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