Schizophrenia Bulletin

Schizophrenia Bulletin Advance Access originally published online on August 4, 2005
Schizophrenia Bulletin 2005 31(3):613-617; doi:10.1093/schbul/sbi043

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Association Between the Neuregulin 1 Gene and Schizophrenia: A Systematic Review

Sarah Tosato
Department of Medicine and Public Health, University of Verona, Section of Psychiatry, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy

Paola Dazzan
Division of Psychological Medicine, Institute of Psychiatry, Kings College, London, SE5 8AF

David Collier
Division of Psychological Medicine, Institute of Psychiatry, Kings College, London, SE5 8AF
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Kings College, London, SE5 8AF

	Abstract

Top Abstract Introduction Caucasian Replication Studies:... East Asian Replication Studies:... Conclusion References

 
Chromosome 8p22–p11 has been identified as a locus for schizophrenia in several genome-wide scans, which has been confirmed by meta-analysis of published linkage data. It appears to be 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to this linkage peak, including systematic fine mapping using extended Icelandic pedigrees that have identified an associated haplotype (HAP_ICE) in the gene neuregulin 1, also known as heuregulin, glial growth factor, NDF43, and ARIA. Neuregulin 1 (NRG1) is a plausible susceptibility gene because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. Encouragingly, this finding was quickly and directly replicated in a Scottish case-control sample by the same investigators with the same 300 kb associated haplotype. Although in Caucasian populations subsequent attempts at replication of this finding have been difficult to interpret, and no individual functional or causative genetic variants have yet been identified, a summary of HAP_ICE association results in about 4,500 subjects is consistent with a small (odds ratio 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP_ICE is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing but not yet compelling evidence for a role for NRG1 in susceptibility to schizophrenia. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus.

Keywords: Psychosis / genetic / susceptibility / ggf2 / nrg1 / chromosome 8p

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	Introduction

Top Abstract Introduction Caucasian Replication Studies:... East Asian Replication Studies:... Conclusion References

 
There is little doubt that chromosome 8p22–p11 harbors 1 or more susceptibility genes for schizophrenia; evidence for the linkage comes from several genome-wide scans for schizophrenia genes,^1–8 although many do not show linkage to this region. Two recent studies have sought to clarify this body of data by meta-analysis of published genome-wide scans for linkage. The first meta-analysis, which used the Multiple Scan Probability method, found that only 3 loci reached genome-wide significance: 8p, 13q, and 22q.⁹ The second meta-analysis, using Genome Scan Meta-analysis, reports a list of 19 rank-based regions in decreasing order of significance, among which the 8p occupies the ninth rank.⁶ The 8p locus is therefore identified in both meta-analyses as a region of susceptibility harboring a schizophrenia susceptibility gene and is 1 of the most robust linkage findings in psychosis. Several attempts have been made to identify the underlying genetic variation that gives rise to the schizophrenia linkage peak on chromosome 8p, using positional candidate gene analysis or systematic fine mapping of the region by association.

In this review, we critically review studies that have investigated the association between neuregulin 1 (NRG1) and schizophrenia. We performed a Medline literature search for the years 1966–April 2005 using the terms neuregulin* and schizophrenia, neuregulin-1 and schizophrenia, neuregulin* and psychiatry, and neuregulin-1 and psychiatry and also examined cross-references from the articles identified. We selected the papers that used genetic methods to evaluate NRG1 as a susceptibility gene for schizophrenia. A total of 14 studies were included.^{8, 10–22}

In the original mapping study⁸ an extended Icelandic pedigree made up of 33 families was used to find significant linkage to a single locus, chromosome 8p. Subsequently, extensive fine mapping with microsatellite markers and single nucleotide polymorphisms (SNPs), using haplotype analysis in both the linkage families and additional cases and controls from Iceland, identified 3 "at-risk" haplotypes (HAP_{A, B, C}) in different branches of the family, which mapped to the neuregulin 1 gene (NRG1). These 3 haplotypes shared a core "at-risk" haplotype, termed HAP_ICE, consisting of 5 SNPs (SNP8NRG221132, SNP8NRG221533, SNP8NRG241930, SNP8NRG243177, SNP8NRG433E1006), and 2 microsatellite markers (478B14-848, 420M9-1395) spanning about 300 kb of the first exon of NRG1 and the upstream sequences. HAP_ICE was highly significantly associated with schizophrenia (p < 6.7 x 10^–6), had a population attributed risk of 16%, was overrepresented in schizophrenic patients (15.4 versus 7.5%) in a sample of 478 patients and 394 controls, and conferred a relative risk of 2.2.

