Patrice Murphy

Genomewide Genetic Linkage Analysis Confirms the Presence of Susceptibility Loci for Schizophrenia, on Chromosomes 1q32.2, 5q33.2, and 8p21-22 and Provides Support for Linkage to Schizophrenia, on Chromosomes 11q23.3-24 and 20q12.1-11.23

We have performed genetic linkage analysis in 13 large multiply affected families, to test the hypothesis that there is extensive heterogeneity of linkage for genetic subtypes of schizophrenia. Our strategy consisted of selecting 13 kindreds containing multiple affected cases in three or more generations, an absence of bipolar affective disorder, and a single progenitor source of schizophrenia with unilineal transmission into the branch of the kindred sampled. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10-cM intervals across the whole genome. We observed LOD scores >3.0 at five distinct loci, either in the sample as a whole or within single families, strongly suggesting etiological heterogeneity. Heterogeneity LOD scores >3.0 in the sample as a whole were found at 1q33.2 (LOD score 3.2; P=.0003), 5q33.2 (LOD score 3.6; P=.0001), 8p22.1-22 (LOD score 3.6; P=.0001), and 11q21 (LOD score 3.1; P=.0004). LOD scores >3.0 within single pedigrees were found at 4q13-31 (LOD score 3.2; P=.0003) and at 11q23.3-24 (LOD score 3.2; P=.0003). A LOD score of 2.9 was also found at 20q12.1-11.23 within in a single family. The fact that other studies have also detected LOD scores >3.0 at 1q33.2, 5q33.2, 8p21-22 and 11q21 suggests that these regions do indeed harbor schizophrenia-susceptibility loci. We believe that the weight of evidence for linkage to the chromosome 1q22, 5q33.2, and 8p21-22 loci is now sufficient to justify intensive investigation of these regions by methods based on linkage disequilibrium. Such studies will soon allow the identification of mutations having a direct effect on susceptibility to schizophrenia.

Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q

Objective To localize genes conferring susceptibility to bipolar affective disorder. Methods Seven families were selected on the basis of containing multiple cases of bipolar affective disorder present in three or more generations, an absence of schizophrenia and unilineal transmission. DNA samples from these families were genotyped with 365 microsatellite markers spaced at approximately 10 cM intervals across the whole genome. All markers were subjected to initial two‐point and three‐point analyses using LOD score and model‐free analysis. All regions producing a result significant at P<0.01 were then subjected to four‐point LOD score analysis under the assumption of heterogeneity. Results A four‐point LOD score of 2.8 was obtained using a dominant model and including unipolar cases as affected in the region of D12S342. Four‐point LOD scores of 2 were obtained around D1S243, D1S251 and D3S1265. The positive results around D1S243 were accounted for by a LOD score of 3.1 occurring in a single pedigree. Conclusions Since there has been previous strong support for linkage to the region of 12q23‐q24 around D12S342, it now seems very probable that it does indeed contain a gene influencing susceptibility to bipolar affective disorder. Some evidence for linkage in the region of 1q near to D1S251 has been reported in one previous study. It therefore seems that this region of 1q and the region of 1p close to D1S243 may also harbour susceptibility genes.

Segregation and linkage analysis in five manic depression pedigrees excludes the 5HT1a receptor gene (HTR1A)

Five kindreds selected through probands attending an Icelandic hospital were recruited for linkage studies of manic depression. The rates of affection were equal for males and females and the age of onset appeared to be predominantly in early adult life, since prevalence did not rise appreciably with age. A complex segregation analysis was performed using the computer program pointer to obtain maximum likelihood estimates of the contributions to liability from multifactorial transmission and a single major locus. Likelihood ratios between models supported a role for a single major locus which was dominant and had moderately high penetrance with, in the case of unipolar illness, additional multifactorial transmission. The bestfitting parameters were used to devise a transmission model for linkage analysis. Three markers on chromosome 5 were studied, at D5S76, D5S6 and D5S39. Strongly negative lod scores were obtained which were less than ‐2 over a distance of 40 cM, which included the region to which the gene for the 5HT1a receptor has been mapped.

New DNA markers with increased informativeness show diminished support for a chromosome 5q11–13 schizophrenia susceptibility locus and exclude linkage in two new cohorts of British and Icelandic families

Genetic linkage of schizophrenia to markers at 5q11.2–13.3 had been reported previously in five Icelandic and two British families, but attempts at replication in independent samples have been unsuccessful. We report here an update on the diagnoses and results of linkage analyses using newer highly polymorphic microsatellite markers at or near the loci D5S76 and D5S39 in the original sample of pedigrees and in two new family samples from Iceland and from Britain. The new results show a reduction in evidence for linkage in the original sample and evidence against linkage in the two new family samples. Although it is possible that a rare locus is present, perhaps in the region 5p14.1–13.1 rather than 5q11.2–13.3, it appears most likely that the original positive lod scores represent an exaggeration of the ‘true’ lod scores due to random effects and that the small lod scores we now obtain could have arisen by chance.

The Marfan syndrome gene locus as a favoured locus for susceptibility to schizophrenia

Marfan syndrome (MS) is a rare autosomal dominant disorder of connective tissue with manifestations in the cardiovascular, ocular and skeletal systems. Genetic linkage analysis with random probes has mapped the MS locus to 15q21.1. There have been several reports of Marfan syndrome co-segregating with schizophrenia within families, which suggest that a common genetic factor may be shared between schizophrenia susceptibility and MS. This could be due to a cytogenetic abnormality affecting both genetic loci or due to co-segregation of two disease loci near each other on the same chromosome. We tested this hypothesis by using genetic linkage analysis with multiplex families. Using three genetic markers spanning the MS locus, we were unable to find evidence of linkage with schizophrenia across the Marfan syndrome locus on chromosome 15.