Genomewide scan in families with schizophrenia from the founder population of Afrikaners reveals evidence for linkage and uniparental disomy on chromosome 1

Abstract

We report on our initial genetic linkage studies of schizophrenia in the genetically isolated population of the Afrikaners from South Africa. A 10-cM genomewide scan was performed on 143 small families, 34 of which were informative for linkage. Using both nonparametric and parametric linkage analyses, we obtained evidence for a small number of disease loci on chromosomes 1, 9, and 13. These results suggest that few genes of substantial effect exist for schizophrenia in the Afrikaner population, consistent with our previous genealogical tracing studies. The locus on chromosome 1 reached genomewide significance levels (nonparametric LOD score of 3.30 at marker D1S1612, corresponding to an empirical P value of.012) and represents a novel susceptibility locus for schizophrenia. In addition to providing evidence for linkage for chromosome 1, we also identified a proband with a uniparental disomy (UPD) of the entire chromosome 1. This is the first time a UPD has been described in a patient with schizophrenia, lending further support to involvement of chromosome 1 in schizophrenia susceptibility in the Afrikaners.

Figure 1

Informative pedigrees included in linkage analyses. Black coloring indicates affected individuals in LC I, and dark and light gray coloring indicate individuals in LCs II and III, respectively.

Figure 2

Single-point analysis results. Single-point Kong and Cox (1997) nonparametric LOD scores calculated using the S_ALL scoring statistic are shown. Results are summarized throughout the genome for three phenotypic LCs: LC I (circles), LC II (triangles), and LC III (squares).

Figure 3

Multipoint analysis results. Multipoint Kong and Cox (1997) nonparametric LOD scores calculated using the S_ALL scoring statistic are shown. Results are summarized throughout the genome for three phenotypic LCs: LC I (solid black line), LC II (dashed line), and LC III (solid gray line).

Figure 4

Comparison of original and fine-mapping results. Multipoint Kong and Cox (1997) nonparametric LOD scores calculated using the S_ALL scoring statistic are shown. Results are summarized for three regions exhibiting strongest evidence for linkage, on chromosomes 1, 9, and 13. The three phenotypic LCs are LC I (solid black lines), LC II (lines with long dashes), and LC III (lines with short dashes).

Figure 5

Isodisomic individual. A, Chromosome 1 genotypes for isodisomic individual and two parents. The isodisomic chromosome is shaded in black, and asterisks (*) indicate markers where mother and offspring genotypes are incompatible. B, Shortest connection between individuals in LC I and a single ancestor who emigrated to South Africa ∼12 generations before present (Karayiorgou et al. 2004). Most affected individuals in our sample are connected to this founder through multiple descent routes. Twelve small pedigrees suitable for linkage analysis and included in our sample are boxed in the diagram. The cluster includes additional informative families when LCs II and III are used. The isodisomic individual is indicated by an arrow (↑).