Largest Schizophrenia Genetic Risk Factor Linked with Mitochondrial Dysfunction

Researchers at Rutgers and Emory University have gained new insights into how schizophrenia (SCZ) develops, by studying 3q29 deletion syndrome, which represents the strongest-known genetic risk factor for the condition. The team analyzed overlapping patterns of altered gene activity in mouse models in which the 3q29 deletion had been engineered in using CRIPSR, and in human brain organoids. Their results showed that both systems exhibited impaired mitochondrial function, which can cause energy shortfalls in the brain and result in psychiatric symptoms and disorders.

“Our data give strong support to the hypothesis that mitochondrial dysregulation is a contributor to the development of schizophrenia,” said Jennifer Mulle, PhD, associate professor of psychiatry, neuroscience, and cell biology at Rutgers Robert Wood Johnson Medical School and a co-senior author of the team’s study, which is published in Science Advances. “The interplay between mitochondrial dynamics and neuronal maturation is an important area for additional detailed and rigorous study.” Mulle and colleagues reported on their findings in a paper titled, “Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion,” in which they concluded, “These data strongly implicate the mitochondrion as an organelle affected by 3q29Del … These findings should motivate further work to determine the mechanisms of these 3q29Del sequelae and their relevance to various clinical phenotypes.”

About one in 30,000 people are born with 3q29 deletion (3q29Del), the authors suggested. The copy number variant (CNV) encompasses 22 protein-coding genes, towards one end of chromosome 3. In addition to increasing the risk for schizophrenia, 3q29 deletion can include intellectual disability, autism spectrum disorder, and congenital heart defects. The effect of 3q29 deletion on schizophrenia risk is more than any single known gene variant, but the contributions of individual genes within the deletion are still being unraveled. The authors further explained, “The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia … Hemizygous loss of this set of genes is associated with at least a 40-fold increase in risk for SCZ; this deletion also increases the risk for additional neurodevelopmental and psychiatric conditions, including intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder.”

Mulle, a member of the Center for Advanced Biotechnology and Medicine at Rutgers, and colleagues first showed that 3q29 deletion was a risk factor for schizophrenia in 2010. For their newly reported research, the team carried out single-cell mRNA sequencing (scRNA-seq) in the human organoids, and mouse model, during early developmental stages, to identify changes in the transcriptome. “… we performed single-cell mRNA sequencing (scRNA-seq) in isogenic human cortical organoids at both early (2-month) and late (12-month) developmental time points and in perinatal [postnatal day 7 (P7)] mouse isocortex,” the investigators noted. “We devised a strategy to systematically identify the most salient transcriptomic effects, both globally and in specific neural cell types, to identify molecular phenotypes for functional analysis.”

Systematic pathway analysis indicated that the 3q29 genetic variant was associated with dysregulation of mitochondrial function and energy metabolism. “… testing revealed changes in mitochondrial protein expression and function at the cellular level, consistently observed in multiple cell types including study participant–derived cell lines,” they noted.

The finding that various schizophrenia-associated chromosomal deletions impair mitochondria runs counter to an expectation in the field that such mutations should alter proteins in the synapses that connect neurons. However, mitochondria are critical for energy-hungry synapses’ function—so these models may not be in conflict.

The findings do also converge with work on another genetic risk factor for schizophrenia, 22q11 deletion syndrome (or DiGeorge syndrome), which has also been found to involve disrupted mitochondrial function. “Mitochondria have been previously implicated in the pathophysiology of neurodevelopmental CNV disorders and idiopathic schizophrenia,” the team pointed out. “A CNV disorder with perhaps the most similar phenotypic profile to 3q29Del in human carriers, 22q11.2Del, harbors at least eight genes that encode mitochondria-linked proteins, several of which are also enriched at synapses.”

It was also surprising that 3q29 cells have poorly functioning mitochondria because only one of the 22 genes in the deletion appears to encode a protein located in mitochondria. “Unlike 22q11.2, which encodes several proteins that function within mitochondria, the mechanistic link to 3q29 genes is not known,” the investigators acknowledged. However, that gene or others within the interval may instead regulate the production or importation of mitochondrial proteins, they suggested.

“For genetic variants associated with schizophrenia, we want to understand the primary pathology at the cellular level,” said Ryan Purcell, PhD, assistant professor of cell biology at Emory University School of Medicine and co-lead author of the study. “This gives us a foothold, which may help cut through schizophrenia’s polygenic complexity and better understand the neurobiology.”

Mitochondria, which are found in every cell, produce energy from sugar or fat. Sometimes this process is aerobic (done with extra oxygen from inhaled air) and sometimes anaerobic (done without oxygen).

As a result of altered mitochondrial function, 3q29 cells lack metabolic flexibility, meaning their mitochondria have difficulty adapting to changes in sources of energy. This may interfere with neuronal development because maturing neurons need to switch to relying on aerobic energy production as they differentiate. “… molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2.”

The newly released study findings may illustrate how 3q29 deletion affects the whole body, not just the brain. The effects on mitochondria are seen in kidney cells as well as in brain cells. Individuals with 3q29 deletion syndrome also tend to be smaller in size, possibly because of altered fat metabolism. “Eventually, we want to understand which cellular changes like these are linked to specific clinical outcomes, which could help in designing more effective therapeutic strategies,” Purcell said.

The authors further concluded, “In the context of emerging reports of mitochondrial phenotypes associated with other risk alleles such as 22q11.2 deletion …  these results point to mitochondria as a possible site of convergent biology downstream of discrete neurodevelopmental variants.”