<p>Schizophrenia and related psychoses occur in all human populations, with the highest rates of diagnosis among Black individuals and those of mainly African ancestry<sup><CitationRef CitationID="CR1">1</CitationRef></sup>. Decades of research have established a highly heritable and polygenic basis for schizophrenia, which is mostly shared across populations<sup><CitationRef AdditionalCitationIDS="CR3" CitationID="CR2">2</CitationRef>–<CitationRef CitationID="CR4">4</CitationRef></sup>. However, a recruitment bias towards European cohorts<sup><CitationRef CitationID="CR5">5</CitationRef></sup> has led to discoveries that are poorly generalizable to African populations. This exclusion of the world’s most genetically diverse populations narrows our understanding of disease biology and risks exacerbating health disparities. Here we show that electronic health records linked with genomic data from the Million Veteran Program (MVP)<sup><CitationRef CitationID="CR6">6</CitationRef></sup>—a national research programme that looks at the effects of&#xa0;genes, lifestyle, military experiences&#xa0;and exposures on the&#xa0;health and wellness of&#xa0;veterans—enable a comprehensive assessment of schizophrenia genetics in populations of African ancestry&#xa0;in the USA. We identify ancestry-independent associations in African populations and expand the catalogue of implicated regions by more than 100 loci. Through statistical fine-mapping and integrative transcriptomic analyses, we refine disease-associated signals to consensus genes with convergent neurobiological functions. These findings provide a much-needed view of schizophrenia’s genetic architecture in populations of African ancestry, and offer biological insights that both extend previous work and broaden its global relevance.</p>

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Biological insights into schizophrenia from ancestrally diverse populations

  • Tim B. Bigdeli,
  • Chris Chatzinakos,
  • Jaroslav Bendl,
  • Peter B. Barr,
  • Sanan Venkatesh,
  • Bryan R. Gorman,
  • Tereza Clarence,
  • Giulio Genovese,
  • Conrad O. Iyegbe,
  • Roseann E. Peterson,
  • Sergios-Orestis Kolokotronis,
  • David Burstein,
  • Jacquelyn L. Meyers,
  • Yuli Li,
  • Sundar Natarajan,
  • Michael O. Francis,
  • Nallakkandi Rajeevan,
  • Kei-Hoi Cheung,
  • Lynn E. DeLisi,
  • Thomas R. Kosten,
  • Hongyu Zhao,
  • Eric Achtyes,
  • Peter F. Buckley,
  • Dolores Malaspina,
  • Douglas Lehrer,
  • Mark H. Rapaport,
  • David L. Braff,
  • Michele T. Pato,
  • Ayman H. Fanous,
  • Carlos N. Pato,
  • Grant D. Huang,
  • Sumitra Muralidhar,
  • J. Michael Gaziano,
  • Saiju Pyarajan,
  • Kiran Girdhar,
  • Donghoon Lee,
  • Gabriel E. Hoffman,
  • Mihaela Aslan,
  • John F. Fullard,
  • Georgios Voloudakis,
  • Philip D. Harvey,
  • Panos Roussos

摘要

Schizophrenia and related psychoses occur in all human populations, with the highest rates of diagnosis among Black individuals and those of mainly African ancestry1. Decades of research have established a highly heritable and polygenic basis for schizophrenia, which is mostly shared across populations24. However, a recruitment bias towards European cohorts5 has led to discoveries that are poorly generalizable to African populations. This exclusion of the world’s most genetically diverse populations narrows our understanding of disease biology and risks exacerbating health disparities. Here we show that electronic health records linked with genomic data from the Million Veteran Program (MVP)6—a national research programme that looks at the effects of genes, lifestyle, military experiences and exposures on the health and wellness of veterans—enable a comprehensive assessment of schizophrenia genetics in populations of African ancestry in the USA. We identify ancestry-independent associations in African populations and expand the catalogue of implicated regions by more than 100 loci. Through statistical fine-mapping and integrative transcriptomic analyses, we refine disease-associated signals to consensus genes with convergent neurobiological functions. These findings provide a much-needed view of schizophrenia’s genetic architecture in populations of African ancestry, and offer biological insights that both extend previous work and broaden its global relevance.