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.
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