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

Cuihua Xia; Ney Alliey-Rodriguez; Carol A Tamminga; Matcheri S Keshavan; Godfrey D Pearlson; Sarah K Keedy; Brett Clementz; Jennifer E McDowell; David Parker; Rebekka Lencer; S Kristian Hill; Jeffrey R Bishop; Elena I Ivleva; Cindy Wen; Rujia Dai; Chao Chen; Chunyu Liu; Elliot S Gershon

doi:10.1038/s41380-024-02876-z

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

Mol Psychiatry. 2024 Dec 21. doi: 10.1038/s41380-024-02876-z. Online ahead of print.

Authors

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
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.