ORLANDO – Stem cell models could boost schizophrenia treatment to a new level, helping to gauge the importance of both rare and common genetic variants that are difficult to study in traditional-style trials, an expert said at the annual congress of the Schizophrenia International Research Society.
The promise of the approach is particularly crucial at this point in the course of schizophrenia research, when the heritability of the disease is being repeatedly underscored in the literature, said Kristen Brennand, PhD, associate professor of neuroscience, genetics and genomics, and psychiatry at the Icahn School of Medicine at Mount Sinai, New York.
“It seems that each new paper that comes out raises that estimate of heritability and the numbers I’ve seen recently are as high as 85%,” she said. “Schizophrenia is as heritable as autism and bipolar, more heritable than BRCA1 breast cancer, it’s more heritable than alcoholism. But that heritability is highly complex.”
Highly penetrant variants that are more easily studied account for only a small sliver of this heritability. Rare variants that are harder to study account for more. And common variants – the count is up to 145 and will almost certainly grow – also play a big role.
“These are variants that all of us carry,” Dr. Brennand said. “We all carry dozens of these variants. Patients just either carry more of them or they’re hitting pathways in a different way than they’re hitting the rest of us.”
Using human-induced pluripotent stem cells (HiPSC) – grown out of skin biopsy samples from schizophrenia patients and then grown into neural progenitor cells and ultimately neurons – are much more practical for studying the genetics of these variants than case-control studies that require tens of thousands of subjects.
Researchers have found that cohorts using HiPSCs concord with the genetic findings from postmortem datasets of schizophrenia patients.
More recently, in work not yet published, she said her lab has focused on rare 2p16.3 deletions of the NRXN1 gene, finding that neuronal branching is reduced and that there is decreased neuronal activity in schizophrenia patients with these deletions.
Her lab is also using HiPSCs and clustered regularly interspaced short palindromic repeats editing to validate the function of common variants and genes linked with schizophrenia. A key finding has been that there could be important relationships between risk genes that are more distant from schizophrenia single-nucleotide polymorphisms (SNPs).
“We’re expanding the list of potential schizophrenia risk genes by considering not just immediately proximal but also distal interactions between schizophrenia SNPs,” Dr. Brennand said. “If there are 224 genes that are next to risk SNPs, you can add a few hundred more potential genes that might be coregulated by these risk SNPs.”
Harnessing the power of HiPSCs could be the gateway to precision medicine in schizophrenia, she said. A drug that might benefit, say, two out of a dozen patients would likely fail in a clinical trial, unless patient selection is improved.
“Perhaps genotype might predict clinical response, perhaps stem cell drug responsiveness might predict clinical response,” she said. “What I envision is this dream where we have patients and we genotype them, and we better understand how their DNA impacts their gene expression, and how their gene expression impacts their synaptic function, and that this might help us better understand their prognosis.”
Dr. Brennand reported a financial relationship with Alkermes.