Kalsi, Gursharan; (2000) The molecular genetics of schizophrenia: A linkage study. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Objectives: The genetic basis of schizophrenia has been clearly demonstrated through numerous well-conducted family, twin and adoption studies. However, the complex nature of the disorder has rendered it difficult to elucidate the mode of transmission and has made it difficult to identify the genes responsible for the disorder. The aim of this thesis is to employ recently developed statistical and molecular techniques to search for susceptibility genes. Hypothesis This thesis tests the hypothesis that linkage analysis can be successful in identifying susceptibility loci for schizophrenia in a sample of families specifically chosen for their large to medium size. From the outset, it was hypothesised that schizophrenia was a heterogenous disorder which was likely to have specific genetic factors operating within specific families. Methods: Given the complex nature of schizophrenia, genetic analysis of the disorder should employ samples and statistical methods capable of estimating several important variables such as lack of homogeneity (admixture), penetrance and the recombination fraction and with sufficient statistical power to test both single and polygenic hypotheses as well. The pedigree dataset for this study consisted of 23 Icelandic and English multiplex families which had been selected on the basis of stringent selection criteria, large to moderate family size, apparent dominant and unilineal transmission and the power to resolve heterogeneity of linkage. The hypothesis of linkage was tested using Restriction Fragment Length Polymorphisms (RFLPs), variable number tandem repeat markers (VNTRs) and highly polymorphic short tandem repeat (microsatellite) markers. The study can divided into three stages. For the first part of my study, I investigated the pericentric region on chromosome 5 implicated by Sherrington et al (1988) as the susceptibility locus by using a larger dataset of pedigrees and testing with more informative markers. Secondly, 1 expanded my study to other regions of the human genome. For this I used polymorphisms at or near the loci encoding candidate genes and favoured loci such as regions at which cytogenetic abnormalities had been reported as well as loci suggested by genome scans conducted by other groups. The third stage was a contribution to a very large collaborative effort initiated by the European Science Foundation. Linkage analyses were performed using parametric (lod score) and model-free linkage methods under the assumption of heterogeneity of linkage. In some instances the non-parametric sib-pair method was also used. The hypothesis of linkage was tested using two affection models assuming dominant transmission. Additionally, a range of chromosomal localisation techniques were employed to map glutamate receptor genes thought to be implicated in the aetiology of schizophrenia. Results: Lod and sib-pair linkage analyses showed that the dopamine receptor genes, D2, D3 and D5, and susceptibility loci on chromosomes 3p24-p26, 6p22-25, 11q, 15q, 22q22, Xp11 were not involved in the genetic susceptibility for schizophrenia in these particular families. An analysis of the pseudoautosomal region on the X chromosome was prompted by reports of sex concordance ratios in affected sib pairs and published positive linkage results. This region also proved negative for linkage. The analysis produced positive results on the pericentric region of chromosome 5 where a maximum lod of 1.19 was obtained and a maximised lod of 2.17 was obtained on chromosome 8p22-21. The glutamate receptor studies successfully localised the gene GRIN2D for the first time and confirmed localisations of the genes encoding the GRIN2A and GRIN2C receptor subtypes. Conclusion: The results are consistent with the hypothesis that linkage analysis may be able to detect susceptibility loci in schizophrenia but that such analysis in our sample failed to reach an acceptable level of statistical significance. When research on other samples is taken into account the hypotheses of linkage at these two loci gains support but are only fully confirmed in relation to the 8p22-21 locus. It seems likely that the failure to identify susceptibility loci unequivocally is due to locus heterogeneity. In order to overcome this problem, the chromosome 6, 8 and 22 data were combined into world wide collaborative samples. The results of this combined study helped to resolve the issue of replication to a certain extent but only in the case of the 8p22-21 locus because the traditional criterion for a confirmed linkage was reached in a replication sample. Efforts to detect linkage disequilibrium with schizophrenia on chromosome 8p should enable the hypothesis of linkage to be confirmed and for the aetiological mutations to be identified.

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