title: 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.
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.
authors.affiliation: Department of Psychiatry and Genetics, Washington University, St. Louis, MO, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Suarez
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.forename: Alan R
authors.initials: AR
authors.lastname: Sanders
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: Carol H
authors.initials: CH
authors.lastname: Jin
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Nancy G
authors.initials: NG
authors.lastname: Buccola
authors.forename: Nancy
authors.initials: N
authors.lastname: Hale
authors.forename: Ann N
authors.initials: AN
authors.lastname: Weilbaecher
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nertney
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.forename: Susan
authors.initials: S
authors.lastname: Green
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Schaffer
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Dominique E
authors.initials: DE
authors.lastname: Hannah
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Mowry
authors.forename: Farooq
authors.initials: F
authors.lastname: Amin
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.forename: Donald W
authors.initials: DW
authors.lastname: Black
authors.forename: William F
authors.initials: WF
authors.lastname: Byerley
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Crowe
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
authors.forename: C Robert
authors.initials: CR
authors.lastname: Cloninger
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Levinson
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Gejman
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D020890:Neuregulin-1; D010375:Pedigree; D012559:Schizophrenia / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1