A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity

In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24–22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non–parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.

[1]  C. A. Smith,et al.  Testing for heterogeneity of recombination fraction values in Human Genetics , 1963, Annals of human genetics.

[2]  Richard J. Haier,et al.  Schizophrenia: The epigenetic puzzle Cambridge University Press, Cambridge (1982). 258 pp. by Irving I. Gottesman and James Shields , 1982, Psychiatry Research.

[3]  D. O’Rourke,et al.  Refutation of the general single-locus model for the etiology of schizophrenia. , 1982, American journal of human genetics.

[4]  C. Bonaïti‐pellié,et al.  Effects of misspecifying genetic parameters in lod score analysis. , 1986, Biometrics.

[5]  L. DeLisi,et al.  Relationship of HLA to schizophrenia in 10 nuclear families , 1987, Psychiatry Research.

[6]  M. Daly,et al.  A genetic linkage map of the human genome , 1987, Cell.

[7]  N. Risch,et al.  Genetic linkage between X-chromosome markers and bipolar affective illness , 1987, Nature.

[8]  Hugh Gurling,et al.  Localization of a susceptibility locus for schizophrenia on chromosome 5 , 1988, Nature.

[9]  K. Lange,et al.  Programs for pedigree analysis: Mendel, Fisher, and dGene , 1988, Genetic epidemiology.

[10]  L. Goldin,et al.  The detection of linkage and heterogeneity in nuclear families for complex disorders: one versus two marker loci. , 1989, American journal of human genetics.

[11]  Sandkuyl La Analysis of affected sib pairs using information from extended families. , 1989 .

[12]  K. Kendler,et al.  The Structured Interview for Schizotypy (SIS): a preliminary report. , 1989, Schizophrenia bulletin.

[13]  M. Baron Genetic linkage in mental illness , 1990, Nature.

[14]  Jurg Ott,et al.  Measuring the inflation of the lod score due to its maximization over model parameter values in human linkage analysis , 1990, Genetic epidemiology.

[15]  N. Risch Linkage strategies for genetically complex traits. I. Multilocus models. , 1990, American journal of human genetics.

[16]  J. Ott Cutting a Gordian knot in the linkage analysis of complex human traits. , 1990, American journal of human genetics.

[17]  D. Rao,et al.  Assessing the effect of multiple linkage tests in complex diseases , 1990, Genetic epidemiology.

[18]  D. Rao,et al.  Power of the linkage test for a heterogeneous disorder due to two independent inherited causes: A simulation study , 1990, Genetic epidemiology.

[19]  N. Risch,et al.  Genetic linkage and complex diseases, with special reference to psychiatric disorders , 1990, Genetic epidemiology.

[20]  N. Risch,et al.  A note on multiple testing procedures in linkage analysis. , 1991, American journal of human genetics.

[21]  S E Hodge,et al.  Sensitivity of lod scores to changes in diagnostic status. , 1992, American journal of human genetics.

[22]  S. Faraone,et al.  Linkage studies of schizophrenia: A simulation study of statistical power , 1992, Genetic epidemiology.

[23]  V. Vieland,et al.  Adequacy of single‐locus approximations for linkage analyses of oligogenic traits , 1992, Genetic epidemiology.

[24]  M. Owen,et al.  Advances and retreats in the molecular genetics of major mental illness. , 1992, Annals of medicine.

[25]  M. First,et al.  The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. , 1992, Archives of general psychiatry.

[26]  N Risch,et al.  Model misspecification and multipoint linkage analysis. , 1992, Human heredity.

[27]  K. Kendler,et al.  A new test for linkage in the presence of locus heterogeneity. , 1992, American journal of human genetics.

[28]  S. Thomas,et al.  Identification and characterization of the tuberous sclerosis gene on chromosome 16 , 1993, Cell.

[29]  I. Gottesman,et al.  Genetically mediated vulnerability to schizophrenia. , 1993, The Psychiatric clinics of North America.

[30]  K. Kendler,et al.  The genetics of schizophrenia: a current, genetic-epidemiologic perspective. , 1993, Schizophrenia bulletin.

[31]  R. Murray,et al.  Schizophrenia: genetics and the maternal immune response to viral infection. , 1993, American journal of medical genetics.

[32]  D. Easton,et al.  Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. , 1993, American journal of human genetics.

[33]  K. Kendler,et al.  The Roscommon Family Study. I. Methods, diagnosis of probands, and risk of schizophrenia in relatives. , 1993, Archives of general psychiatry.

[34]  K. Kendler,et al.  The Roscommon Family Study. II. The risk of nonschizophrenic nonaffective psychoses in relatives. , 1993, Archives of general psychiatry.

[35]  M C Speer,et al.  A microsatellite genetic linkage map of human chromosome 18. , 1993, Genomics.

[36]  K. Kendler,et al.  The Roscommon Family Study. III. Schizophrenia-related personality disorders in relatives. , 1993, Archives of general psychiatry.

[37]  J. Todd,et al.  A genome-wide search for human type 1 diabetes susceptibility genes , 1994, Nature.

[38]  Reply to Faraway , 1994 .

[39]  K. Kendler,et al.  An epidemiologic, clinical, and family study of simple schizophrenia in County Roscommon, Ireland. , 1994, The American journal of psychiatry.

[40]  Faraway Jj Testing for linkage under heterogeneity: a test versus C test. , 1994 .

[41]  M. James,et al.  Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome llq , 1994, Nature.

[42]  H. Cann,et al.  Report of the Second International Workshop on Human Chromosome 6. , 1994, Genomics.

[43]  C. R. Cloninger,et al.  Turning point in the design of linkage studies of schizophrenia. , 1994, American journal of medical genetics.

[44]  J. Weissenbach,et al.  An international two–stage genome–wide search for schizophrenia susceptibility genes , 1995, Nature Genetics.

[45]  L. Siever,et al.  Schizophrenia susceptibility and chromosome 6p24–22 , 1995, Nature Genetics.

[46]  Melanie C. Green,et al.  Schizophrenia susceptibility and chromosome 6p24–22 , 1995, Nature Genetics.

[47]  K. Kendler,et al.  Examining the validity of DSM-III-R schizoaffective disorder and its putative subtypes in the Roscommon Family Study. , 1995, The American journal of psychiatry.

[48]  M. Carrington,et al.  Recombination rates across the HLA complex: use of microsatellites as a rapid screen for recombinant chromosomes. , 1995, Human molecular genetics.

[49]  J. Ott,et al.  Schizophrenia susceptibility and chromosome 6p24–22 , 1995, Nature Genetics.

[50]  K. Kendler,et al.  Gender and Schizophrenia Results of an Epidemiologically-based Family Study , 1995, British Journal of Psychiatry.

[51]  Margot Albus,et al.  Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib–pair linkage analysis , 1995, Nature Genetics.

[52]  J. Ziegle,et al.  Evidence for a susceptibility locus for schizophrenia on chromosome 6pter–p22 , 1995, Nature Genetics.

[53]  R. Straub,et al.  Irish study on high-density schizophrenia families: field methods and power to detect linkage. , 1996, American journal of medical genetics.

[54]  J. Witte,et al.  Genetic dissection of complex traits. , 1994, Nature genetics.