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PMID: 16400611 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample.

American journal of human genetics ·Vol. 78 ·No. 2 ·2006-02-00 ·Pages 315-33

Suarez BK, Duan J, Sanders AR, Hinrichs AL, Jin CH, Hou C, Buccola NG, Hale N, Weilbaecher AN, Nertney DA, Olincy A, Green S, Schaffer AW, Smith CJ, Hannah DE, Rice JP, Cox NJ, Martinez M, Mowry BJ, Amin F, Silverman JM, Black DW, Byerley WF, Crowe RR, Freedman R, Cloninger CR, Levinson DF, Gejman PV

Abstract

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees--263 of European ancestry (EA) and 146 of African American ancestry (AA)--together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 all-possible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Z(lr)] threshold >/=2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >2.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families.

MeSH Terms
Adolescent Adult African Americans/genetics Chromosome Mapping Chromosomes, Human, Pair 11/genetics Chromosomes, Human, Pair 8/genetics Female Genetic Linkage Genetic Predisposition to Disease Genome, Human Humans Male Nerve Tissue Proteins/genetics Neuregulin-1 Pedigree Schizophrenia/genetics Whites/genetics
Chemicals
NRG1 protein, human Nerve Tissue Proteins Neuregulin-1
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Suarez Brian K
Department of Psychiatry and Genetics, Washington University, St. Louis, MO, USA.
Duan Jubao
Sanders Alan R
Hinrichs Anthony L
Jin Carol H
Hou Cuiping
Buccola Nancy G
Hale Nancy
Weilbaecher Ann N
Nertney Deborah A
Olincy Ann
Green Susan
Schaffer Arthur W
Smith Christopher J
Hannah Dominique E
Rice John P
Cox Nancy J
Martinez Maria
Mowry Bryan J
Amin Farooq
Silverman Jeremy M
Black Donald W
Byerley William F
Crowe Raymond R
Freedman Robert
Cloninger C Robert
Levinson Douglas F
Gejman Pablo V
References (72)
72 references, click to expand
  1. Complex low-copy repeats associated with a common polymorphic inversion at human chromosome 8p23.
    Genomics. 2003 Aug;82(2):238-44 PMID: 12837273
  2. A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set.
    Am J Hum Genet. 2003 Aug;73(2):271-84 PMID: 12844283
  3. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit.
    Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8993-8 PMID: 12851458
  4. The molecular genetics of schizophrenia: new findings promise new insights.
    Mol Psychiatry. 2004 Jan;9(1):14-27 PMID: 14581932
  5. Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.
    Am J Hum Genet. 2004 Jun;74(6):1154-67 PMID: 15108123
  6. Prevalence and correlates of self-reported psychotic symptoms in the British population.
    Br J Psychiatry. 2004 Oct;185:298-305 PMID: 15458989
  7. Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis.
    Am J Hum Genet. 2004 Dec;75(6):1106-12 PMID: 15492927
  8. A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder.
    Arch Gen Psychiatry. 1988 Apr;45(4):328-36 PMID: 3355320
  9. The Roscommon Family Study. I. Methods, diagnosis of probands, and risk of schizophrenia in relatives.
    Arch Gen Psychiatry. 1993 Jul;50(7):527-40 PMID: 8317947
  10. The Roscommon Family Study. II. The risk of nonschizophrenic nonaffective psychoses in relatives.
    Arch Gen Psychiatry. 1993 Aug;50(8):645-52 PMID: 8343035
  11. The Roscommon Family Study. III. Schizophrenia-related personality disorders in relatives.
    Arch Gen Psychiatry. 1993 Oct;50(10):781-8 PMID: 8215802
  12. Continuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family study.
    Arch Gen Psychiatry. 1993 Nov;50(11):871-83 PMID: 8215813
  13. Chromosome-based method for rapid computer simulation in human genetic linkage analysis.
    Genet Epidemiol. 1993;10(4):217-24 PMID: 8224802
  14. The Roscommon Family Study. IV. Affective illness, anxiety disorders, and alcoholism in relatives.
    Arch Gen Psychiatry. 1993 Dec;50(12):952-60 PMID: 8250681
  15. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative.
    Arch Gen Psychiatry. 1994 Nov;51(11):849-59; discussion 863-4 PMID: 7944874
  16. Schizophrenia and chromosomal deletions within 22q11.2.
    Am J Hum Genet. 1995 Jun;56(6):1502-3 PMID: 7762575
  17. Schizophrenia: a genome scan targets chromosomes 3p and 8p as potential sites of susceptibility genes.
