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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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.
Tabor HK, Risch NJ, Myers RM . Opinion: candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 2002; 3: 391–397.
Badner JA, Gershon ES . Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405–411.
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.
Harrison PJ, Owen MJ . Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–419.
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.
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.
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.
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.
Dempster AP, Laird NM, Rubin DB . Maximum likelihood from incomplete data via the EM algorithm. J R Stat Soc B 1977; 39: 1–38.
Excoffier L, Slatkin M . Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol 1995; 12: 921–927.
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.
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.
Clayton D, Jones H . Transmission/disequilibrium tests for extended marker haplotypes. Am J Hum Genet 1999; 65: 1161–1169.
Clayton D . A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.
Kwok PY . SNP genotyping with fluorescence polarization detection. Hum Mutat 2002; 19: 315–323.
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.
Lewontin RC . The interaction of selection and linkage. I. General considerations: heterotic models. Genetics 1964; 49: 46–49.
Hedrick PW . Gametic disequilibrium measures: proceed with caution. Genetics 1987; 117: 331–341.
Cardon LR, Abecasis GR . Using haplotype blocks to map human complex trait loci. Trends Genet 2003; 19: 135–140.
Conti, Witt JS . Hierarchical modelling of linkage disequilibrium: genetic structure and spatial relations. Am J Hum Genet 2003; 72: 351–363.
Acknowledgements
This work was partly funded by NSFC (China), NARSAD, the Psychiatry Research Trust and the Wellcome Trust.
Author information
Authors and Affiliations
Corresponding author
Additional information
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).
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001485
Keywords
This article is cited by
-
GABAergic Abnormalities Associated with Sensorimotor Cortico-striatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naïve Patients with Schizophrenia
Neuroscience Bulletin (2020)
-
Meta-analysis reveals associations between genetic variation in the 5′ and 3′ regions of Neuregulin-1 and schizophrenia
Translational Psychiatry (2017)
-
Schizophrenia-risk variant rs6994992 in the neuregulin-1 gene on brain developmental trajectories in typically developing children
Translational Psychiatry (2014)
-
No Association Between NRG1 and ErbB4 Genes and Psychopathological Symptoms of Schizophrenia
NeuroMolecular Medicine (2014)
-
Personalized medicine in psychiatry: problems and promises
BMC Medicine (2013)