Support for a Chromosome 18p Locus Conferring Susceptibility to Functional Psychoses in Families with Schizophrenia, by Association and Linkage Analysis

Abstract

The action of antipsychotic drugs on dopamine receptors suggests that dopaminergic signal transmission may play a role in the development of schizophrenia. We tested eight candidate genes (coding for dopamine receptors, the dopamine transporter, and G-proteins) in 59 families from Germany and Israel, for association. A P value of .00055 (.0044 when corrected for the no. of markers tested) was obtained for the intronic CA-repeat marker G-olfalpha on chromosome 18p. The value decreased to .000088 (.0007) when nine sibs with recurrent unipolar depressive disorder were included. Linkage analysis using SSLP markers densely spaced around G-olfalpha yielded a maximum two-point LOD score of 3.1 for a marker 0.5 cM distal to G-olfalpha. Multipoint analysis under the assumption of heterogeneity supported this linkage-whether the affected pheotype was defined narrowly or broadly-as did nonparametric linkage (NPL). In 12 families with exclusively maternal transmission of the disease, the NPL value also supported linkage to this marker. In order to test for association/linkage disequilibrium in the presence of linkage, the sample was restricted to independent offspring. When this sample was combined with 65 additional simplex families (each of them comprising one schizophrenic offspring and his or her parents), the 124-bp allele of G-olfalpha was transmitted 47 times and was not transmitted 21 times (P=.009). These results suggest the existence, on chromosome 18p, of a potential susceptibility locus for functional psychoses.

Investigation of the G protein subunit Gαolf gene (GNAL) in attention deficit/hyperactivity disorder

“…Those findings are, however, not universal (Badner and Gershon, 2002;Van Broeckhoven and Verheyen, 1999), and their interpretation is further complicated by the putative presence of a parent-of-origin effect in this region (Petronis, 2000). Stronger evidence of linkage has been reported in this region for bipolar families with paternal transmission of the phenotype (Gershon et al, 1996;Nothen et al, 1999;Stine et al, 1995), and with maternal pedigrees for schizophrenia (Schwab et al, 1998). The investigation of GNAL as a candidate gene in this region for both bipolar disorder (Tsiouris et al, 1996;Turecki et al, 1996;Zill et al, 2003) and major depression (Zill et al, 2002) yielded negative results.…”

Alternative transcripts and evidence of imprinting of GNAL on 18p11.2

“…This region was subsequently confirmed in several BPAD linkage studies, 2,3 and provided the maximum LOD score in a study of chromosome 18 in 59 German and Israeli SZ pedigrees. 4 It is worth noting that the study by Schwab et al included 24 cases of affective disorders, including two with BPAD. Interestingly, a parent-oforigin effect was observed in all of these studies.…”

“…Interestingly, Schwab et al found a positive association of a microsatellite marker in intron 5 of the GNAL gene with SZ. 4 However, attempts to identify coding region variants of GNAL that associate with BPAD or SZ have failed. Given the preponderance of genetic evidence implicating this locus and the known biology of G olf , we revisited this gene to search for other potentially significant variants.…”

TGFB-induced factor (TGIF): a candidate gene for psychosis on chromosome 18p

“…10 One of the regions, 18p11.3, has been reported as a potential susceptibility locus for psychotic disorders in different populations, but a putative candidate gene or genes in this region has not been identified. [11][12][13] In this current study, we sought to confirm our previous finding of association of a specific allele of marker D18S63, on 18p11.3, with psychosis, using an independent population from the CVCR. We also performed fine mapping of the region to determine which genes were in strong linkage disequilibrium (LD) with the D18S63 marker.…”

“…The three sources of information (DIGS, FIGS and available records) were analyzed by bilingual psychiatrists to obtain a lifetime consensus diagnosis for each affected subject, using a process of best estimation described in previous studies of the CVCR. [10][11][12][13][14][15][16] A consensus diagnosis of lifetime history of psychosis was also arrived at, utilizing the methodology described in Escamilla et al 17 Assessors and best estimate teams were the same for Samples 1 and 2, and there was no change in protocol, as Sample 2 was technically the next group of families recruited after Sample 1.…”