    Am J Med Genet. 1995 Jun 19;60(3):252-60 PMID: 7573181
  18. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results.
    Nat Genet. 1995 Nov;11(3):241-7 PMID: 7581446
  19. An international two-stage genome-wide search for schizophrenia susceptibility genes.
    Nat Genet. 1995 Nov;11(3):321-4 PMID: 7581457
  20. Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree.
    Am J Med Genet. 1996 Apr 9;67(2):162-71 PMID: 8723043
  21. Population stratifications can cause false positive linkage results if founders are untyped.
    Ann Hum Genet. 1996 May;60(Pt 3):261-3 PMID: 8800443
  22. Additional support for schizophrenia linkage on chromosomes 6 and 8: a multicenter study. Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8.
    Am J Med Genet. 1996 Nov 22;67(6):580-94 PMID: 8950417
  23. Accurate inference of relationships in sib-pair linkage studies.
    Am J Hum Genet. 1997 Aug;61(2):423-9 PMID: 9311748
  24. Allele-sharing models: LOD scores and accurate linkage tests.
    Am J Hum Genet. 1997 Nov;61(5):1179-88 PMID: 9345087
  25. The unified biosocial model of personality in schizophrenia families and controls.
    Psychopathology. 1998;31(1):45-51 PMID: 9500686
  26. PedCheck: a program for identification of genotype incompatibilities in linkage analysis.
    Am J Hum Genet. 1998 Jul;63(1):259-66 PMID: 9634505
  27. Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium.
    Am J Med Genet. 1998 Jul 10;81(4):275-81 PMID: 9674971
  28. NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees.
    Am J Med Genet. 1998 Jul 10;81(4):282-9 PMID: 9674972
  29. Comprehensive human genetic maps: individual and sex-specific variation in recombination.
    Am J Hum Genet. 1998 Sep;63(3):861-9 PMID: 9718341
  30. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.
    Nat Genet. 1998 Sep;20(1):70-3 PMID: 9731535
  31. Estimation of pairwise relationships in the presence of genotyping errors.
    Am J Hum Genet. 1998 Nov;63(5):1563-4 PMID: 9792888
  32. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.
    Arch Gen Psychiatry. 1999 Feb;56(2):162-8 PMID: 10025441
  33. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia.
    Mol Psychiatry. 2004 Dec;9(12):1091-9 PMID: 15241432
  34. A common inversion under selection in Europeans.
    Nat Genet. 2005 Feb;37(2):129-37 PMID: 15654335
  35. Whole-genome patterns of common DNA variation in three human populations.
    Science. 2005 Feb 18;307(5712):1072-9 PMID: 15718463
  36. The genetics of schizophrenia and bipolar disorder: dissecting psychosis.
    J Med Genet. 2005 Mar;42(3):193-204 PMID: 15744031
  37. Suggestive linkage of schizophrenia to 5p13 in Costa Rica.
    Mol Psychiatry. 2005 Jul;10(7):651-6 PMID: 15700049
  38. Fine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family.
    Psychiatr Genet. 2005 Sep;15(3):205-10 PMID: 16094256
  39. Neuregulin 1 (NRG1 ) and schizophrenia: analysis of a US family sample and the evidence in the balance.
    Psychol Med. 2005 Nov;35(11):1599-610 PMID: 16219118
  40. Microsatellites versus single-nucleotide polymorphisms in linkage analysis for quantitative and qualitative measures.
    BMC Genet. 2005;6 Suppl 1:S122 PMID: 16451580
  41. The effect of linkage disequilibrium on linkage analysis of incomplete pedigrees.
    BMC Genet. 2005;6 Suppl 1:S6 PMID: 16451672
  42. Linkage disequilibrium and allele-frequency distributions for 114 single-nucleotide polymorphisms in five populations.
    Am J Hum Genet. 2000 Jan;66(1):216-34 PMID: 10631153
  43. Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22.
    Science. 2000 Apr 28;288(5466):678-82 PMID: 10784452
  44. Psychiatric disorders in foster home reared children of schizophrenic mothers.
    Br J Psychiatry. 1966 Aug;112(489):819-25 PMID: 5966555
  45. Hallucinations and delusions as points on continua function. Rating scale evidence.
    Arch Gen Psychiatry. 1969 Nov;21(5):581-6 PMID: 5823480
  46. Mental illness in the biological and adoptive families of adpoted schizophrenics.
    Am J Psychiatry. 1971 Sep;128(3):302-6 PMID: 5570994
  47. The adopted-away offspring of schizophrenics.
    Am J Psychiatry. 1971 Sep;128(3):307-11 PMID: 5570995
  48. Refutation of the general single-locus model for the etiology of schizophrenia.
    Am J Hum Genet. 1982 Jul;34(4):630-49 PMID: 7102677