NRG1 is a plausible susceptibility gene for schizophrenia²³ because of its involvement in neurodevelopment, regulation of glutamate and other neurotransmitter receptor expression, and synaptic plasticity. For example, the neuregulin plays a role in neuronal migration,^24–25 gamma-aminobutyric acid receptor subunit expression and neurite outgrowth,^26–27 N methyl D aspartate receptor subunit expression,²⁸ and alpha7 nicotinic acetylcholine receptor expression.²⁹

	Caucasian Replication Studies: Europe, the United States, and South Africa

Top Abstract Introduction Caucasian Replication Studies:... East Asian Replication Studies:... Conclusion References

 
Encouragingly, the same Icelandic authors confirmed the presence of an identical core at-risk haplotype in a case-control study of subjects from a Scottish population, with 10.2 versus 5.9% in the cases and controls, and a similar relative risk.¹⁷ However neither the original nor the Scottish sample was able to identify individual microsatellites or markers associated with schizophrenia; nor were any of the markers that make up the haplotype obviously functional. This may mean that the causative polymorphisms in the NRG1 gene are as yet undiscovered or lie in a different gene nearby.

The core at-risk haplotype of 7 markers can be identified using only 3 markers (the SNP SNP8NRG221533 and the 2 microsatellites 478B14-848 and 420M9-1395). For this reason, this 3-marker haplotype was then chosen to genotype a large sample of schizophrenia cases and controls from unrelated Caucasians born in the United Kingdom or Ireland.²⁰ The 3-marker haplotype was in excess in the cases compared to controls (9.5 versus 7.5%; p < 0.04) even if the relative risk was lower, at 1.25, than in the 2 primary studies. When the cases were stratified into those with and those without evidence of a family history of schizophrenia, the relative risk was higher in the cases with a positive family history, at 1.63. As seen for the Icelandic and Scottish population, none of these 3 markers showed individual association.

More recently, NRG1 was investigated in an Irish case-control sample using 17 microsatellite markers and 3 SNPs (see figure 1), which failed to find association with HAP_ICE and schizophrenia.¹¹ Instead, a refined 2-marker haplotype in intron 1 of the gene, termed HAP_Bire, was identified, which was present in 19.4% of cases and 12.3% of controls. This consists of markers 420M9-1395 and D8S1810 at the centromeric end of HAP_ICE. A related haplotype, HAP_D, which has marker 420M9-116I12 in addition, was also associated with schizophrenia. Both of these haplotypes are close to an expressed sequence of unknown function (AF176921 [GenBank] .1, Unigene HS551128, MSTP131 or MST131). This gene is predominantly expressed in the small intestine and bone but is also present in the brain and peripheral nervous system at significant levels. The same investigators also genotyped the same Scottish sample investigated in the first replication.¹⁷ Reassuringly, they found the Hap_Bire haplotype also present in excess in the Scottish cases (17 versus 13.5%).¹¹

View larger version (41K): [in this window] [in a new window]   Fig. 1. Haplotypes of the Neuregulin 1 Gene and Schizophrenia. Studies included are 8, 10–17, 18–22 (study 13 is not included in figure). The HAPICE risk haplotype was analyzed in all studies except Yang et al.21 and was negative unless specifically indicated. Block 1 and block 2 indicate haplotype blocks in the gene,19 with low linkage disequilibrium between 478B14-848 and the single nucleotide polymorphisms at the 5' end of HAPICE. *U.S. sample analyzed by the same investigators showed no evidence for association. #Most significant associated haplotype also included 2 single nucleotide polymorphisms not previously investigated, rs2439272 and rs6988339. More strongly associated with "deficit" schizophrenia; most significant associated haplotype also included microsatellite 478B14-642. +HAPICE markers analyzed in 2 separate blocks.

 
Five SNPs from HAP_ICE were investigated in a case-control study from the Netherlands (figure 1).¹⁰ One HAP_ICE SNP (SNP8NRG221533) was significantly more frequent in patients with schizophrenia—but with the opposite allele to the original study. When the subjects were divided into "deficit" and "non-deficit" schizophrenia, the association was apparent with the latter category only.³⁰ A haplotype between SNP8NRG221533 and the microsatellite 417B14-848 was also significantly associated with non-deficit schizophrenia.

