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medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.27.24312631
preprint
1
Article
Biological Insights from Schizophrenia-associated Loci in Ancestral Populations
Bigdeli Tim B. http://orcid.org/0000-0003-2215-5946

Chatzinakos Chris
Bendl Jaroslav
Barr Peter B.
Venkatesh Sanan
Gorman Bryan R.
Clarence Tereza
Genovese Giulio
Iyegbe Conrad O.
Peterson Roseann E.
Kolokotronis Sergios-Orestis
Burstein David
Meyers Jacquelyn L.
Li Yuli
Rajeevan Nallakkandi
Sayward Frederick
Cheung Kei-Hoi
Project Among African-Americans to Explore Risks for Schizophrenia (PAARTNERS)
Consortium on the Genomics of Schizophrenia (COGS)
Genomic Psychiatry Cohort (GPC) Investigators
DeLisi Lynn E.
Kosten Thomas R.
Zhao Hongyu
Achtyes Eric
Buckley Peter
Malaspina Dolores
Lehrer Douglas
Rapaport Mark H.
Braff David L.
Pato Michele T.
Fanous Ayman H.
Pato Carlos N.
Consortium PsychAD
Cooperative Studies Program (CSP) #572
Million Veteran Program (MVP)
Huang Grant D.
Muralidhar Sumitra
Gaziano J. Michael
Pyarajan Saiju
Girdhar Kiran
Lee Donghoon
Hoffman Gabriel E.
Aslan Mihaela
Fullard John F.
Voloudakis Georgios
Harvey Philip D.
Roussos Panos http://orcid.org/0000-0002-4640-6239

28 8 2024
2024.08.27.24312631https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.08.27.24312631
nihpp-2024.08.27.24312631.pdf
ABSTRACT

Large-scale genome-wide association studies of schizophrenia have uncovered hundreds of associated loci but with extremely limited representation of African diaspora populations. We surveyed electronic health records of 200,000 individuals of African ancestry in the Million Veteran and All of Us Research Programs, and, coupled with genotype-level data from four case-control studies, realized a combined sample size of 13,012 affected and 54,266 unaffected persons. Three genome-wide significant signals — near PLXNA4 , PMAIP1 , and TRPA1 — are the first to be independently identified in populations of predominantly African ancestry. Joint analyses of African, European, and East Asian ancestries across 86,981 cases and 303,771 controls, yielded 376 distinct autosomal loci, which were refined to 708 putatively causal variants via multi-ancestry fine-mapping. Utilizing single-cell functional genomic data from human brain tissue and two complementary approaches, transcriptome-wide association studies and enhancer-promoter contact mapping, we identified a consensus set of 94 genes across ancestries and pinpointed the specific cell types in which they act. We identified reproducible associations of schizophrenia polygenic risk scores with schizophrenia diagnoses and a range of other mental and physical health problems. Our study addresses a longstanding gap in the generalizability of research findings for schizophrenia across ancestral populations, underlining shared biological underpinnings of schizophrenia across global populations in the presence of broadly divergent risk allele frequencies.
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