A Genomewide Screen for Schizophrenia Genes in an Isolated Finnish Subpopulation, Suggesting Multiple Susceptibility Loci

Abstract

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Here, we report the results from a three-stage genomewide screen performed in a study sample from an internal isolate of Finland. An effort was made to identify genes predisposing for schizophrenia that are potentially enriched in this isolate, which has an exceptionally high lifetime risk for this trait. Ancestors of the local families with schizophrenia were traced back to the foundation of the population in the 17th century. This genealogical information was used as the basis for the study strategy, which involved screening for alleles shared among affected individuals originating from common ancestors. We found four chromosomal regions with markers revealing pairwise LOD scores>1.0: 1q32.2-q41 (Z(max)=3.82, dominant affecteds-only model), 4q31 (Z(max)=2. 74, dominant 90%-penetrance model), 9q21 (Z(max)=1.95, dominant 90%-penetrance model), and Xp11.4-p11.3 (Z(max)=2.01, recessive 90%-penetrance model). This finding suggests that there are several putative loci predisposing to schizophrenia, even in this isolate.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

“…48 Schizophrenia susceptibility genes have been proposed on many chromosomes including 1q, 5q, 6p, 6q, 8p, 10p, 13q, 18p and 22q (reviewed in O'Donovan et al 11 ). PLXNA2 is located in the 1q32 region, a schizophrenia locus that was originally identified in a family-based linkage study 16 and has received support from several independent studies. [18][19][20] However, there have been several studies that did not confirm this locus.…”

“…PLXNA2 is located approximately 35 kb upstream of D1S2891, a marker for which Hovatta et al 16 have observed a maximum pairwise LOD score of 3.82 in a linkage study for schizophrenia. In a subsequent fine-mapping project, the same group identified a marker (D1S245) with an LOD score of 2.3 that lies within 1 Mb of the PLXNA2 gene.…”

“…We identified a gene on chromosome 1q32, plexin A2 (PLXNA2), as a candidate gene for schizophrenia. Several linkage studies previously reported schizophrenia susceptibility loci in the 1q22-42 region; [16][17][18][19][20] other studies, however, have been unable to reproduce these results. [21][22][23] The findings described here might be important for the elucidation of this controversial schizophrenia locus.…”

A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia

“…A study of Finnish twins used microsatellite markers that had previously been shown to form a schizophrenia linked allelic haplotype spanning 1q32.2-q41. 23 The most telomeric of these markers (ie those immediately proximal to TRAX/DISC) displayed the strongest linkage and association to quantitative measures of visuospatial working memory and visual attention. 24 Also, a family-based, genome-wide scan using a number of quantitative traits of cognitive functions observed some evidence of linkage (lod41.5) to verbal memory functions at the 1q41 locus 25 ( Figure 1).…”

MPZL1/PZR, a novel candidate predisposing schizophrenia in Han Chinese

“…1 There is substantial evidence supporting the genetic etiology of schizophrenia in a number of systematic linkage scans. To date, some schizophrenia susceptibility loci, one of which is 1q21-22, [2][3][4][5] close to the location of the MPZL1/PZR gene have been reported. MPZL1 (myelin protein zero like 1), a 43-kDa hyperphosphorylated transmembrane glycoprotein mapped to 1q23.3, was identified by Zhao and Zhao.…”