  49. Best estimate of lifetime psychiatric diagnosis: a methodological study.
    Arch Gen Psychiatry. 1982 Aug;39(8):879-83 PMID: 7103676
  50. A chi-square test to distinguish allelic association from other causes of phenotypic association between two loci.
    Genet Epidemiol. 1985;2(1):79-84 PMID: 4054594
  51. Programs for Pedigree Analysis: MENDEL, FISHER, and dGENE.
    Genet Epidemiol. 1988;5(6):471-2 PMID: 3061869
  52. Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's Danish identical and fraternal discordant twins.
    Arch Gen Psychiatry. 1989 Oct;46(10):867-72 PMID: 2802925
  53. Allele frequency estimation from data on relatives.
    Am J Hum Genet. 1991 Jan;48(1):22-5 PMID: 1985459
  54. Are schizophrenia and affective disorder related? preliminary data from a family study.
    Am J Psychiatry. 1993 Feb;150(2):278-85 PMID: 8304989
  55. Inference of population structure using multilocus genotype data.
    Genetics. 2000 Jun;155(2):945-59 PMID: 10835412
  56. Strauss (1969) revisited: a psychosis continuum in the general population?
    Schizophr Res. 2000 Sep 29;45(1-2):11-20 PMID: 10978868
  57. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23.
    Am J Hum Genet. 2001 Mar;68(3):661-73 PMID: 11179014
  58. The sequence of the human genome.
    Science. 2001 Feb 16;291(5507):1304-51 PMID: 11181995
  59. Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements.
    Am J Hum Genet. 2001 Apr;68(4):874-83 PMID: 11231899
  60. A schizophrenia-susceptibility locus at 6q25, in one of the world's largest reported pedigrees.
    Am J Hum Genet. 2001 Jul;69(1):96-105 PMID: 11389481
  61. Schizophrenia spectrum disorders: an autosomal-wide scan in multiplex pedigrees.
    Schizophr Res. 2001 Dec 1;52(3):145-60 PMID: 11705708
  62. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q.
    Hum Mol Genet. 2001 Dec 15;10(26):3037-48 PMID: 11751686
  63. Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.
    Nat Genet. 2002 Jan;30(1):97-101 PMID: 11731797
  64. Clustering of pedigrees using marker allele frequencies: impact on linkage analysis.
    Genet Epidemiol. 2001;21 Suppl 1:S61-6 PMID: 11793748
  65. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia.
    Mol Psychiatry. 2002;7(4):405-11 PMID: 11986984
  66. A high-resolution recombination map of the human genome.
    Nat Genet. 2002 Jul;31(3):241-7 PMID: 12053178
  67. Genome-wide scan for linkage to schizophrenia in a Spanish-origin cohort from Costa Rica.
    Am J Med Genet. 2002 Jul 8;114(5):497-508 PMID: 12116183
  68. Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes.
    Mol Psychiatry. 2002;7(6):542-59 PMID: 12140777
  69. Neuregulin 1 and susceptibility to schizophrenia.
    Am J Hum Genet. 2002 Oct;71(4):877-92 PMID: 12145742
  70. The discovery of susceptibility genes for mental disorders.
    Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13365-7 PMID: 12374853
  71. The Lifetime Dimensions of Psychosis Scale (LDPS): description and interrater reliability.
    Schizophr Bull. 2002;28(4):683-95 PMID: 12795498
  72. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.
    Am J Hum Genet. 2003 Jul;73(1):34-48 PMID: 12802786
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/500272
Published
2006-02-00
Epub
2006-00-03
Pages
315-33
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1380238
Subset
IM
Grants
NIMH NIH HHS · R01 MH061675 · United States
NIMH NIH HHS · R01 MH60879 · United States
NIMH NIH HHS · R01 MH59566 · United States
NIMH NIH HHS · R01 MH59588 · United States
NIMH NIH HHS · R01 MH59586 · United States
NIMH NIH HHS · R01 MH59587 · United States
NIMH NIH HHS · R01 MH59565 · United States
NIMH NIH HHS · R01 MH060870 · United States
NIMH NIH HHS · R01 MH61675 · United States
NIMH NIH HHS · R01 MH059571 · United States
NIMH NIH HHS · R01 MH059565 · United States
NIMH NIH HHS · R01 MH59571 · United States
NIMH NIH HHS · R01 MH059587 · United States
NIMH NIH HHS · R01 MH059586 · United States
NIMH NIH HHS · R01 MH059566 · United States
NIMH NIH HHS · R01 MH059588 · United States
NIMH NIH HHS · R01 MH60870 · United States
NIMH NIH HHS · R01 MH060879 · United States
External Links
PubMed source DOI: 10.1086/500272 PMC Full Text View journal details
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