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Second Neuregulin Gene Supported In Schizophrenia Genetic Studies

30 January 2009. Looking to explain a linkage between schizophrenia and the chromosome 10q22-q23 region, two groups have converged on a common candidate, the Neuregulin3 gene (NRG3). The story is not completely clear, as one study shows an association between variants in NRG3 with schizophrenia in a Chinese population, while the other finds no association with schizophrenia as a whole, but with one of a group of nine select traits associated with the disease. Nonetheless, the work should stimulate further study of NRG3, a less-examined cousin to the more famous candidate risk gene Neuregulin1 (NRG1).

The biological rationale for NRG3 led both groups to consider the gene a likely source of the 10q22-q23 linkage. Like NRG1, NRG3 is expressed in the central nervous system and encodes a transmembrane protein with an extracellular domain that is cleaved to produce a soluble trophic factor. Both the neuregulin 1 and neuregulin 3 factors bind the Erb4 receptor, whose gene (ERBB4) has also been linked to schizophrenia in some populations (for a comprehensive review of NRG1/ERBB4 biology, see Mei and Xiong, 2008).

In one study, published in December in Biological Psychiatry, Ying-Jay Liou of the National Yang-Ming University in Taipei, Taiwan, and colleagues followed up on an earlier report of an association between 10q22-q23 and schizophrenia in a population of Han Chinese descent (Faraone et al., 2006). First author Ying-Chieh Wang and coworkers analyzed nine SNPs spanning the 5’ end of the NRG3 gene in a case-control group of 270 schizophrenia patients and 235 healthy subjects, and a family study of 280 parent-child trios with one affected member. Two of the nine SNPs appeared to be associated with schizophrenia.

More recently, David Valle and colleagues at the Johns Hopkins University in Baltimore, Maryland, followed up their own previous work identifying 10q22-q23 as a potential susceptibility locus in an Ashkenazi Jewish population (Fallin et al., 2003). In the new work, which came out on January 9 in the American Journal of Human Genetics, first authors Pei-Lung Chen and Dimitrios Avramopoulos fine-map 1,414 single nucleotide polymorphisms (SNPs) across 12.5 Mb in 1,515 subjects from the same ethnic group, including patient-parent pairs and unrelated controls. They found no significant SNP associations with schizophrenia overall. However, when the researchers replaced the binary schizophrenia phenotype with a set of nine more detailed heritable endophenotypes, they did find a significant association among three SNPs located together in a 13kb region in intron 1 of the NRG3 gene and the delusion phenotype. No signals were found for other categories including negative symptoms, hallucination, disability, and disorganization, among others.

Finding an association with just one endophenotype may not seem all that compelling, but the location of the SNPs in the 5’ part of the NRG3 gene calls to mind similar variants in NRG1 that do affect schizophrenia risk. Valle and colleagues also note that among the top 20 SNPs with the highest p values for association with quantitative traits, 13 were in or around the NRG3 gene. There is evidence from other studies that NRG3 variants interact with both NRG1 and ERBB4 in schizophrenia (Benzel et al., 2007). On the other hand, the two studies identify different variants in the same gene—the positive SNPs in the Chinese study were not associated with disease or endophenotypes in the Ashkenazi Jewish population, Valle and colleagues note. Nonetheless, the combination of biology and suggestive genetic results make the NRG3 gene a prime candidate for more research.—Pat McCaffrey.

References:
Chen PL, Avramopoulos D, Lasseter VK, McGrath JA, Fallin MD, Liang KY, Nestadt G, Feng N, Steel G, Cutting AS, Wolyniec P, Pulver AE, Valle D. Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. Am J Hum Genet. 2009 Jan;84(1):21-34. Abstract

Wang YC, Chen JY, Chen ML, Chen CH, Lai IC, Chen TT, Hong CJ, Tsai SJ, Liou YJ. Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. Biol Psychiatry. 2008 Dec 15;64(12):1093-6. Epub 2008 Aug 16. Abstract

Comments on News and Primary Papers
Comment by:  Lin Mei
Submitted 30 January 2009
Posted 30 January 2009

Diagnosis of schizophrenia is psychiatric and based on patients’ self-reported experience or behavior. There are positive symptoms, negative symptoms, and cognitive deficits. Evidently, schizophrenia is a complex disease. No wonder current antipsychotics are effective for some, but not for all symptoms (in particular, negative symptoms and cognitive deficits). It would be no surprise if schizophrenia is classified or subclassified into different disorders in future when tools are available.

