Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q.

Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3. 82) was obtained. The sibling recurrence risk (lambdas) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing.

[1]  T. Matise,et al.  Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium. , 1998, American journal of medical genetics.

[2]  J. Ott,et al.  Sometimes it's hot, sometimes it's not , 1998, Nature Genetics.

[3]  L. Siever,et al.  Genome scan of schizophrenia. , 1998, The American journal of psychiatry.

[4]  L Kruglyak,et al.  Genome scan of schizophrenia. , 1996, The American journal of psychiatry.

[5]  J. Nurnberger,et al.  Chromosome 6 workshop. , 1998, Psychiatric genetics.

[6]  P. Szatmari,et al.  Clinical and methodological factors related to reliability of the best-estimate diagnostic procedure. , 1997, The American journal of psychiatry.

[7]  D. Weeks,et al.  Comparison of nonparametric statistics for detection of linkage in nuclear families: single-marker evaluation. , 1997, American journal of human genetics.

[8]  N J Cox,et al.  Allele-sharing models: LOD scores and accurate linkage tests. , 1997, American journal of human genetics.

[9]  E. Gershon,et al.  Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees. , 1997, Genomics.

[10]  D. Hinds,et al.  A full genome search in multiple sclerosis , 1996, Nature Genetics.

[11]  L Kruglyak,et al.  Parametric and nonparametric linkage analysis: a unified multipoint approach. , 1996, American journal of human genetics.

[12]  David Curtis.  Genetic dissection of complex traits , 1996, Nature Genetics.

[13]  J. Witte,et al.  Genetic dissection of complex traits , 1996, Nature Genetics.

[14]  J. Nurnberger,et al.  Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies , 1996, Psychological Medicine.

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

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

[17]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[18]  A. Frances.  The Diagnostic Interview for Genetic Studies , 1994 .

[19]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[20]  S A Seuchter,et al.  Linkage analysis in nuclear families. 1: Optimality criteria for affected sib-pair tests. , 1994, Human heredity.

[21]  S A Seuchter,et al.  Linkage analysis in nuclear families. 2: Relationship between affected sib-pair tests and lod score analysis. , 1994, Human heredity.

[22]  E. Gershon,et al.  Linkage Analysis of Fifty-Seven Microsatellite Loci to Bipolar Disorder , 1993, Neuropsychopharmacology.

[23]  J. Rabe-Jabłońska,et al.  [Affective disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association -- diagnostic and statistical manual of mental disorders]. , 1993, Psychiatria polska.

[24]  Alan Bird,et al.  Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy , 1993, Nature Genetics.

[25]  N C Andreasen,et al.  The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. , 1992, Archives of general psychiatry.

[26]  N. Risch.  Linkage strategies for genetically complex traits. II. The power of affected relative pairs. , 1990, American journal of human genetics.

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

[28]  Yuri M. Svirezhev,et al.  Multi-Locus Models , 1990 .

[29]  L. DeLisi,et al.  A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder. , 1988, Archives of general psychiatry.

[30]  G. Lathrop,et al.  Easy calculations of lod scores and genetic risks on small computers. , 1984, American journal of human genetics.

[31]  J. Endicott,et al.  A diagnostic interview: the schedule for affective disorders and schizophrenia. , 1978, Archives of general psychiatry.