Multiple single-nucleotide polymorphisms (SNPs) identified in a meta-analysis of genome-wide association studies, taken together, appear to confer susceptibility to schizophrenia, a family-based replication study confirmed.

The replication study found that effects of about 90% of the SNPs were in agreement with those seen in the genome-wide association studies - an almost impossible chance finding, according to Edwin J. van den Oord, PhD, of Virginia Commonwealth University in Richmond, and colleagues.

In particular, replications were seen for promising SNPs in the TCF4 gene for European populations (P=2.53 × 10^-10) and NOTCH4 for both Europeans (P=5.22 × 10^-7) and individuals of all ancestries (P=3.16 × 10^-7), the researchers reported online in JAMA Psychiatry.

Multiple genetic factors and mutations are believed to play a role in risk for schizophrenia, and recent genome-wide association studies have identified some potentially important loci.

To further explore these associations in affected families, and thereby avoid the potential for confounding by population stratification, van den Oord and colleagues first conducted a meta-analysis of 18 studies from which they identified 9,380 SNPs with the most significant P values.

For the replication analysis, they then used samples obtained primarily from a repository at the National Institute of Mental Health, representing 6,298 patients from 1,811 families who were of European, African, or Asian ancestry.

Overlap between SNPs identified in the meta-analysis, and those from the patient repository were seen not only for TCF4 and NOTCH4, but also for FEZ1 in Europeans and GRIK3 and BRD1 in combined analysis of all groups.

The combined analysis also implicated BCL2, which is thought to be involved in growth and differentiation of neurons and has been seen in low levels in the temporal cortex of patients with schizophrenia.

Other promising genes included POM121L2, NT5C2, and AS3MT.

The researchers observed that their initial calculations “confirm the polygenetic nature of schizophrenia and show that we replicated a substantial number of susceptibility alleles with small effects.”

“The most significant pathway finding, axon guidance, includes genes involved in the process by which neurons send out axons to reach the correct targets. Growing axons sense guidance cues in the environment and respond by undergoing cytoskeletal changes that determine the direction of axon growth,” van den Oord’s group explained.

Specific genes in the axon guidance pathway included ROBO2, an axon guidance receptor, and NFASC, which governs a protein required for neurite growth and stabilization.

The pathway analysis also revealed that large groups of SNPs replicated together.

“Other studies have reached a similar conclusion that for schizophrenia, many SNPs with small effects may be involved and these SNPs replicate as a group,” the researchers commented.

Chemical transmission pathways also contributed, including those involved in calcium transport.

“Calcium signaling in particular has previously been identified as a core theme in the etiology of schizophrenia through large-scale genetic studies,” they noted.

A final group of implicated pathways were those involved in immune function, particularly in the area of the major histocompatibility class 1 on chromosome 6, where the replication values of P

<0.01 were almost four times higher in Europeans.

"Pathway analyses of the many small effects reveal several biological themes involved in brain function, immune response, and biological functions of potential importance for the development of schizophrenia," stated van den Oord and colleagues.

In an accompanying editorial, John Hardy, PhD, of the UCL Institute of Neurology in London, commented on the promise of these findings, which "convincingly show that there are genetic loci that contribute to the risk of schizophrenia and that these loci map, at least in part, to pathways that make sense."

"They begin to offer the hope that realistic modeling of precise molecular effects, for example at the synapse, might be mediated through these risk loci once the pathogenic variant at each locus is identified," Hardy suggested.

But much work remains to be done, according to Hardy.

There is still a long way to go, but after this study, "we can be confident that we are on a road that will lead to dissection of some of the pathogenesis of this major disorder," he stated.

The study was sponsored by the National Human Genome Research Institute.

The authors reported no conflicts of interest.

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Primary source: JAMA Psychiatry
Source reference: Aberg K, et al “A comprehensive family-based replication study of schizophrenia genes” JAMA Psychiatry 2013; DOI: 10.1001/jamapsychiatry.2013.288.

Additional source: JAMA Psychiatry
Source reference: Hardy J “Psychiatric genetics: are we there yet?” JAMA Psychiatry 2013; DOI: 10.1001/jamapsychiatry.2013.216.