The beauty of the current study is to take advantage of detailed clinical information of schizophrenia patients and classify them to generate nine factors. Remarkably, a strong association was identified by using the delusion factor as quantitative trait phenotype. The finding itself identifies NRG3 as a candidate gene of "schizophrenia." In addition, it could represent a first step toward subclassification of schizophrenia for better diagnosis and treatment.

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Related News: Unkind Cuts of NRG3 May Lead to Schizophrenia

Comment by:  Assen Jablensky
Submitted 15 September 2010
Posted 15 September 2010

Common or rare genetic variation in NRG3 influences risk for schizophrenia?
Emerging evidence implicating NRG3 as a likely susceptibility gene in population samples as diverse as the Ashkenazi Jews, Han Chinese, Australians of Anglo-Irish ancestry, and white Americans is certainly a “noteworthy” occurrence in schizophrenia genetics. The latest addition to the evidence (Kao et al., 2010) provides considerable support to earlier (Fallin et al., 2003; Wang et al., 2008) and recent findings of association of several polymorphisms (rs10883866, rs6584400, rs10748842) within a conserved linkage disequilibrium (LD) block in intron 1 of the NRG3 gene with a delusion-laden factor and a neurocognitive quantitative trait in the schizophrenia phenotype (Chen et al., 2009; Morar et al., 2010).

A fundamental contribution of the present study is the cloning and detailed characterization of full-length NRG3 transcripts from postmortem fetal, child, adolescent, and adult brain samples (whole brain, hippocampus, and dorsolateral prefrontal cortex). Sequencing of the cDNA clones and expression analysis revealed a complex picture of alternative splicing, abundance of developmentally regulated transcripts in schizophrenia brains, and, notably, increased expression of a fetal brain-derived clone (hFBNRG3), which introduces a premature stop codon resulting in a truncated protein and a possibly destabilized NRG3-ErbB4 signalling pathway. In their clinical collections (a family-based sample and a partially independent case-control sample), the authors report significant associations of rs10748842 (representing 12 SNPs located in the LD block within intron 1) with schizophrenia, with the PANSS (Positive and Negative Syndrome Scale) subscale score on delusion severity, as well as with the PANSS negative symptom load.

Overall, the findings from this investigation and the earlier studies appear to be in a broad agreement, converging on a plausible role of NRG3 in schizophrenia pathogenesis. However, there is a fly in the ointment: The associations found in the present study exhibit a risk allele reversal compared to previously reported results; namely, all significant associations are with the major, common alleles, rather than with the minor alleles, as in Chen et al. (2009) and Morar et al. (2010). While many reasons for genuine allele flipping can be invoked (multi-locus interactions, variation in local patterns of LD, environmental exposures, ethnic background differences—see Clarke and Cardon, 2010), the explanation for the flip in this particular context is not obvious, and NRG3 should remain on the examination bench. Even in the GWAS era, studies proceeding from biologically and clinically anchored hypotheses remain rewarding and potentially productive.

References:

Chen PL, Avramopoulos D, Lasseter VK, McGrath JA, Fallin MD, Liang K-Y, Nestadt G, Feng N, Steel G, Cutting AS, Wolyniec P, Pulver AE, Valle D. Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. Am J Hum Genet. 2009;84:21-34. Abstract

Clarke GM, Cardon LR. Aspects of observing and claiming allele flips in association studies. Genet Epidemiol. 2010;34:266-74. Abstract

Fallin MD, Lasseter VK, Wolyniec PS, McGrath JA, Nestadt G, Valle D, Liang KY, Pulver AE. Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet. 2003;73:601-11. Abstract

Kao WT, Wang Y, Kleinman JE, Lipska BK, Hyde TM, Weinberger DR, Law AJ. Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15619-24. Abstract

Morar B, Dragovic M, Waters FAV, Chandler D, Kalaydjieva L, Jablensky A. Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. Mol Psychiatry. 2010 June 15. Abstract

Wang YC, Chen JY, Chen ML, Chen CH, Lai IC, Chen TT, Hong CJ, Tsai SJ, Liou YL. Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. Biol Psychiatry. 2008;64:1093-6. Abstract

View all comments by Assen Jablensky