A Schizophrenia-Susceptibility Locus at 6q25, in One of the World's Largest Reported Pedigrees

Abstract

We have completed a genome scan of a 12-generation, 3,400-member pedigree with schizophrenia. Samples from 210 individuals were collected from the pedigree. We performed an "affecteds-only" genome-scan analysis using 43 members of the pedigree. The affected individuals included 29 patients with schizophrenia, 10 with schizoaffective disorders, and 4 with psychosis not otherwise specified. Two sets of white-European allele frequencies were used-one from a Swedish control population (46 unrelated individuals) and one from the pedigree (210 individuals). All analyses pointed to the same region: D6S264, located at 6q25.2, showed a maximum LOD score of 3.45 when allele frequencies in the Swedish control population were used, compared with a maximum LOD score of 2.59 when the pedigree's allele frequencies were used. We analyzed additional markers in the 6q25 region and found a maximum LOD score of 6.6 with marker D6S253, as well as a 6-cM haplotype (markers D6S253-D6S264) that segregated, after 12 generations, with the majority of the affected individuals. Multipoint analysis was performed with the markers in the 6q25 region, and a maximum LOD score of 7.7 was obtained. To evaluate the significance of the genome scan, we simulated the complete analysis under the assumption of no linkage. The results showed that a LOD score >2.2 should be considered as suggestive of linkage, whereas a LOD score >3.7 should be considered as significant. These results suggest that a common ancestral region was inherited by the affected individuals in this large pedigree.

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

“…In a sample of large Eastern Canadian SZ families, Brzustowicz et al 13 observed under parametric linkage analysis a lod score of 6.5 in chromosome 1q21-q22 under the assumption of heterogeneity. Lindholm et al 14 reported, in one very large SZ pedigree of Sweden, a lod score of 6.6 in 6q25.2 and described a 6 cM haplotype in this region segregating with the disorder. However, we 15 and others, [16][17][18][19][20][21][22] as well as a meta-analysis, 23 reported negative results in 1q21-q22, whereas two studies 24,25 provided confirmations.…”

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

“…The finding in 6q25 for SCZ is probably a product of the very significant score that was obtained in the study of one pedigree from Sweden. 30 The 6q23 finding in BPD cannot be attributed to a specific study as none reported significant findings in this exact location. It is noteworthy, however, that significant evidence for linkage in this location was found in Arab pedigrees from Israel 31,32 under a broad diagnostic model that included some patients with affective symptoms (mainly SA disorder, both types).…”

“…The first focus (from proximal to distal) of interest on chromosome 6q (F-1) is centered at 96 Mb with significant results for SCZ-related disorders demonstrated by two studies, 25,27 and supported from findings in SCZ, 24,26,28,30 and for both SCZ and BPD. 39 The second focus of findings (F-2) is at 105 Mb, mainly in BPD, with one significant study 42 and several supporting studies, 37,38,46 but also studies on SCZ, 24 autism 52 and multiple sclerosis.…”

“…PARK2, a gene that causes autosomal recessive juvenile parkinsonism, was identified at 162-163 Mb on 6q 56 where linkage to SCZ was found in a large Swedish pedigree. 30 Mutations in the gene AHI1 at 6q23 (136 Mb) were found to be causative in Joubert syndrome, a severe autosomal recessive neurological disorder characterized by motor abnormalities, cognitive difficulties and autistic symptoms. 57,58 …”

Génétique de la schizophrénie et de la maladie bipolaire

“…Dans un grand échantillon de l'est du Canada, le groupe de Anne Bassett [27] a observé, en analyse de liaison paramétrique, un lod score de 6,5 sur le chromosome 1q21-q22, lié à 75 % des familles de l'échantillon. E. Lindholm et al [28] viennent de rapporter un lod score de 6,6 avec des marqueurs situés sur le chromosome 6q25.2, avec un haplotype de 6 cM ségrégant avec la maladie dans des familles de Suède affectées par la SZ. Ces études suggèrent la possibilité d'effets de gènes majeurs pour chacune des psychoses, mais dans de petits sousensembles de familles, confirmant ainsi l'existence d'une hétérogénéité et d'une transmission complexe de la SZ et de la BP.…”