Many Genes Add to Schizophrenia Risk

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."

They then looked at potential related pathways for the numerous small-effect alleles, and found three that were significant:

Axon guidance, P=5.26 × 10 ^-6
Developmental biology, P= 1.29 × 10 ^-5
Neuronal systems, P=1.37 × 10 ^-5

"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.