Publicly available hiPSC lines with extreme polygenic risk scores for modeling schizophrenia

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>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 characterize a collection of twelve 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 three independent laboratories, identifying 9 out of 12 meeting our criteria. We report a standardized resource of publicly available hiPSCs, with which we collectively commit to conducting future CRISPR-engineering, in order to facilitate comparison and integration of functional validation studies across the field of psychiatric genetics.</jats:p>

A comparison of ten polygenic score methods for psychiatric disorders applied across multiple cohorts

“…While these top vs bottom decile odds ratios ( Figure 1c and 2c ) are much larger than the odds ratio obtained by using PGS to screen a general population ( Figure 1d and 2d ) or patients in a healthcare system to identify people at high risk 40; 41 , these comparisons are useful for research purposes, which could for example make cost-effective experimental designs focussing on individuals with high vs low PGS 42 . The odds ratio of top 10% vs middle 10% are much less impressive, up to median of 5.5 for SCZ and 2 for MDD, but more fairly represents the value of PGS in population settings.…”

Patient-Derived Midbrain Organoids to Explore the Molecular Basis of Parkinson's Disease

“…The most straightforward path when studying variants carrying a high risk and penetrance is to generate isogenic controls using Crispr-Cas9 gene editing. Alternatively, in order to study lower-risk variants with reduced penetrance, more elaborate strategies may be necessary, such as relying on hiPSC lines from related donors, or taking into account polygenic risk scores in patient and control selection criteria in order to recreate a continuous variable for risk scores (116), an approach that has seen recent applications in the field of schizophrenia research (117). Furthermore, the way in which hiPSC cells are cultured in the lab may have an important effect on their ability to generate reproducible organoid structures.…”

Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

“…1). Likewise, RNA-sequencing data from hiPSC-derived neural progenitor cells (NPCs) (Hoffman et al, 2017), NGN2-induced glutamatergic neurons (Ho et al, 2016;Zhang et al, 2013), ASCL1/DLX2-induced GABAergic neurons (Barretto et al, 2020;Yang et al, 2017), ASCL1/NURR1/LMX1A-induced dopaminergic neurons (Rehbach et al, 2020), as well as differentiated forebrain neurons (FB, comprised of a mixture of neurons and astrocytes), confirmed expression of many candidate host genes (Gordon et al, 2020;Ou et al, 2020;Wruck and Adjaye, 2020) (Fig. 1A).…”