Schizophrenia: Ancient Scrolls, Genomic Sequencing and Synaptic Pruning

Schizophrenia: Ancient Scrolls, Genomic Sequencing and Synaptic Pruning

By Jonathan LoTempio
Scientific Program Analyst, NHGRI

Through the ages, the disease we now know as schizophrenia has been described as a gift of heaven, an imbalance of four bodily humors, a punishment from the gods and a demonic possession. It wasn't until the mid-19th century that Emil Kraeplin, a German psychiatrist, used the term "dementia praecox" for a "mental weakness occurring at a youthful age." More than 50 years later, Eugen Bleuler, a Swiss psychiatrist, named the condition "schizophrenia" from the Greek roots schizo (split) and phren (mind), meaning "split mind."

An important hallmark of the disease has been its tendency to run in families. The illness occurs in less than 1 percent of the general population, but it occurs in 10 percent of people who have a first-degree relative with the disorder, such as a parent, brother or sister. This genetic association has recently provided a vital clue for deciphering the molecular basis of schizophrenia, which is critical to speed the development of treatments and possibly even prevent the affliction.

The February Genome Advance of the Month describes a leap forward in understanding the heritability and progression of schizophrenia from a study by researchers at Harvard Medical School and the Broad Institute. The study,  published  in the February 11, 2016 issue of Nature,  signals the potential for research using large numbers of whole genome sequences (DNA sequences of a person's entire genome, including both the coding and non-coding regions), innovative biological methods and advanced software toolkits for analysis.

The research team, led by Steven McCarroll, Ph.D. and Aswin Sekar, leveraged existing resources to analyze the mass of information. They drew whole genome sequences from the Psychiatric Genomics Consortium (PGC), brain samples from NIH's Genotype-Tissue Expression (GTEx) and software from the NHGRI Genome Sequencing Informatics Tools (GS-IT) program.

The analysis of genome data from 65,000 healthy and affected individuals from PGC and gene expression from healthy people's genomes in GTEx showed that patients with a higher number of copies of the gene C4 were more frequently affected by schizophrenia. According to the study, the C4 gene appeared to trigger excessive "pruning" of teenagers' still-maturing brain connections. Pruning, a normal process in the maturing teenage brain, gets rid of excess brain connections. But, too much pruning can impair mental function.

Noting this, the team looked at brain cells in culture to find out where the products (proteins) from the gene were located. They grew brain cells in a petri dish and examined them for the C4A or C4B proteins, produced by the C4 gene. Large deposits of C4A were found on the brain cells and on the connections between them, called synapses, providing evidence that these proteins are produced by or deposited on neurons and synapses.

A mouse model was used to examine how the C4 gene functioned in a living brain. The team found that mice with two copies of the gene had the lowest synapse count; mice with no functioning copies of the gene had the highest synapse count. Mice with one functional copy and one nonfunctional copy had a synapse count in between the two extremes.

The team used these observations to support their claim that C4A is important in synaptic pruning, and that excessive synaptic pruning could be a possible root cause of schizophrenia. This finding is exciting because drugs and therapies could be developed to target the root cause of the disease, rather than the symptoms. In addition, the approaches used in this study could be used for the study of other complex diseases.

Read the study

• Sekar A, et al. Schizophrenia risk from complex variation of complement component 4. Nature, 530(7589):177-83. 2016. [PubMed]

Posted: March 18, 2016