Subsequently, another study genotyped 5 markers (figure 1) in 233 Caucasian families of Dutch descent from South Africa and 210 Caucasian trios from the United States.¹² While in the American sample there was no association with schizophrenia for any markers or haplotypes, in the South African sample the authors found several haplotypes related to HAP_ICE, the most significant of which is a 3-marker haplotype (SNP8NRG243177–478B14848–420M91395), the same alleles of which were overtransmitted to schizophrenic cases.

Finally, NRG1 was investigated in a Portuguese population.¹⁶ The sample consisted of 111 trios and a cohort of 321 cases and 242 controls, testing 45 NRG1 SNPs and microsatellite markers (see figure 1) spanning the entire gene. Association was found with individual markers (including SNP8NRG11221132), and 3 haplotypes were identified that were nominally significant and underrepresented in patients, HAP2C (in the region of HAP_ICE), HAP7B, and HAP9A, both at the 3' end of the gene. HAP2C contains 2 SNPs from HAP_ICE (including SNP8NRG11221132, which uniquely marks the haplotype). While no association was seen with HAP_Bire or HAP_D,¹¹ this study observed a nonsignificant excess of HAP_ICE in a subsample of schizophrenic patients with a positive family history, and a summary analysis of HAP_ICE data from all Caucasian studies that examined it indicates a significant association with an odds ratio of about 1.5. In conclusion, in European populations, 1 haplotype seems to be present in excess in subjects with schizophrenia: the core at-risk haplotype HAP_ICE.

Analysis of Irish high-density schizophrenia families,¹⁹ however, was negative for all markers and haplotypes and was not included in the above summary analysis. The Irish high-density study used 7 markers: 3 markers (SNP8NRG221533, 478B14-848, 420M9-1395) tagging HAP_ICE; 2 other SNPs (SNP8NRG241930, SNP8NRG243177) that showed the highest single point association in the Scottish sample;¹⁷ and finally, the 2 microsatellites in intron 1 (D8S1810, 420M9-116I12) that form part of HAP_Bire in the independent Irish sample described above.¹¹ In contrast with the findings in the Icelandic, Scottish, and Irish samples, no evidence of overtransmission of any of these markers and haplotypes was observed. Furthermore, no new associated haplotypes were identified in this sample. The authors conclude that if NRG1 contains susceptibility alleles for schizophrenia, they impact weakly on risk in Irish high-density schizophrenia families.

	East Asian Replication Studies: China and Japan

Top Abstract Introduction Caucasian Replication Studies:... East Asian Replication Studies:... Conclusion References

 
The second major ethnic group to be analyzed for association between NRG1 and schizophrenia is the Chinese. Because of the geographic and population history divergence between these 2 groups, one would expect the haplotype structure of NRG1 to be different between the 2 populations. However, if the same association with HAP_ICE were found, this would be compelling evidence in favor of true association. The first study analyzed 248 Chinese Han trios but genotyped only 3 SNPs from NRG1, including 1 from HAP_ICE (SNP8NRG221533) and 2 others chosen at random from public databases (exon 2 rs3924999 and intron 5 rs2954041).²¹ The authors found a strong association between the haplotype of these SNPs and schizophrenia (p < .000001); however, while this study provides general evidence that the NRG1 gene is associated with schizophrenia in Chinese Han, it is incomplete, in that it cannot be directly compared with studies in Caucasians because the set of markers contains only 1 that overlaps with previous analyses.

In a separate Chinese Han sample from Shanghai, 13 microsatellite markers were grouped into 4 regions, in 540 patients with schizophrenia and 279 controls.¹⁸ None of these markers was present in HAP_ICE. The authors performed a haplotype analysis in each region and found an association between regions 2 and 3 and schizophrenia (figure 1). The first region contains a 4-marker haplotype from the 5' region of the gene (2H127320, D8S1711, 29H12-121L21, 478B14-642), and the second region contains a 5-marker haplotype (487-2, 478B14-848, 420M9-1395, 420M93663); both of these overlap with HAP_ICE but have no markers in common. Once again, while this study provides general evidence that the NRG1 gene is associated with schizophrenia in Chinese Han, it is incomplete, in that it cannot be directly compared with studies in Caucasians because the set of markers contains only 1 that overlaps with previous analyses.

