Two large studies reveal genes and genome regions that influence schizophrenia risk

Good news! Apparently, we are finally making good progress to identify genetic indicators for mental disorders. Three days ago, I blogged here about another similar study.

"In a landmark genetic study of more than 121,000 people, an international consortium called SCHEMA [SCHizophrenia Exome Meta-Analysis], ... has identified extremely rare protein-disrupting mutations in 10 genes that strongly increase an individual's risk of developing schizophrenia — in one instance, by more than 20-fold. A second, complementary study in a larger but overlapping group of 320,400 people ... brings to 287 the number of regions of the genome associated with schizophrenia risk, including ones containing genes identified by SCHEMA.

Together, these studies underscore an emerging view of schizophrenia as a breakdown in communication at the synapse (the junction between neurons), and illustrate how different kinds of genetic variation affecting the same genes can influence the risk for different psychiatric and neurodevelopmental disorders. ...

By sequencing whole exomes from 24,248 people with schizophrenia and 97,322 without, the SCHEMA team identified ultra-rare variants in 10 genes that dramatically increased a person's risk of developing schizophrenia. These variants, called PTVs for “protein truncating variants,” prevent cells from producing a gene’s full-length functional protein. 
"In general, any given person has a roughly one percent chance of developing schizophrenia in their lifetime," ... "But if you have one of these mutations, it becomes a 10, 20, even 50 percent chance." ...
Insights into two of the 10 genes from the SCHEMA study, GRIN2A and GRIA3, further implicate the synapse as a key part of schizophrenia's mechanistic roots. These two genes encode portions of the glutamate receptor, a cellular antenna found at the synapse that allows neurons to receive chemical signals from neighboring neurons. Pharmacological studies have previously suggested that glutamate signaling may be involved in schizophrenia, but the SCHEMA study provides the first solid genetic evidence of this. Additionally, GRIN2A activity in the brain peaks during adolescence, around the time people suffering schizophrenia begin to experience symptoms. ..."

From the abstract of the first research paper:

"Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3–50, P < 2.14 × 10−6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders, epilepsy and severe neurodevelopmental disorders, although different mutation types are implicated in some shared genes. ..."

From the abstract of the first research paper:

"Schizophrenia has a heritability of 60–80%, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies."

Two large studies reveal genes and genome regions that influence schizophrenia risk | Broad Institute International collaborations analyze common and rare DNA variants in hundreds of thousands of people, further elucidating genetic roots of psychiatric disorder

Rare coding variants in ten genes confer substantial risk for schizophrenia (no public access)

Mapping genomic loci implicates genes and synaptic biology in schizophrenia (no public access)

A Manhattan plot of the SCHEMA findings. The red dots indicate genes with a significant relationship to schizophrenia risk.