Focus on Causality in ESC/iPSC-Based Modeling of Psychiatric Disorders

Abstract

Genome-wide association studies (GWAS) have identified an increasing number of genetic variants that significantly associate with psychiatric disorders. Despite this wealth of information, our knowledge of which variants causally contribute to disease, how they interact, and even more so of the functions they regulate, is still poor. The availability of embryonic stem cells (ESCs) and the advent of patient-specific induced pluripotent stem cells (iPSCs) has opened new opportunities to investigate genetic risk variants in living disease-relevant cells. Here, we analyze how this progress has contributed to the analysis of causal relationships between genetic risk variants and neuronal phenotypes, especially in schizophrenia (SCZ) and bipolar disorder (BD). Studies on rare, highly penetrant risk variants have originally led the field, until more recently when the development of (epi-) genetic editing techniques spurred studies on cause-effect relationships between common low risk variants and their associated neuronal phenotypes. This reorientation not only offers new insights, but also raises issues on interpretability. Concluding, we consider potential caveats and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders.

Chromatin Remodeler CHD8 in Autism and Brain Development

“…Then, cellular abnormalities, including altered neurotransmission and network activity, can be assessed in a more naturalistic environment that may be more permissive to disease-relevant phenotypes. For example, this approach has allowed us to assess iPSC-derived cells from healthy controls and patients with schizophrenia for various phenotypes ranging from myelination to behavior (reviewed in [ 83 , 84 ]). Highly penetrant mutations in CHD8 might make an even better case for ESC/iPSC-based disease modeling than highly polygenic diseases like schizophrenia.…”

Single-Cell Transcriptomics Supports a Role of CHD8 in Autism

“…Further coiling of the chromatinized DNA-strand in 3D-space leads to the formation of a closed, transcriptionally inactive, chromatin structure. Epigenetic processes, such as posttranslational modifications of free histone tails, chromatin remodeling, and DNA modifications, act together to regulate chromatin conformation in a spatially and temporally controlled manner during development and beyond (reviewed in [ 15 , 16 ]. Consistent with this critical function, alterations in epigenetic factors driving these processes have been increasingly recognized as the genetic cause for various neurodevelopmental syndromes (reviewed in [ 17 , 18 ]).…”

Stem Cell-Based Disease Modeling and Cell Therapy

“…The availability ESCs and the advent of patient-specific iPSCs have opened new opportunities to investigate gene mutation and genetic risk variants in living disease-relevant cells [ 38 ] such as long QT syndrome, amyotrophic lateral sclerosis (ALS), and genetic variants-associated psychiatric disorders. Long QT syndrome mutation carriers have higher risk of cardiac events than unaffected family members [ 53 ].…”

“…The authors also discussed the pros and cons of past and new research avenues, potential caveats, and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders. Combinations of different approaches from iPSC-based modeling, animal studies, and deep patient phenotyping will enable stepwise progress on our understanding of psychiatric disorders and light up new perspectives on future therapies [ 38 ].…”

“…This Special Issue includes both research [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ] and reviews articles [ 10 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ] which cover wide ranges of stem cell research: adult stem cells, cancer stem cells, pluripotent stem cells, and complex 3D organoid/cell aggregate models [ 26 , 27 , 33 ], with the focuses on stem cell biology/technology [ 10 , 23 , 24 , 25 , 26 , 31 , 32 , 34 ], and stem cell-based disease modeling [ 10 , 27 , 29 , 31 , 33 , 38 , 43 ] and cell therapy [ 24 , 28 , 30 , 32 , 35 , 36 , 37 , 39 , 40 , 41 ].…”