Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia

Kristina Dobrindt; Hanwen Zhang; Debamitra Das; Sara Abdollahi; Tim Prorok; Sulagna Ghosh; Sarah Weintraub; Giulio Genovese; Samuel K Powell; Anina Lund; Schahram Akbarian; Kevin Eggan; Steven McCarroll; Jubao Duan; Dimitrios Avramopoulos; Kristen J Brennand

doi:10.1159/000512716

Publicly Available hiPSC Lines with Extreme Polygenic Risk Scores for Modeling Schizophrenia

Complex Psychiatry. 2021 Feb;6(3-4):68-82. doi: 10.1159/000512716. Epub 2020 Nov 2.

Authors

Kristina Dobrindt^{1

2}, Hanwen Zhang³, Debamitra Das⁴, Sara Abdollahi⁴, Tim Prorok³, Sulagna Ghosh^{5

6}, Sarah Weintraub³, Giulio Genovese^{5

6}, Samuel K Powell^{1

2}, Anina Lund^{1

2}, Schahram Akbarian², Kevin Eggan^{6

7}, Steven McCarroll^{5

6}, Jubao Duan^{3

8}, Dimitrios Avramopoulos⁴, Kristen J Brennand^{1

2}

Affiliations

¹ Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomics, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, Illinois, USA.
⁴ Department of Genetic Medicine and Psychiatry, Johns Hopkins University, Baltimore, Maryland, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁶ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
⁷ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
⁸ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois, USA.

Abstract

Schizophrenia (SZ) is a common and debilitating psychiatric disorder with limited effective treatment options. Although highly heritable, risk for this polygenic disorder depends on the complex interplay of hundreds of common and rare variants. Translating the growing list of genetic loci significantly associated with disease into medically actionable information remains an important challenge. Thus, establishing platforms with which to validate the impact of risk variants in cell-type-specific and donor-dependent contexts is critical. Towards this, we selected and characterized a collection of 12 human induced pluripotent stem cell (hiPSC) lines derived from control donors with extremely low and high SZ polygenic risk scores (PRS). These hiPSC lines are publicly available at the California Institute for Regenerative Medicine (CIRM). The suitability of these extreme PRS hiPSCs for CRISPR-based isogenic comparisons of neurons and glia was evaluated across 3 independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs on which we hope to perform genome engineering and generate diverse kinds of functional data, with comparisons across studies facilitated by the use of a common set of genetic backgrounds.

Keywords: CRISPR/Cas9; Human induced pluripotent stem cell; Polygenic risk score; Schizophrenia.