New biological insights emerge via genetic studies in schizophrenia

Dr Degenhardt Franziska presenting
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Schizophrenia is a clinically-defined syndrome and not a single biological entity. Even so, the heritability seen in family studies suggest that the search for genetic components would be fruitful. Over a decade of advancements in our understanding of genetics has proven this correct. The genetic variants which differ between schizophrenia and healthy controls point to the importance of synaptic function, developmental plasticity, the immune system and epigenetics, as well as neurotransmission in our efforts to gain insight into schizophrenia.

In part, the rapid progress in our understanding of schizophrenia is due to developments in gene array and sequencing technologies, accompanied by a massive reduction in cost to assess genetic variables. The establishment of international research consortia that can accrue many thousands of patients and controls to genome-wide association studies, in an effort to better understand the heritability of schizophrenia, has also proven to be extremely important.

The identical twin of someone with schizophrenia has an almost 50% chance of developing the disorder

The frequency of schizophrenia in the general population is around 1%, Jeremy Hall (University of Cardiff, UK) told the Educational Update Session. If your fraternal co-twin has schizophrenia, however, the chance that you too will develop the disease is 17%. And if your identical twin has schizophrenia, you have a 48% chance of suffering from the disorder – almost fifty times the background risk of 1%.

The overall estimate of heritability for schizophrenia is 70-80%. But the fact that the concordance in identical twins is 48% -- and not 100% -- shows that environment also plays an important part in conjunction with genetic factors. Indeed, one of the pathways that genetic studies identifies as of likely relevance concerns epigenetic regulation. 

 

Variety in variants

Genetic variants associated with schizophrenia converge on plasticity, epigenetics and immune function

As with many conditions, the genetic contribution to schizophrenia is made up of a few very rare variants with a large impact on risk and many more common variants which each contribute a small amount to the risk of developing schizophrenia. When taken together, however, their overall impact on risk is large. The number of genetic variants contributing to risk of schizophrenia is certainly in the hundreds, and quite likely more than a thousand, Professor Hall estimated. These variants range from single nucleotide polymorphisms (SNPs) through variants in copy number (which can be either deletions or duplications) to large chromosomal translocations.

Many SNPs associated with schizophrenia overlap with those found in autism spectrum disorders

The latter – an example being the chromosome 1;11 translocation -- are quite rare, perhaps being found in single families. But they prove the principle of genetic involvement.

More frequent, but still rare, are the sub-microscopic deletions and duplications which together are known as copy number variants (CNVs). These are found in 2-3% of people with schizophrenia. The 22q 11.2 deletion, which is associated with a wide range of conditions including schizophrenia, is an example. So too is a deletion in the NRXN (neurexin) gene.

 

SNPs have big effect when combined

SNPs count as “common” if they occur in more than 1% of the population. And genome-wide sequencing of people with schizophrenia and controls has identified many common SNPs which occur with different frequency in the two populations. Variants in SETD1A, which cause loss of protein function, are implicated in schizophrenia and related to the epigenetically-relevant histone methylation pathway.

The largest genome-wide association study (reference below), from the Schizophrenia Working Group of the Psychiatric Genomics Consortium, sequenced the genome of more than 37,000 patients and 113,000 controls  and found 108 schizophrenia-associated genetic loci. Adding together the increased risk associated with all SNPs identified as significant accounted for around 30% of the estimated genetic vulnerability to schizophrenia. There was considerable overlap between these SNPs and those thought to be important in bipolar disorder.

The largest GWAS study identified genes giving new insights into biology and supported existing ideas about the importance of glutamatergic neurotransmission

Copy number variants associated with schizophrenia are also often associated with other neurodevelopmental disorders such as autism and intellectual disability.

 

Fresh insights into biology

Overall, analysis of the genetic factors associated with schizophrenia implicates the glutamate, GABA and dopamine neurotransmitter systems. The signal is strongest for glutamate, but there is new interest in the apparent importance of the D2 subtype of the dopamine receptor (DRD2).

The gene variant data also clearly points towards the involvement of voltage-gated calcium channels. Other significant variants are in genes involved in control of synaptic function and developmental plasticity (such as the Complement Component 4 gene), epigenetic regulation, and the immune system –  particularly genes relating to the CD19 and CD20 B-cell lineage markers. 

Genetic data don’t entirely conform to current diagnostic categories

Several gene variants linked to schizophrenia are also linked to bipolar disorder and to autism, suggesting we may have to revisit our diagnostic classifications. But the promise of these data is that the biological insights they provide will suggest new therapeutic targets. The challenge now is to translate this new knowledge into tangible benefits for patients.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

Symposium references
  1. Biological insights from 108 schizophrenia-associated genetic loci. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature 511, 421–427, 2014
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