hill¹³, Jeffrey R Bishop¹⁴, Elena I Ivleva⁵, Cindy Wen¹⁵, Rujia Dai¹⁶, Chao Chen^{17

18

19}, Chunyu Liu^{20

21}, Elliot S Gershon^{22

23}

Affiliations

¹ MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
³ Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
⁴ Institute of Neuroscience, University of Texas Rio Grande Valley, Harlingen, TX, USA.
⁵ Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁷ Departments of Psychiatry and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
⁸ Institute of Living, Hartford Healthcare Corp, Hartford, CT, USA.
⁹ Departments of Psychology and Neuroscience, BioImaging Research Center, University of Georgia, Athens, GA, USA.
¹⁰ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Institute for Translational Psychiatry, Münster University, Münster, Germany.
¹² Department of Psychiatry and Psychotherapy, Lübeck University, Lübeck, Germany.
¹³ Department of Psychology, Rosalind Franklin University of Medicine and Science, Chicago, IL, USA.
¹⁴ Department of Experimental and Clinical Pharmacology and Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁶ Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
¹⁷ MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
¹⁸ Furong Laboratory, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
¹⁹ National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
²⁰ MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. LiuCh@upstate.edu.
²¹ Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA. LiuCh@upstate.edu.
²² Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA. egershon@bsd.uchicago.edu.
²³ Department of Human Genetics, The University of Chicago, Chicago, IL, USA. egershon@bsd.uchicago.edu.

PMID: 39709506
PMCID: PMC12092190 (available on 2026-06-01)
DOI: 10.1038/s41380-024-02876-z

Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Cuihua Xia et al. Mol Psychiatry. 2025 Jun.

. 2025 Jun;30(6):2673-2685.

doi: 10.1038/s41380-024-02876-z. Epub 2024 Dec 21.

Authors

Affiliations

¹ MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
³ Department of Human Genetics, The University of Chicago, Chicago, IL, USA.
⁴ Institute of Neuroscience, University of Texas Rio Grande Valley, Harlingen, TX, USA.
⁵ Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁷ Departments of Psychiatry and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
⁸ Institute of Living, Hartford Healthcare Corp, Hartford, CT, USA.
⁹ Departments of Psychology and Neuroscience, BioImaging Research Center, University of Georgia, Athens, GA, USA.
¹⁰ Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Institute for Translational Psychiatry, Münster University, Münster, Germany.
¹² Department of Psychiatry and Psychotherapy, Lübeck University, Lübeck, Germany.
¹³ Department of Psychology, Rosalind Franklin University of Medicine and Science, Chicago, IL, USA.
¹⁴ Department of Experimental and Clinical Pharmacology and Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Interdepartmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁶ Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
¹⁷ MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
¹⁸ Furong Laboratory, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
¹⁹ National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. chenchao@sklmg.edu.cn.
²⁰ MOE Key Laboratory of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. LiuCh@upstate.edu.
²¹ Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA. LiuCh@upstate.edu.
²² Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA. egershon@bsd.uchicago.edu.
²³ Department of Human Genetics, The University of Chicago, Chicago, IL, USA. egershon@bsd.uchicago.edu.

PMID: 39709506
PMCID: PMC12092190 (available on 2026-06-01)
DOI: 10.1038/s41380-024-02876-z

Abstract

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes, and isoforms showed significant genomic associations with specific Biotypes in a Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in the adult brain and fetal brain. TWAS inflation was addressed by the inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes TMEM140, ARTN, C1orf115, CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.

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Conflict of interest statement

Competing interests: CX: None. NA-R: None. CAT: B-SNIP Diagnostics, Board of Managers; Kynexis, Scientific Advisory Board and retainer; Merck DSMB; Neuventis, Board, own stock. MSK: B-SNIP Diagnostics, Board of Managers; Advisor to Alkermes. GDP: B-SNIP Diagnostics, Board of Managers. SKK: B-SNIP Diagnostics, Board of Managers. BC: B-SNIP Diagnostics, Board of Managers; Kynexis Corporation, Scientific Advisory Board. JEM: B-SNIP Diagnostics, Board of Managers. DP: None. RL: None. SKH: None. JRB: None. EII: B-SNIP Diagnostics, Board of Managers. CW: None. RD: None. CC: None. CL: None. ESG: B-SNIP Diagnostics, Board of Managers; Consultant: Kynexis Corporation. Ethics approval and consent to participate: All methods were performed in accordance with the relevant guidelines and regulations. B-SNIP recruitment sites were in Athens GA (the University of Georgia and Augusta University Medical College of Georgia), Baltimore MD (Maryland Psychiatric Research Center), Boston MA (Beth Israel Deaconess Medical Center), Chicago IL (the University of Illinois-Chicago and University of Chicago), Dallas TX (UT Southwestern Medical Center), Detroit MI (Wayne State University), and Hartford CT (Institute of Living). All recruitments, interviews, and laboratory data collections were completed at those locations. The Institutional Review Board at participating institutions approved the projects; all participants provided informed consent prior to involvement.

Update of

Genetic Analysis of Psychosis Biotypes: Shared Ancestry-Adjusted Polygenic Risk and Unique Genomic Associations.
Xia C, Alliey-Rodriguez N, Tamminga CA, Keshavan MS, Pearlson GD, Keedy SK, Clementz B, McDowell JE, Parker D, Lencer R, Hill SK, Bishop JR, Ivleva EI, Wen C, Dai R, Chen C, Liu C, Gershon ES. Xia C, et al. medRxiv [Preprint]. 2024 Dec 8:2024.12.05.24318404. doi: 10.1101/2024.12.05.24318404. medRxiv. 2024. Update in: Mol Psychiatry. 2025 Jun;30(6):2673-2685. doi: 10.1038/s41380-024-02876-z. PMID: 39677452 Free PMC article. Updated. Preprint.

References

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1. Hill SK, Reilly JL, Keefe RS, Gold JM, Bishop JR, Gershon ES et al. Neuropsychological impairments in schizophrenia and psychotic bipolar disorder: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Am J Psychiatry 2013; 170(11): 1275–1284. - PMC - PubMed
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Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Affiliations

Genetic analysis of psychosis Biotypes: shared Ancestry-adjusted polygenic risk and unique genomic associations

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous