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.

Figure A1

Illustration of the counting of sib pairs. Because there is no optimal method for counting independent affected half sib pairs when there are full and half sibs in the same family, all possible half sib pairs (AHAPs) have been counted in these cases. Consider, for instance, the two families shown here. Pedigree A is counted as two statistically independent AFSPs and three AHAPs. Pedigree B is counted as two AFSPs and four AHAPs.

Figure 1

Results of the STRP genome scan for SZ. Z_lr scores for the entire sample are plotted on the Y-axis, and genomic position (cM on CIDR map) by chromosome (p-ter to q-ter) is plotted on the X-axis.

Figure 2

Results of the STRP genome scan for SZ on chromosome 8 and the subsequent SNP fine mapping. Positive Z_lr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 8 is plotted on the X-axis (0–80 cM). Similarly, positive Z_lr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA sample (green line), and AA sample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 8 is plotted on the X-axis (0–80 cM). The PPP3CC gene is located at 39 deCODE cM, and the NRG1 (GGF2 isoform) gene spans 53–54 deCODE cM. The common inversion on chromosome 8p spans ∼18–22 deCODE cM and is marked.

Figure 3

Results of the STRP genome scan for SZ on chromosome 11 and the subsequent SNP fine mapping. Positive Z_lr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 11 is plotted on the X-axis (30–120 cM). Similarly, positive Z_lr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA subsample (green line), and AA subsample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 11 is plotted on the X-axis (30–120 cM).

Figure 4

Results of the STRP genome scan for SZ on chromosome 4 and the subsequent SNP fine mapping. Positive Z_lr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 4 is plotted on the X-axis (0–60 cM). Similarly, positive Z_lr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA subsample (green line), and AA subsample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 4 is plotted on the X-axis (0– 60 cM).

Figure 5

Results of the STRP genome scan for SZ on chromosome 5 and the subsequent SNP fine mapping. Positive Z_lr scores for the STRP scan for the entire sample (yellow line), EA subsample (blue line), and AA subsample (red line) are plotted on the Y-axis, and genomic position (CIDR cM converted to deCODE cM from p-ter, to allow plotting of the fine-mapping data) on chromosome 5 is plotted on the X-axis (10–100 cM). Similarly, positive Z_lr scores for the scanning STRPs plus the fine-mapping SNPs for the entire sample (orange line), EA subsample (green line), and AA subsample (purple line) are plotted on the Y-axis, and genomic position (deCODE cM from p-ter) on chromosome 5 is plotted on the X-axis (10–100 cM).