In a previous study, a genome scan of a subset of schizophrenia families from Palau, Micronesia gave evidence suggestive of linkage to microsatellite markers at 2p13-14. In addition, in a large extended multiplex pedigree (K1583), an 11 cM 2p13-14 haplotype segregated with the illness in eight distantly related schizophrenics. The haplotype region includes a neutral amino acid transporter, ASCT1. We mutation-screened the coding region, flanking intronic sequence and 5'-untranslated region of this transporter in affected members of K1583, two Palauan controls and one Caucasian control. Most polymorphisms were found to be silent or common to all samples scanned. A G/A heterozygote within intron 3 was found in one schizophrenic member of K1583, but was not found in any of the other affected members of K1583. A G/A heterozygote within intron 6 was found in two of six schizophrenics tested in K1583, and in one control. As none of the sequence polymorphisms segregated with illness in the eight schizophrenics, it is unlikely that changes in the 5'-untranslated region, coding sequence or flanking intronic sequence of the ASCT gene predispose to schizophrenia in these families.

Eight Utah multigenerational families, each with three to six cases of schizophrenia, were phenotyped with two specific measures of inhibitory neurophysiological functioning, P50 auditory sensory gating (P50), and antisaccade ocular motor performance (AS). A genomewide linkage analysis was performed to screen for loci underlying a qualitative phenotype combining the P50 and AS measures. For this composite inhibitory phenotype, the strongest evidence for linkage was to the D22s315 marker on chromosome 22q (lod score = 3.55, theta = 0) under an autosomal dominant model. Simulation analyses indicate that this 3.55 lod score is unlikely to represent a false positive result. Lod scores were 2.0 or greater for markers flanking D22s315. A nonparametric linkage (NPL) analysis of the chromosome 22 data showed evidence for allele sharing over the broad region surrounding D22s315 with a maximum NPL score of 3.83 (p = .002) for all pedigrees combined.

Bennett, P.a; Coon, H.b; Lenox, R. H.c; Hoff, M.a; Rosenthal, J.a; Byerley, W.d Author Information

Jensen, J.a; Coon, H.a; Hoff, M.a; Rosenthal, J.a; Reimherr, F.a; Wender, P.a; Myles-Worsley, M.a; Freedman, R.b; Byerley, W.a Author Information

Eight multiplex Utah schizophrenia pedigrees were screened for linkage by applying a non-parametric linkage program, GENEHUNTER, using 30 chromosome 6 DNA markers. The overall maximum NPL score of the combined pedigrees was 1.50 (P = 0.079) at marker D6s281, located near the q terminus. The highest overall maximum NPL score for an individual pedigree was 2.81 (P = 0.043). In the chromosome 6p region, where numerous positive findings have been reported, we obtained no positive results.

A large multiplex schizophrenia pedigree ascertained from the Micronesian nation of Palau was genotyped with 406 microsatellite DNA markers evenly distributed throughout the genome. Assuming autosomal dominant inheritance, the highest genome-wide lod scores were found for DNA loci mapping to 2p13–14; the maximum lod score was 2.17 (theta = 0.05) at D2S441. A nonparametric APM analysis was also suggestive at D2S441 (APM score = 2.96, P = 0.011). Of the 14 affected cases in this extended family, eight share a large haplotype in this region spanning ∼11 cM. When 16 other families containing 65 schizophrenic cases were typed in a follow-up study of this region, the maximum lod score remained positive (maximum at D2S441 1.69, theta = 0.20). APM results also remained positive at D2S441 for all 17 families (APM score = 4.87, P = 0.0006). The linkage and haplotype sharing results provide suggestive evidence for a 2p locus predisposing to schizophrenia in a subset of families in the Palauan population.

Anticipation, a phenomenon in which the symptoms of an inherited disease become more severe and age of onset occurs earlier across generations, has become an issue of importance in schizophrenia. If anticipation is found in families manifesting the illness, a possible type of genetic mutation would be implicated for predisposition to schizophrenia, as anticipation is now known to result from expansion of unstable trinucleotide repeat sequences. Two recent studies have tested for evidence of this phenomenon in schizophrenia families and came to differing conclusions; it is possible that anticipation occurs only in a subset of families. Our sample shows significant decreases in age of onset and increases in severity across generations. To investigate possible ascertainment bias, we looked at early onset parents and found no consistent anticipation effects in this group. We did find some increase in anticipation for mother-child vs father-child pairs; this possible imprinting effect may indicate true anticipation, though the evidence is not strong in our small sample, and the most conservative interpretation of our results is that the differences are due to ascertainment bias.

