Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms

Abstract

A genomewide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1615 affected and 1602 unaffected genotyped individuals, and the analysis of all 807 families included 1900 affected and 1839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5861 single nucleotide polymorphisms (SNPs; Illumina version 4.0 linkage map). Suggestive evidence for linkage (European families) was observed on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genomewide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region. In this era of genomewide association and deep resequencing studies, consensus linkage regions deserve continued attention, given that linkage signals can be produced by many types of genomic variation, including any combination of multiple common or rare SNPs or copy number variants in a region.

Figure 1. Genomewide linkage results

Shown for 707 European ancestry families (top) and for all 807 families (bottom) are linkage results across the genome. The X-axis values are cumulative chromosomal locations in centiMorgans (deCODE map), with chromosome boundaries shown as vertical gridlines. The Y-axis values are Kong-Cox lod scores for nonparametric analyses, or heterogeneity lod (hlod) scores for parametric analyses. Black lines represent nonparametric lod scores, red lines represent hlod scores under a dominant model, and purple lines represent hlod scores under a recessive model (see text for details of the models). Dotted lines show the empirical thresholds for genomewide suggestive evidence for linkage (less than 1 peak of this magnitude expected by chance, in the absence of linkage) for nonparametric and parametric analyses. The parametric threshold takes into account that two such tests (dominant and recessive) were performed.