A collaboration with the original Icelandic investigators examined a Chinese Han sample using both a family trios and a case-control design.¹⁵ A total of 25 microsatellite markers and 3 SNPs was genotyped, spanning across almost all (1.1 megabase) the NRG1 gene and including all markers in HAP_ICE. However, HAP_ICE did not show transmission distortion or association with schizophrenia; indeed, the risk alleles from HAP_ICE were more common in the controls than in the cases, indicating that these are not likely to be causative polymorphisms. Instead, researchers identified a novel haplotype (HAP_CHINA2) that overlaps with HAP_ICE, showing both transmission distortion and association in the cases (8.5 versus 4.0%; p = .0047). Two further haplotypes were significant, but each by 1 method only. HAP_CHINA1 (29H12-1 and D8S1711), upstream of HAP_ICE, was significant in the case-control comparison only, and HAP_CHINA3 (317J8-2123, 317J8-1, 317J8-2, 317J8-4858) at the 3' end of the gene was significant by family-based analysis only. HAP_CHINA2 is a 4-marker haplotype (478B14-642, 487-2, 420M9-1395, D8S1810) that conferred a relative risk of 2.2. This haplotype is similar in composition to the associated haplotypes of Tang et al.,¹⁸ with 3 out of 4 markers in common with their "region 3" associated haplotype. However, Li et al. did not genotype 2 markers (29H12-7320 and 420M9-3663) that are part of the "region 2" and "region 3" haplotypes, respectively,¹⁵ so again the data cannot be compared directly. However, these findings are important because they show that a common area (within the locus of NRG1) is implicated in both Han Chinese and European populations.

A further case-control and a family-based association study were performed using 1,724 Chinese Han individuals. Concordant with other studies in China, HAP_ICE was very rare and showed no evidence for association. However, a haplotype of the 3 informative SNPs (SNP8NRG221533, SNP8NRG241930, SNP8NRG243177) and the 2 microsatellites (478B14-848, 420M9-1395) from HAP_ICE were associated with schizophrenia and overtransmitted to offspring, albeit with different alleles to HAP_ICE. Because of evidence that there is a haplotype boundary between the SNPs and the microsatellites, the authors analyzed the SNPs and microsatellites separately, and only the 2 microsatellites showed significant association. These 2 markers form part of the "region 3" haplotype previously found to be significant,¹⁸ and 1 of them (420M9-1395) is present in HAP_CHINA2.

Finally, 1 amino acid change SNP (Arg38Gln, rs3924999) that is within the second exon of NRG1 was genotyped in a Taiwanese sample.¹³ The authors chose it because the second exon of NRG1 is present in all isoforms of NRG1. However, it was not associated with schizophrenia, although there was a trend for overtransmission of the opposite allele (Gln38), rather than the previously associated Arg38 allele.²¹

One negative case-control study was conducted in a sample of Japanese individuals.¹⁴ No association was found between any of the 7 markers forming HAP_ICE and schizophrenia. The results were likewise negative in both positive and negative family history cases. This is consistent with findings in the Chinese population, where HAP_ICE is not a risk factor. Other Chinese risk haplotypes were not examined.

	Conclusion

Top Abstract Introduction Caucasian Replication Studies:... East Asian Replication Studies:... Conclusion References

 
In summary, although in Caucasian populations attempts at replication of the association between NRG1 and schizophrenia have been mixed, and no individual functional or causative genetic variants have yet been identified, a summary of HAP_ICE association results in about 4,500 subjects is consistent with a small (odds ratio 1.5) but significant effect of this haplotype on schizophrenia risk. In Chinese Han populations, where HAP_ICE is not found, there is good evidence from several studies of association with other markers in the same region. Overall, there is convincing, but not compelling, genetic evidence of a role for NRG1 in susceptibility to schizophrenia. Further work is required to reach consensus, especially ensuring that all studies have genotyped the same set of markers so that results can be compared and combined across studies more easily. Other genes from this region have also been implicated in schizophrenia, not by systematic mapping but, rather, by positional candidate gene analysis; these include MSTP131, frizzled-3, and the calcineurin A gamma subunit gene. Not only are these alternative explanations for the linkage seen between chromosome 8p and schizophrenia, but it is equally possible that there is more than 1 susceptibility gene at this locus. However, there have been few attempts at replicating these findings, and until a body of data develops, their role in the disease is uncertain.

	Footnotes

 
To whom correspondence should be addressed; tel: +39-045 8074441, fax: +39-045 585871, e-mail: stosato{at}mail.univr.it.

	Acknowledgments

 
We are grateful to Mirella Ruggeri, an associate professor of psychiatry in the Department of Medicine and Public Health, University of Verona, for supporting this work.

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Top Abstract Introduction Caucasian Replication Studies:... East Asian Replication Studies:... Conclusion References

 

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