Six pedigrees segregating manic-depressive illness (MDI) were analyzed for linkage to 21 highly polymorphic microsatellite DNA markers on chromosome 18. These markers span almost the entire length of the chromosome, and gaps between markers are less than 20 cM. In particular, we analyzed several markers localizing to the pericentromeric region of chromosome 18 which generated lod scores suggestive of linkage in an independent study. Lod score analysis was performed and results were examined by family. One region produced positive lod scores, though at 18q23 and not in the pericentromeric region. We additionally used two nonparametric methods because the true mode of transmission of MDI is unknown; results were again somewhat suggestive for markers in the region of 18q23 but not in the pericentromeric region.

In response to reported schizophrenia linkage findings on chromosomes 3, 6 and 8, fourteen research groups genotyped 14 microsatellite markers in an unbiased, collaborative (New) sample of 403–567 informative pedigrees per marker, and in the Original sample which produced each finding (the Johns Hopkins University sample of 46–52 informative pedigrees for chromosomes 3 and 8, and the Medical College of Virginia sample of 156–191 informative pedigrees for chromosome 6). Primary planned analyses (New sample) were two-point heterogeneity lod score (lod2) tests (dominant and recessive affected-only models), and multipoint affected sibling pair (ASP) analysis, with a narrow diagnostic model (DSM-IIIR schizophrenia and schizoaffective disorders). Regions with positive results were also analyzed in the Original and Combined samples. There was no evidence for linkage on chromosome 3. For chromosome 6, ASP maximum lod scores (MLS) were 2.19 (New sample, nominal p = .001) and 2.68 (Combined sample, p=.0004). For chromosome 8, maximum lod2 scores (tests of linkage with heterogeneity) were 2.22 (New sample, p=.0014) and 3.06 (Combined sample, p = .00018). Results are interpreted as inconclusive but suggestive of linkage in the latter two regions. We discuss possible reasons for failing to achieve a conclusive result in this large sample. Design issues and limitations of this type of collaborative study are discussed, and it is concluded that multicenter follow-up linkage studies of complex disorders can help to direct research efforts toward promising regions.

S: 1996 World Congress on Psychiatric Genetics: II. LINKAGE AND CANDIDATE LOCI FOR THE PSYCHOSES: EMPHASIS ON SCHIZOPHRENIA: PDF Only

Myles-Worsley, M.1; Coon, H.1; Polloi, A.2; Tiobech, J.2; Hoff, M.1; Rosenthal, J.1; Yaw, J.1; Byerley, W.1Author Information

Alterations in gamma-aminobutyric acid (GABA) neurotransmission have been indirectly implicated in the pathogenesis of schizophrenia. Using nine multiplex pedigrees, we tested for linkage between schizophrenia and simple sequence repeat polymorphisms for the GABAA receptor alpha 1, alpha 2, alpha 4, alpha 5, alpha 6, beta 1 and beta 3 subunit genes. Evidence of linkage was not found when assuming either autosomal dominant or autosomal recessive inheritance. The non-parametric sib pair test also did not reveal significant evidence of deviation from expected segregation ratios.

In a previous study [Coon et al., Am J Hum Genet 52:1234-1249, 1993], we found suggestive evidence of linkage between manic-depressive illness (MDI) in eight multiplex pedigrees and D5S62, a DNA marker mapping to the telomeric region of 5q. As the D1 dopamine receptor gene (DRD1) maps to this region and as alterations in dopaminergic neurotransmission have been indirectly implicated in the pathogenesis of MDI, we directly searched for mutations in the coding region of the DRD1 gene in 22 unrelated cases of bipolar I (BPI) disorder derived from multiplex families. Using single strand conformation polymorphism (SSCP) analysis, we did not observe any abnormal SSCP variants in the BPI cases that differed from controls.

Nine multiplex schizophrenia families were genotyped with 15 microsatellite markers mapping to the short and long arm of chromosome 18. Assuming either autosomal dominant or recessive inheritance evidence of linkage was not found. In addition, the non-parametric sib pair test did not reveal significant evidence of linkage.

Nine multiplex schizophrenia families were genotyped with seven highly polymorphic microsatellite loci used in the construction of an index map of chromosome 21. Assuming either autosomal dominant or recessive transmission, evidence of linkage was not found. In addition, the nonparametric sib-pair test did not yield significant evidence of linkage.

Six kindreds containing multiple cases of Manic-depressive illness (MDI) were genotyped with seven highly polymorphic microsatellite loci used in the construction of an index map for chromosome 21. The kindreds were also genotyped with a microsatellite polymorphism for PFKL, a chromosome 21 locus that has shown suggestive linkage to MDI in one pedigree [Straub et al., 1993: The American Society of Human Genetics]. Evidence of linkage was not found assuming either autosomal dominant or recessive inheritance. The nonparametric affected sib pair test did not yield significant evidence of linkage.