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New Genetic Variations May Help Pinpoint Schizophrenia Risk

Deborah Brauser

Sep 25, 2013

 

Newly identified genetic variations may help explain the cause of schizophrenia and aid in the detection of individuals at high risk of developing the disorder, new research suggests.

The 3-part analysis consisted of a large genome-wide association (GWA) prospective study, a GWA meta-analysis, and a replication of single-nucleotide polymorphisms (SNPs) in a total of almost 60,000 individuals.

Combined results identified 22 different locations in the human genome (13 of which are considered to be newly discovered and 1 previously implicated in bipolar disorder) that are associated with schizophrenia development. They also identified 2 distinct gene pathways to the disorder: a calcium channel and the micro-RNA 137 transcript.

“This study gives us the clearest picture to date of 2 different pathways that might be going wrong in people with schizophrenia,” said principal investigator Patrick F. Sullivan, MD, professor in the Departments of Genetics and Psychiatry and director of the Center for Psychiatric Genomics at the University of North Carolina School of Medicine in Chapel Hill, in a release.

“If finding the causes of schizophrenia is like solving a jigsaw puzzle, then these new results give us the corners and some of the pieces of the edges. We’ve debated this for a century, and we are now zeroing in on answers,” added Dr. Sullivan.

The study was published online August 25 in Nature Genetics.

12 Regions of Interest

The first of the 3-stage analysis consisted of a GWA study, which identified a national sample from the Swedish Hospital Discharge of 5001 adults with a clinical diagnosis of schizophrenia and 6243 age- and sex-matched peers who did not have the disorder (control group). DNA was extracted from blood samples given by all participants and was genotyped.

The second stage included the Swedish results plus a meta-analysis of 17 previous, worldwide, schizophrenia-related GWA studies of 8832 patients with the disorder and 12,067 healthy peers.

The final stage consisted of replication of SNPs in 168 different genomic regions in an independent sample of 7413 individuals with schizophrenia, 19,762 healthy peers, and 581 trio groups consisting of 2 parents and 1 offspring.

The total number of participants in the entire 3-part analysis was 59,899.

Results from the Swedish GWA study showed that 312 SNPs “met a genome-wide significant threshold” for association with schizophrenia; they were found in 2 genomic regions: the major histocompatibility complex (MHC) (n = 241) and chromosome 2 (n = 71) areas.

“We replicated the MHC association reported in previous studies,” write the investigators.

“The association with schizophrenia on chromosome 2 (rs35220450) is new, showed highly consistent effects in the Sw1–Sw6 genotyping batches…and encompasses C2orf69C2orf47 and TYW5 (also known as C2orf60),” they add.

In a re-evaluation of the meta-analysis data, 5 regions were significantly associated with schizophrenia development: the MHC, the AS3MT-CNNM2-NT5C2, the MAD1L1, the RP11- 586K2.1, and the TCF4.

When combining these data with data from the Swedish GWA study, the investigators identified 12 genomic regions of interest.

Clear Path to Understanding

Finally, the researchers examined association results for SNPs in 194 genomic regions from all participants in the Swedish study, the meta-analysis, and the replication evaluation. They found significant associations with schizophrenia in 22 genomic regions, 13 of which are considered “new.”

NCAN, which was one of the significant locations, has been implicated previously in the development of bipolar disorder.

The first of 2 distinct pathways to schizophrenia identified in the study was a calcium channel pathway, which includes the genes CACNA1C and CACNB2.

“The genetics and biology of calcium channels have been the subject of considerable investigation, owing to their importance in fundamental neuronal processes and human diseases,” write the investigators.

They add that some antipsychotics, such as pimozide, act at calcium channels ― as do calcium blockers such as verapamil and nifedipine.

In addition, other medications “that act on the protein products of CACNA1C and CACNB2 for a different therapeutic indication could be repurposed for the treatment of schizophrenia,” they write.

Also of importance in the current study was the micro-RNA 137 pathway, which is a known regulator of neurodevelopment.

“We now have a clear and obvious path to getting a fairly complete understanding of the genetic part of schizophrenia. That wouldn’t have been possible 5 years ago,” said Dr. Sullivan.

“What’s really exciting about this is now we can use standard, off-the-shelf genomic technologies to help us fill in the missing pieces.”

He added that more research is now “very urgently” needed that will concentrate on understanding better the 2 newly identified pathways.

The study was funded by grants from the National Institute of Mental Health, the Stanley Center for Psychiatric Research, the Sylvan Herman Foundation, the Karolinska Institute, and the Swedish Research Council. The study authors have disclosed several financial relationships, which are listed in the original article.

Nat Genet. Published online August 25, 2013. Abstract

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