A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees.

We have completed a genome scan of a 12-generation, 3,400-member pedigree with schizophrenia. Samples from 210 individuals were collected from the pedigree. We performed an "affecteds-only" genome-scan analysis using 43 members of the pedigree. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. Two sets of white-European allele frequencies were used-one from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD score of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253-D6S264) that segregated, after 12 generations, with the majority of the affected individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the significance of the genome scan, we simulated the complete analysis under the assumption of no linkage. The results showed that a LOD score >2.2 should be considered as suggestive of linkage, whereas a LOD score >3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree.

[1]  W. Honer,et al.  Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. , 2000, Science.

[2]  J. Suvisaari,et al.  Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. , 2000, Human molecular genetics.

[3]  R. Fick,et al.  Subtle overlapping deletions in the terminal region of chromosome 6q24.2-q26: three cases studied using FISH. , 1999, American journal of medical genetics.

[4]  P. Sham,et al.  Model-Free Analysis and Permutation Tests for Allelic Associations , 1999, Human Heredity.

[5]  J. Suvisaari,et al.  A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci. , 1999, American journal of human genetics.

[6]  W. Honer,et al.  Linkage of familial schizophrenia to chromosome 13q32. , 1999, American journal of human genetics.

[7]  U. Pettersson,et al.  Linkage analysis of a large Swedish kindred provides further support for a susceptibility locus for schizophrenia on chromosome 6p23. , 1999, American journal of medical genetics.

[8]  N. Andreasen,et al.  Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q. , 1999, American journal of medical genetics.

[9]  J. Nurnberger,et al.  Chromosome 6 workshop report. , 1999, American journal of medical genetics.

[10]  C. Gillberg,et al.  Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. , 1999, Human molecular genetics.

[11]  C. Stefanis,et al.  Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21 , 1998, Nature Genetics.

[12]  R. Straub,et al.  A schizophrenia locus may be located in region 10p15-p11. , 1998, American journal of medical genetics.

[13]  T. Matise,et al.  NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees. , 1998, American journal of medical genetics.

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

[15]  V. Vieland,et al.  Chromosome 5 workshop. , 1998, Psychiatric genetics.

[16]  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.

[17]  G. Rouleau,et al.  Schizophrenia and chromosome 6p. , 1997, American journal of medical genetics.

[18]  R. Straub,et al.  Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families , 1997, Molecular Psychiatry.

[19]  P. Goodfellow,et al.  Empirical genomewide significance levels established by whole genome simulations , 1997, Genetic epidemiology.

[20]  N. Morton,et al.  A metric map of humans: 23,500 loci in 850 bands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[21]  L. Siever,et al.  Additional support for schizophrenia linkage on chromosomes 6 and 8: a multicenter study. Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8. , 1996, American journal of medical genetics.

[22]  A. Roter,et al.  An approach to high-throughput genotyping. , 1996, Genome research.

[23]  R. Murray,et al.  A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22). , 1996, American journal of medical genetics.

[24]  J. Endicott,et al.  Penetrance of schizophrenia‐related disorders in multiplex families after correction for ascertainment , 1996, Genetic epidemiology.

[25]  R. Straub,et al.  A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity , 1995, Nature Genetics.

[26]  J. Ott,et al.  Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes. , 1995, American journal of medical genetics.

[27]  D. Housman,et al.  Follow-up report of potential linkage for schizophrenia on chromosome 22q: Part 3. , 1995, American journal of medical genetics.

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

[29]  A A Schäffer,et al.  Faster sequential genetic linkage computations. , 1993, American journal of human genetics.

[30]  N. Freimer,et al.  Incorrect specification of marker allele frequencies: effects on linkage analysis. , 1993, American journal of human genetics.

[31]  S. Pulst,et al.  Linkage of familial Alzheimer disease to chromosome 14 in two large early-onset pedigrees: effects of marker allele frequencies on lod scores. , 1993, American journal of medical genetics.

[32]  J. Ott,et al.  Strategies for characterizing highly polymorphic markers in human gene mapping. , 1992, American journal of human genetics.

[33]  A. Farmer,et al.  A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. , 1991, Archives of general psychiatry.

[34]  M. Boehnke,et al.  Allele frequency estimation from data on relatives. , 1991, American journal of human genetics.

[35]  J. A. Fraser Roberts,et al.  Investigations of the heredity of psychoses and mental deficiency in two North Swedish parishes , 1937 .

[36]  Torsten Sjöougren Investigations Of The Heredity Of Psychoses And Mental Deficiency In Two North Swedish Parishes , 1935 .