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Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype

Abstract

To determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case–control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5′end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAPChina 1), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAPChina 2) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3′ end of the NRG1 gene, HAPChina 3, was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case–control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese.

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References

  1. Cardno AG, Gottesman II . Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet 2000; 97: 12–17.

    Article  CAS  PubMed  Google Scholar 

  2. Tabor HK, Risch NJ, Myers RM . Opinion: candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002; 3: 391–397.

    Article  CAS  PubMed  Google Scholar 

  3. Badner JA, Gershon ES . Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405–411.

    Article  CAS  PubMed  Google Scholar 

  4. Lewis CM, Levinson DF, Wise LH, Delisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Harrison PJ, Owen MJ . Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–419.

    Article  CAS  PubMed  Google Scholar 

  6. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E et al. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 2003; 72: 83–87.

    Article  CAS  PubMed  Google Scholar 

  8. Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S et al. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry 2003; 8: 485–487.

    Article  CAS  PubMed  Google Scholar 

  9. Yang JZ, Si TM, Ruan Y, Ling YS, Han YH, Wang XL et al. Association study of neuregulin 1 gene with schizophrenia. Mol Psychiatry 2003; 8: 706–709.

    Article  CAS  PubMed  Google Scholar 

  10. Dempster AP, Laird NM, Rubin DB . Maximum likelihood from incomplete data via the EM algorithm. J R Stat Soc B 1977; 39: 1–38.

    Google Scholar 

  11. Excoffier L, Slatkin M . Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.

    CAS  PubMed  Google Scholar 

  12. Hawley M, Kidd K . HAPLO: a program using the EM algorithm to estimate the frequencies of multi-site haplotypes. J Hered 1995; 86: 409–411.

    Article  CAS  PubMed  Google Scholar 

  13. Long JC, Williams RC, Urbanek M . An E-M algorithm and testing strategy for multiple-locus haplotypes. Am J Hum Genet 1995; 56: 799–810.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Clayton D, Jones H . Transmission/disequilibrium tests for extended marker haplotypes. Am J Hum Genet 1999; 65: 1161–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kwok PY . SNP genotyping with fluorescence polarization detection. Hum Mutat 2002; 19: 315–323.

    Article  CAS  PubMed  Google Scholar 

  17. Gretarsdottir S, Sveinbjornsdottir S, Jonsson HH, Jakobsson F, Einarsdottir E, Agnarsson U et al. Localization of a susceptibility gene for common forms of stroke to 5q12. Am J Hum Genet 2002; 70: 593–603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lewontin RC . The interaction of selection and linkage. I. General considerations: heterotic models. Genetics 1964; 49: 46–49.

    Google Scholar 

  19. Hedrick PW . Gametic disequilibrium measures: proceed with caution. Genetics 1987; 117: 331–341.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Cardon LR, Abecasis GR . Using haplotype blocks to map human complex trait loci. Trends Genet 2003; 19: 135–140.

    Article  CAS  PubMed  Google Scholar 

  21. Conti, Witt JS . Hierarchical modelling of linkage disequilibrium: genetic structure and spatial relations. Am J Hum Genet 2003; 72: 351–363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was partly funded by NSFC (China), NARSAD, the Psychiatry Research Trust and the Wellcome Trust.

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Correspondence to D A Collier.

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Electronic-database information

Accession Numbers and URLs for data in this article are as follows:

deCODE genetics http://www.decode.com/nrg1/markers for SNPs and microsatellite markers in the NRG1 locus sequence;

GenBank, http://www.ncbi.nlm.nih.gov/Genbank/ for NRG1 (AF491780);

Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for NRG1 (MIM 142445), SCZD (MIM 181500) and SCZD6 (MIM 603013));

Third Party Annotation, DDBJ/EMBL/GenBank databases for NRG1 (TPA: BK000383).

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Li, T., Stefansson, H., Gudfinnsson, E. et al. Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype. Mol Psychiatry 9, 698–704 (2004). https://doi.org/10.1038/sj.mp.4001485

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